Summary

These lecture notes cover the mechanisms of microbial pathogenicity, including the role of microbes in cancer, inflammation, and necrosis. They discuss disease transmission, pathogenicity of various microorganisms (bacteria, viruses, fungi), and host defense mechanisms. The notes also explore the link between microbes and cancer.

Full Transcript

SBT 319 – MECHANISMS OF MICROBIAL PATHOGNICITY COURSE OUTLINE The pathogenic microorganisms (bacteria, mycoplasma, rickettsiae, chlamydia, viruses, and fungi). Disease transmission. pathogenicity of viral diseases, prions, bacteria mycoplasmas and fungi. Microbial disease aetiolog...

SBT 319 – MECHANISMS OF MICROBIAL PATHOGNICITY COURSE OUTLINE The pathogenic microorganisms (bacteria, mycoplasma, rickettsiae, chlamydia, viruses, and fungi). Disease transmission. pathogenicity of viral diseases, prions, bacteria mycoplasmas and fungi. Microbial disease aetiology. Interaction between microorganisms and animal or plant hosts. Host Defense mechanisms. Bacterial diseases of man, and plants. Pathogenicity of bacterial pathogens of plants and their control. Microbial pathogens A pathogen is anything that can produce disease. A pathogen may also be referred to as an infectious agent, or simply a germ. Infectious diseases are cause by pathogens, whichinclude bacteria, fungi, protozoa, worms, viruses, virus-like agents-virusoids/viroids, and even infectious proteins called prions. A pathogen is defined as an organism causing disease to its host, with the severity of the disease symptoms referred to as virulence. The signs and symptoms of infection may be caused directly by the pathogen or the host’s responses in action. Some hallmarks of bacterial infection, including the swelling and redness at the site of infection and the production of pus (mainly dead white blood cells), are the direct result of immune system cells attempting to destroy the invading microorganisms. Fever, too, is a defensive response, as the increase in body temperature can inhibit the growth of some microorganisms. In pathology, pathogenesis is the process by which a disease or disorder develops. It can include factors which contribute not only to the onset of the disease or disorder, but also to its progression and maintenance’ Types of pathogenesis include: microbial infection, inflammation, tissue breakdown, malignancy. MALIGNANCY - The term "malignancy" refers to the presence of cancerous cells that have the ability to spread to other sites in the body (metastasize) or to invade nearby (locally) and destroy tissues. Cancer cells often form their own ‘microenvironment’ around a tumor to support its growth, and any microbes residing in and around that tumor have the potential to directly and indirectly alter its microenvironment in ways that influence cancer cell development. For example, microbes, and the metabolic factors they produce - toxins, or indirectly following activation of the cell's immune response against the pathogen, can damage host cell DNA through various mechanisms and epigenetic changes. Furthermore, microbial proliferation and/or biofilm formation can significantly alter the local environment. And research indicates that cancer cells and microbes can even provide resources for one another through symbiotic association— sharing immune system protection and growth factors amongst several other factors. Microbes and cancer Twelve microbial species, including viruses, bacteria and even fungi have been classified as human carcinogens by the International Agency for Research on Cancer or the National Toxicology Program (IARCNTP). Viruses Viruses are the most common pathogens associated with cancers - including anal, cervical, hepatocellular (liver) etc. Reports suggest that about 1.5 million global cancer cases are caused by tumor viruses. Examples of viruses that are associated with tumor development include Epstein Barre Virus (HBV), Human Papillomavirus (HPV), Hepatitis B (HBV) and Hepatitis C (HCV). The mechanism of carcinogenesis differs depending on the type of virus. For instance, HBV can fuse with human genome and grow in the liver cells and increase carcinogenic activity in the liver by manipulating signal pathways causing liver cancer. Bacteria Several species of bacteria have been shown to reside inside tumor cells and may, therefore, influence the progression of cancer. For example, Fusobacterium nucleatum alters the gut microbiome and increases cancer gene expression associated with colorectal cancer. Increased activity of helicobacter pylori is directly associated with stomach cancer, the fith-most common cancer worldwide. It does so by producing cancer-causing proteins (oncoproteins) that change the cell properties of the stomach. Chlamydia trachomatis and other sexually transmitted bacteria are associated with ovarian cancer. Fungi Some fungi have also been associated with certain types of cancer. Long-term candida infections promote oral cancer through secretions of various metabolites. Even commensal fungi could induce carcinogenesis, in the presence of certain lifestyle changes. For example, upon excessive alcohol intake, oral Candida albicans can produce enzymes that are associated with cancer development. Parasites - Even certain eukaryotic and multicellular parasites are known human carcinogens. Examples of caricinogenic paarsites include liver flukes, blood flukes, Clonorchis sinensis and Toxoplasma gondii, which together can result in cancers such as liver, bladder, colorectal and brain cancer. Microbes in cancer treatment Though many microbial agents can increase cancer risk, the microbiome also presents immense, untapped potential when it comes to understanding, treating and possibly even preventing cancer. While certain microbes have been labeled procarcinogens (cancer causing agents), several other microbes and microbe-derived drugs have been found to be anticarcinogens (capable of treating and/or suppressing cancer progression). For example, commensal flora may be used to control cancer proliferation. Probiotics from bioactive food can aid in metabolism and immune system modulation – which in turn can even prevent cancer cell gowth and division. Taking this a step further, some studies have suggested that probiotic microbes and their metabolic products may be involved in chemoprevention of several types of cancer. INFLAMMATION Role of INFLAMMATION in pathogenesis - Inflammation is part of the body's defense mechanism. It is the process by which the immune system recognizes and removes harmful and foreign stimuli and begins the healing process. Inflammation can be either acute or chronic. The most common reasons for chronic inflammation include:  Autoimmune disorders, such as lupus, where your body attacks healthy tissue.  Exposure to toxins, like pollution or industrial chemicals.  Untreated acute inflammation, such as from an infection or injury. Inflammation Inflammation is the immune system's response to harmful stimuli, such as pathogens, damaged cells, toxic compounds, or irradiation, and acts by removing injurious stimuli and initiating the healing process. Inflammation is a defense mechanism that is vital to health. Usually, during acute inflammatory responses, cellular and molecular events and interactions efficiently minimize impending injury or infection. This mitigation process contributes to restoration of tissue functioning and resolution of the acute inflammation. However, uncontrolled acute inflammation may become chronic, contributing to a variety of chronic inflammatory diseases’ Various pathogenic factors, such as infection, tissue injury, or cardiac infarction, can induce inflammation by causing tissue damage. The etiologies of inflammation can be infectious or non- infectious. In response to tissue injury, the body initiates a chemical signaling cascade that stimulates responses aimed at healing affected tissues. These signals activate leukocyte chemotaxis from the general circulation to sites of damage. These activated leukocytes produce cytokines that induce inflammatory responses. Although inflammatory response processes depend on the precise nature of the initial stimulus and its location in the body, they all share a common mechanism, which can be summarized as follows: 1) cell surface pattern receptors recognize detrimental stimuli; 2) inflammatory pathways are activated; 3) inflammatory markers are released; and 4) inflammatory cells are recruited. Pattern recognition receptor activation Microbial structures known as pathogen- associated molecular patterns (PAMPs) can trigger the inflammatory response through activation of germline-encoded pattern- recognition receptors (PRRs) expressed in both immune and nonimmune cells. Some PRRs also recognize various endogenous signals activated during tissue or cell damage and are known as danger- associated molecular patterns (DAMPS). DAMPs are host biomolecules that can initiate and perpetuate a non- infectious inflammatory response. Disrupted cells can also recruit innate inflammatory cells in the absence of pathogens by releasing DAMPs. How normal microbes inhibit inflammation:- By- products of metabolic processes in bacteria, including some short-chain fatty acids, can play a role in inhibiting inflammatory processes. Some bacteria are good for inflammation - Short chain fatty acids (SCFA) has long been understood to be a beneficial metabolite produced by gut bacteria via colonic fermentation of indigestible fibres. In terms of probiotics, research indicated that Lactobacillus​spp, bifidobacteria​, and Akkermansia muciniphil ​helped produce the inflammation-reducing SCFA butyrate. Role of Necrosis in Pathogenesis Necrosis ('death') is a form of cell injury which results in the premature death of cells in living tissue by autolysis. Necrosis is caused by factors external to the cell or tissue, such as infection, or trauma which result in the unregulated digestion of cell components. In contrast, apoptosis is a naturally occurring programmed and targeted cause of cellular death. While apoptosis often provides beneficial effects to the organism, necrosis is almost always detrimental and can be fatal. Cellular death due to necrosis does not follow the apoptotic signal transduction pathway, but rather various receptors are activated and result in the loss of cell membrane integrity and an uncontrolled release of products of cell death into the extracellular space. This initiates in the surrounding tissue an inflammatory response, which attracts leucocytes and nearby phagocytes which eliminate the dead cells by phagocytosis. However, microbial damaging substances released by leukocytes create collateral damage to surrounding tissues. This excess collateral damage inhibits the healing process. Thus, untreated necrosis results in a build-up of decomposing dead tissue and cell debris at or near the site of the cell death. A classic example is gangrene. For this reason, it is often necessary to remove necrotic tissue surgically, a procedure known as debridement. There are two broad pathways in which necrosis may occur in an organism. The first of these two pathways initially involves oncosis, where swelling of the cells occurs. Affected cells then proceed to blebbing, and this is followed by pyknosis, in which nuclear shrinkage transpires. In the final step of this pathway cell nuclei are dissolved into the cytoplasm, which is referred to as karyolysis. The second pathway is a secondary form of necrosis that is shown to occur after apoptosis and budding. In these cellular changes of necrosis, the nucleus breaks into fragments (known as karyorrhexis. Histopathological changes - The nucleus changes in necrosis and characteristics of this change are determined by the manner in which its DNA breaks down:  Karyolysis” the chromatin of the nucleus fades due to the loss of the DNA by degradation.  Karyorrhexis: the shrunken nucleus fragments to complete dispersal. Pyknosis: the nucleus shrinks, and the chromatin condenses. Examples Of Bacterial/Fungal Pathogens that Cause Necrosis More often, many different types of bacteria are involved in a necrotizing infection including:  Enterococci.  Staphylococcus aureus.  Clostridium perfringens.  Anaerobic and gram negative bacteria such as E. coli. Clostridium perfringens - Gas gangrene - C. perfringens is associated with myonecrosis and gas gangrene (a highly lethal, necrotising infection of skeletal muscle and subcutaneous tissue. Clostridium bacteria release toxins that destroy blood cells, blood vessels and muscle tissue. This causes severe blisters, swelling and skin discoloration. The bacteria create gas that makes wounds smell bad when they open. The toxins also cause widespread inflammation. Necrotizing Fasciitis Necrotizing fasciitis, also known as flesh-eating disease, is a bacterial infection that affects the tissue under your skin called fascia. Necrotizing fasciitis is a serious bacterial infection that can spread rapidly, destroying muscle and fat tissue in the body ("Necrotizing" means causing the death of tissues). It can be caused by more than one type of bacteria including group A Streptococcus (group A strep), Klebsiella, Clostridium, E. coli, Staphylococcus aureus and Aeromonas hydrophila among others. Bacteria that cause necrotizing fasciitis are sometimes referred to as "flesh- eating bacteria." There are two types of necrotizing fasciitis: polymicrobial (also called Type I) and monomicrobial (also called Type II). Polymicrobial necrotizing fasciitis is an infection caused by more than one type of bacteria, usually mixed anaerobic and aerobic bacteria. Monomicrobial necrotizing fasciitis is usually caused by group A Streptococcus or Staphylococcus aureus. Most cases of necrotizing fasciitis occur sporadically and are not linked to similar infections in others. The most common way of developing necrotizing fasciitis is when bacteria enter the body through a break in the skin, like a cut, scrape, burn, insect bite, or puncture wound. Necrotizing fasciitis is most common among people that have other health problems or are immune- compromised, such as those with diabetes, cancer, or kidney disease. Treatment of Necrosis - There are many causes of necrosis, and as such treatment is based upon how the necrosis came about. Treatment of necrosis typically involves two distinct processes: Usually, the underlying cause of the necrosis must be treated before the dead tissue itself can be dealt with. Debridement, referring to the removal of dead tissue by surgical or non-surgical means, is the standard therapy for necrosis. Depending on the severity of the necrosis, this may range from removal of small patches of skin to complete amputation of affected limbs or organs. Chemical removal of necrotic tissue is another option in which enzymatic debriding agents, categorised as proteolytic, fibrinolytic or collagenases, are used to target the various components of dead tissue. In select cases, special maggot therapy using Lucilia sericata using larvae has been employed to remove necrotic tissue and infection. In plants, If calcium is deficient, pectin cannot be synthesized, and therefore the cell walls cannot be bonded and thus an impediment of the meristems. This will lead to necrosis of stem and root tips and leaf edges. For due to plant pathogens. Categories of diseases Not all diseases are caused by pathogens. There are four main types of disease: (i) infectious diseases; (ii) Deficiency diseases - include: Immune deficiency; Protein Energy Malnutrition; Scurvy, Rickets; Beri Beri, Hypocalcemia, Osteomalacia (softening of bones) – vitamin D deficiency, Vitamin K Deficiency, Pellagra – niacin deficiency etc. Disease types (iii) Hereditary diseases (including both genetic diseases and non-genetic hereditary diseases E.g. Chromosomal abnormalities; Single gene defects; Teratogenic problems); and (iv) Physiological diseases - A physiological disorder is a condition in which the organs in the body malfunction causes illness. Examples are Asthma, Glaucoma, and Diabetes. Teratogenic problems that cause disease: A teratogen is any agents or substances that may produce physical or functional defects in the human/animal embryo or fetus. Teratogens may cause a birth defect in the child. Or a teratogen may halt the pregnancy outright. Scientists in the twentieth century classified teratogens into four categories, physical, chemical, or infectious agents and maternal conditions. Teratogenic agents include infectious agents (brucella, rubella, cytomegalovirus, varicella, herpes simplex, toxoplasma, syphilis, etc.); physical agents (ionizing agents, or other agents that contribute to hyperthermia, or elevated body temperature); ochratoxins; maternal health factors (diabetes); environmental chemicals (organic mercury compounds, polychlorinated biphenyl or PCB). The Concept of disease Diseases caused by pathogens are called infectious diseases, although there are some non- communicable infectious diseases, such as parasitic diseases in which the parasite's life cycle does not include direct host-to-host transmission. Non –Infectious Disease Non –Infectious Disease (also called Non- communicable diseases) are those diseases that are not caused by a pathogen and cannot be shared from one person to another. Unlike infectious diseases, non-infectious diseases are not communicable or contagious, although some kinds can be passed down genetically to the children of a carrier. Noncommunicable diseases also lasts for a long period of time. Therefore are also known as a chronic disease. A combination of genetic, physiological, lifestyle, and environmental factors can cause these diseases. Some risk factors include: unhealthy diets; lack of physical activity; smoking and secondhand smoke; excessive use of alcohol Inherited Diseases aka Genetic disorders Genetic disorders are caused by errors in genetic information that produce diseases in the affected people. These errors may include: A change in the chromosome numbers, such as Down syndrome; A defect in a single gene caused by mutation, such as Cystic Fibrosis. Noncommunicable diseases Some of the main types of noncommunicable diseases include:arthritis; attention deficit disorder (ADHD); autism spectrum disorder (ASD); bipolar disorder; eczema; epilepsy, cancer; chronic respiratory disease like asthma; etc. cardiovascular disease, cancer, chronic respiratory disease like asthma; epilepsy; diabetes,, etc. The most common chronic respiratory diseases include: occupational lung diseases, such as black lung; asthma; cystic fibrosis, etc. Cystic fibrosis Cystic fibrosis is an incurable genetic disease that affects tens of thousands of people all over the globe and manifests itself in the accumulation of thick, sticky mucus in the lungs. Because their immune systems are compromised, CF patients also suffer from frequent bacterial (P. aeruginosa) and fungal infections -- which infiltrate the patient's sinuses first and then spread into the lower respiratory tract. Infectious disease A basic paradigm of human infection is that acute bacterial disease is caused by fast growing planktonic bacteria while chronic infections are caused by slow-growing, aggregated bacteria, a phenomenon known as a biofilm. Biofilms are often defined as ‘A coherent cluster of bacterial cells imbedded in a biopolymer matrix, which, compared with planktonic cells, shows increased tolerance to antimicrobials and resists the antimicrobial properties of the host defence’. Bacteria can readily transition between planktonic and biofilm lifestyles. Growth in either the planktonic or biofilm lifestyle has significant consequences for bacterial infection. One of the most striking differences between planktonic and biofilm bacteria is antibiotic tolerance, in which biofilm bacteria exhibit increased survival on exposure to multiple classes of antimicrobials. Acute infections are often attributed to the action of planktonic bacteria, since they are generally curable with antibiotics, whereas chronic infections are described as involving biofilms, as they are resistant to antibiotic therapies. THE GERM THEORY OF DISEASE Germ theory, in medicine, the theory that certain diseases are caused by the invasion of the body by microorganisms. Various germ theories, Early Germ Theories - sometimes known as “animacular” theories, had been proposed for hundreds of years before 1850. In the 19th century, the animacular theory was associated with an outdated past. The idea of tiny, invisible animals flying through the air and spreading disease. The ancient belief was that diseases were often held to be the result of infection by particles released by decomposing materials. These particles were also sometimes proposed to be a kind of seed, or spore; the word “germ” derives from the Latin verb “to sprout.” Microorganisms are said to have been first directly observed in the 1670s by Anton van Leeuwenhoek, an early pioneer in microbiology, considered "the Father of Microbiology". Leeuwenhoek is said to be the first to see and describe bacteria, yeast, the teeming life in a drop of water (such as algae), and the circulation of blood corpuscles in capillaries. The word "bacteria" didn't exist yet, so he called these microscopic living organisms "animalcules", meaning "little animals". Those "very little animalcules" he was able to isolate from different sources, such as rainwater, pond and well water, and the human mouth and intestine. The germ theory of disease is the currently accepted scientific theory for many diseases. It states that microorganisms known as pathogens or "germs" can lead to disease. "Germ" may refer to not just a bacterium but to any type of microorganism or even non- living pathogen that can cause disease, such as protists, fungi, viruses, prions, or viroids. Germ theory Lister, Koch, and Pasteur The French chemist and microbiologist Louis Pasteur, the English surgeon Joseph Lister, and the German physician Robert Koch are given much of the credit for development and acceptance of the theory. Joseph Lister Lister is known as the inventor of antiseptic surgical techniques, which helped to dramatically reduce the infection mortality rate. Lister revolutionized surgical practice by utilizing carbolic acid (phenol) to exclude atmospheric germs and thus prevent putrefaction in compound fractures of bones. Dr. Joseph Lawrence, the creator of LISTERINE® mouthwash, wanted to name his work after a scientist who paved the way. Lister, an English doctor and surgeon, became the first surgeon to perform an operation in a chamber sterilized with pulverized antiseptic. Louis Pasteur Louis Pasteur’s accomplishments from the 1860s through the 1880s include disproving spontaneous generation, showed that fermentation and putrefaction are caused by organisms in the air. Pasteur showed how heat could kill microbes (“pasteurization” was first used in the French wine industry), and developing the first laboratory vaccines, most famously for chicken cholera, anthrax, and rabies. By carrying out research on the science of fermentation, Pasteur discovered that the process was caused by a living organism, which he called ‘ferment’. By discovering that fermentation was caused by living organisms, Pasteur debunked the theory of spontaneous generation. Many other scientists at the time believed that such microorganisms appeared out of thin air – the so-called ‘spontaneous generation’ theory. theory of spontaneous generation The theory of spontaneous generation held that living creatures could arise from nonliving matter and that such processes were commonplace and regular. For instance, it was hypothesized that certain forms such as fleas could arise from inanimate matter such as dust, or that maggots could arise from dead flesh. During his experiments in the 1860s, French chemist Louis Pasteur developed modern germ theory. He proved that food spoiled because of contamination by invisible bacteria, not because of spontaneous generation. Pasteur stipulated that bacteria caused infection and disease. Louis Pasteur’s Swan Flask Experiments Essential to these tests was an unusual glass flask with a long, thin, bent tube attached to the neck – Pasteur called it a swan-necked flask. Using these flasks, he boiled liquids (therefore killing all of the microorganisms inside) and then left them to cool. The design of the flask allowed the boiled liquid to be in contact with the air, while preventing any dust or dirt from entering. Louis Pasteur’s Swan Flask Experiments Pasteur tested many different liquids in this way, including those which usually ferment very easily. He found that none of them fermented after being boiled. He concluded that the processes of fermentation and decay were caused by microorganisms present in the air, and that these microorganisms could be killed by heating. Pasteur showed how heat could kill microbes (“pasteurization” was first used in the French wine industry), and milk industry. He is also renowned for developing the first laboratory vaccines, most famously for chicken cholera, anthrax, and rabies. Pasteur – using the experimental techniques he had begun to develop in his earlier work, Pasteur went on to discover several species of bacteria. He also developed ways of making bacteria and viruses less dangerous so that they could be used for vaccination. ROBERT KOCH – his role in germ theory: About ten years after Pasteur’s famous fermentation experiments, the German microbiologist Robert Koch was working to establish a new method for matching specific microorganisms to the disease. Robert Koch first became known for his superior laboratory techniques in the 1870s, and is credited with proving that specific germs caused anthrax, cholera, and tuberculosis. The German doctor Robert Koch is considered the founder of modern bacteriology. His discoveries made a significant contribution to the development of the so called first ‘magic bullets’ - chemicals developed to attack specific bacteria - and Koch was awarded a Nobel Prize in 1905. Koch’s Postulates, which prove both that specific germs cause specific diseases and that disease germs transmit disease from one body to another, are fundamental to the germ theory. Koch continued to improve his methods and techniques. By solidifying liquids such as broth with gelatine, for instance, he created a solid medium for growing bacteria which was easier to handle than the liquids used by Pasteur. However, he soon realized that gelatin, was not the optimal medium for bacterial growth, as it did not remain solid at 37 °C, the ideal temperature for growth of most human pathogens. As suggested to him by Walther and Fanny Hesse, Koch began to utilize agar to grow and isolate pure cultures. Agar remains solid at 37 °C, is not degraded by most bacteria. Koch's assistant Julius Richard Petri developed the Petri dish, which made the observation of bacteria even easier. Koch and his team also developed ways of staining bacteria to improve the bacteria’s visibility under the microscope. Koch’s postulates Ultimately, Koch’s research led to the creation of Koch’s postulates, a series of four generalized principles linking specific microorganisms to specific diseases that remain today the "gold standard" in medical microbiology. These postulates,not only outlined a method for linking cause and effect of an infectious disease but also established the significance of laboratory culture of infectious agents. KOCH’S Four Postulates: They are listed as follows: (i) The organism must always be present, in every case of the disease, but absent from healthy individuals. This first postulate was made obsolete even in Koch’s own time as asymptomatic carriers of disease- causing microbes were discovered, prompting Koch to amend or abandon this postulate (ii) Postulate Two: The organism must be isolated from a host containing the disease and grown in pure culture. This is in general understood to mean that the microbe should be able to be grown in something a sterile growth medium. Many types disease carrying microbes, including types of bacteria and viruses, still cannot be grown like this. Postulates three and four also cannot be fulfilled as written if the pure culture of the disease is unavailable. iii) Postulate Three: “A previously healthy individual, after infection with the micro-organism from the pure culture, shows the same symptoms as the one from which the micro- organism originally originated.” While purposeful infection of humans with disease has been done historically, this is rare due to ethical concerns. In most cases, the individuals used to fulfil the third postulate tend to be animals. This makes it impossible to fulfil this postulate, and by extension, the fourth postulate, in diseases specific to humans iv) Postulate Four: “The microorganism can be transferred from the infected and diseased individuals back into a pure culture.” This is essentially a repeat of step two using a different source. Koch’s postulates, need to be demonstrated in order to establish that a microbe causes a disease. This can be done using physical techniques as originally proposed or using molecular techniques like gene sequencing etc. Koch’s postulates were presented in 1890, at a time when germ theory was still controversial and before the discovery of viruses, to which Koch’s postulates, as they were originally written, do not apply. Virus research has been transformed by genetic techniques developed decades after Koch’s death. Updated criteria for determining viruses that cause disease are sometimes still referred to as Koch’s postulates. These involve animals being infected with the suspect virus and viruses being grown in cells, which would not be considered a “pure culture”. MICROBIAL PATHOGENESIS Pathogen history One of the first pathogens observed by scientists was Vibrio cholerae, described in detail by Filippo Pacini in 1854. He described how it causes diarrhea as well as developed effective treatments against it. Most of these findings went unnoticed until Robert Koch rediscovered the organism in 1884 and linked it to the disease. During the long course of evolution, disease- causing pathogenic microbes have developed a variety of virulence mechanisms and virulence encoding factors or genes. The degree of pathogenesis caused by the microbe is determined by the virulence factors involved and other intrinsic mechanisms, such as the number of microbial entities that are administered in the host system, the route of administration, and a host’s specific defense mechanisms. The significant differences between a virulent pathogenic bacterium and its closest nonpathogenic relative may result from a very small number of genes. Genes that contribute to the ability of an organism to cause disease are called virulence genes. The proteins they encode are called virulence factors. Virulence genes Virulence genes are frequently clustered together, either in groups on the bacterial chromosome called pathogenicity islands or on extrachromosomal virulence plasmids. These genes may also be carried on mobile bacteriophages. A pathogen may arise when groups of virulence genes are transferred together into a previously avirulent bacterium. The acquisition of virulence factors that lead to the development of pathogenic forms is mainly acquired through horizontal gene transfer of virulent factors, including toxins, adhesins, and aggressins. Pathogenesis of Bacterial Diseases pathogen must maintain a reservoir – place to live before and after causing infection be transported to host be transported to host adhere to, colonize, and/or invade host multiply or complete life cycles on or in host and initially evade host defenses damage host leave host and return to reservoir or enter new host. Attachment and Colonization by the Bacterial Pathogen Adherence – mediated by special molecules or structures called adhesins colonization – establishment of a site of microbial establishment or microbial reproduction on or within host. Mechanisms of Adherence to Cell or Tissue Surfaces Nonspecific adherence involves nonspecific attractive forces which allow approach of the bacterium to the eukaryotic cell surface. Bateria can attach to host cells through: 1. hydrophobic interactions 2. surface electrostatic charges/attractions 3. Brownian movement 4. recruitment and trapping by biofilm polymers 5. gravitational forces The more hydrophobic cells adhere strongly to hydrophobic surfaces, while hydrophilic cells strongly adhere to hydrophilic surfaces. Both hydrophilic and hydrophilic cells occur in a microbial population, hence only part of them participate in the adhesion. Note: microrganisms can switch between hydrophobic and hydrophilic phenotypes in response to changes in environmental conditions (temp., nutrient composition. Etc.) & growth phases. Considering that medical implants such as catheters, mechanical heart valves or pace makers are constructed from hydrophobic materials (silicon, stainless steel etc.), hydrophobic microbes easily attach to them. One solution to this problem is using implants from anti-biofilm materials that can delay or completely avoid the adhesion of microbes. Natural macromolecules (e.g. gluten, fibrinogen etc.) can be more resistant to the bacterial or fungal colonization due to their lower hydrophobicity and can be used with success in tissue engineering. Biofilm formation Biofilm formation on tissues is another medical problem because of the strong resistance of these microbial structures to drugs/antibiotics. Adhesion is the first step to colonization of tissues and prevention of this process is a good strategy to preventing disease. Use of specific adherence mechanisms by pathogens Specific adherence mostly involves interaction between receptors of pathogen and host cells, to form permanent specific lock-and-key bonds between complementary molecules on each cell surface. Examples of specific adherence mechanism 1.MYCOBACTERIUM Bacterial cell surface adhesins play a major role in facilitating host colonization and subsequent establishment of infection. The surface of Mycobacterium tuberculosis, expresses numerous adhesins with varied chemical nature, including proteins, lipids, lipoproteins, and glycoproteins. Examples of specific adherence mechanism in plants: Crown Gall (A. tumefaciens) The bacterium transfers part of its DNA to the plant, and this DNA integrates into the plant’s genome, causing the production of tumours and associated changes in plant metabolism. Most of the genes involved in crown gall disease are not borne on the chromosome of A. tumefaciens but on a large plasmid, termed the Ti (tumour-inducing) plasmid. In the same way, most of the genes that enable Rhizobium strains to produce nitrogen-fixing nodules are contained on a large plasmid termed the Sym (symbiotic) plasmid. The Infection process of A. tumefasciens Agrobacterium tumefaciens is found commonly on and around root surfaces - the region termed the rhizosphere - where it seems to survive by using nutrients that leak from the root tissues. But it infects only through wound sites, either naturally occurring or caused by transplanting of seedlings and nursery stock. In natural conditions, the motile cells of A. tumefaciens are attracted to wound sites by chemotaxis - they recognize and respond to wound phenolic compounds. Thus, one of the functions of the Ti plasmid is to code for additional, specific chemotactic receptors that are inserted in the bacterial membrane and enable the bacterium to recognise wound sites. At higher concentrations phenolic compounds activate the virulence genes (Vir genes) on the Ti plasmid. These genes coordinate the infection process and, in particular: lead to the production of proteins (permeases) that are inserted in the bacterial cell membrane for uptake of compounds (opines) that will be produced by the tumours. cause the production of an endonuclease - a restriction enzyme - that excises part of the Ti plasmid termed the T-DNA (transferred DNA). The excised T-DNA is released by the bacterium and enters the plant cells, where it integrates into the plant chromosomes and dictates the functioning of those cells. The actual mechanism of transfer is still unclear, but it seems to require a conditioning process, perhaps mediated by the production of cytokinins by the bacterium. When integrated into the plant genome, the genes on the T-DNA code for: production of cytokinins production of indoleacetic acid synthesis and release of novel plant metabolites - the opines and agrocinopines. The plant hormones upset the normal balance of cell growth, leading to the production of galls and thus to a nutrient-rich environment for the bacteria. Invasion – Breaching of Anatomical Barriers Penetration of skin Can be active penetration of host’s mucous membranes or epithelium membranes or epithelium can be passive penetration – e.g., skin lesions, insect bites, wounds Penetration of mucous membranes –Most common route of entry –Two general mechanisms Directed uptake Exploitation of antigen sampling Penetration of mucous membranes – Directed uptake of cells Some pathogens induce non- phagocytic cells into endocytosis –Causes uptake of bacterial cells »Bacteria attaches to cell then triggers uptake Disruption of cytoskeleton due to endocytosis may cause changes in cell membrane –Termed ruffling Penetration of mucous membranes Microbes move to tissues through transcytosis – Most organisms are destroyed by macrophages – Some organisms have developed mechanisms to survive phagocytosis » Bacteria escape cells by inducing apoptosis Infections caused by viruses Tissue trophism – Most viruses have an affinity for specific tissues; that is, they display tissue specificity or trophism. Examples of viral tissue tropism: Poliovirus selectively infect and destroy certain nerve cells, depending on the presence/concentration of surface receptors; Enteroviruses can multiply in the intestine, partly because they resist inactivation by digestive enzymes, bile and acid. many viruses will only infect certain cells that carry the surface receptos; e.g. The CD4 transmembrane protein expressed by a subset of human T-lymphocytes is widely considered as the main receptor for HIV-1. CD4 interacts with the HIV-1 surface envelope glycoprotein, gp120 with high affinity. In addition to gp120 receptor, HIV also requires an interaction with specific coreceptors, CXCR4 or CCR5, to initiate infection. Other examples, Rabies virus uses the acetylcholine receptor present on neurons as a receptor; hepatis B virus binds to receptors found on liver cells. Rabies virus receptor Nicotinic acetylcholine receptor, the nAChR was the first rabies virus receptor identified and this receptor is felt to be important for the spread of the virus from the neuromuscular junction at peripheral sites in order to gain access to the CNS along peripheral nerves. MICROBIAL DISEASE AETIOLOGY The word "aetiology" is mainly used in medicine, where it is the science that deals with the causes or origin of disease, the factors which produce or predispose toward a certain disease or disorder. The sources of infection The sources of infection can be divided into two main groups. These are exogenous and endogenous sources. A source of infection is endogenous when the infectious agent comes from the patient’s own body, usually from his own normal flora. Endogenous sources of infections become important when the normal flora becomes disrupted. ENDOGENOUS INFECTIONS A source of infection is endogenous when the infectious agent comes from the patient’s own body, usually from his own normal flora. Disease can occur when microbes included in normal bacteria flora enter a sterile area of the body such as the brain or muscle or the bloodstream. Example of a disease which has both endogenous and exogenous source of infection: Mycobacterium tuberculosis are components of the normal flora of humans, found most often in dry and oily locales. Most cases of post-primary tuberculosis (TB), which occur years after a primary infection, are caused by endogenous reactivation of latent infection, also known as Secondary or Reactivated Tuberculosis. Exogenous reinfection with a new TB strain may be responsible for some cases of post-primary TB. Transmission of Infection by Gastrointestinal Endoscopy and Bronchoscopy Contaminated endoscopes are the medical devices frequently associated with outbreaks of health care-associated infections. Most contemporary flexible endoscopes cannot be heat sterilized and are designed with multiple channels, which are difficult to clean and disinfect. The ability of bacteria to form biofilms on the inner channel surfaces can contribute to failure of the decontamination process. Endoscopy-related infections can be divided into two types: endogenous and exogenous. Endoscopic procedures most often result in endogenous infections (i.e., infections resulting from the patient's own microbial flora), and Escherichia coli, Klebsiella spp., Enterobacter spp., and enterococci are the species most frequently isolated. Examples of endogenous infections include pneumonia resulting from aspiration of oral secretions in a sedated patient during flexible bronchoscopy and bacteremia in patients with biliary obstruction. The exogenous microorganisms most frequently associated with transmission are Pseudomonas aeruginosa and Salmonella spp. during flexible gastrointestinal (GI) endoscopy and P. aeruginosa and mycobacteria during bronchoscopy. These microorganisms can be transmitted from previous patients or contaminated reprocessing equipment by contaminated endoscopes or its accessory equipment. Exogenous infection should be prevented by strict endoscope disinfection procedures. Infection of brain tissue by microbes The brain is well protected against microbial invasion by cellular barriers, such as the blood-brain barrier (BBB) and the blood- cerebrospinal fluid barrier (BCSFB). In addition, cells within the central nervous system (CNS) are capable of producing an immune response against invading pathogens. Bacteria, amoebae, fungi, and viruses are capable of CNS invasion, with the latter using axonal transport as a common route of infection. CNS infections are frequently caused by viruses, such as the enteroviruses, which cause the majority of cases of aseptic meningitis and meningoencephalitis. EXOGENOUS SOURCES OF INFECTION The exogenous sources of infection introduce organisms from any where outside to inside the body, which is the case most of the time. Exogenous sources of infections can be either be human, animal, or environmental in origin. Disease can be transmitted from animals to humans or from humans to non-human animals (the latter is sometimes called reverse zoonosis or anthroponosis). Exogenous sources of infection Food is another important and very common source of infection due to the everyday pattern of dealing with such material. Food is not only a vehicle when transmission is considered, but it is also a good environment where bacteria or any other pathogen can multiply and produce toxins. Water is a major source of infection only in case of being in contact with sewage. Examples of viruses are Poliomyelitis and Hepatitis A viruses. Faecal bacteria such as E. coli can produce water borne outbreaks in case of water contamination with sewage. Soil can be contaminated with human or animal feaces that contain several pathogenic organism which have sporing capabilities enabling them to survive in harsh environments such as Clostridium tetani which causes tetanus, Cl. botulinum which causes food poisoning and B. anthracis which causes anthrax in animals mainly. Examples of pathogenic fungi found in soil are Coccidioides immitis and Blastomyces. Air can be contaminated with organisms shed from skin or the respiratory tract such as S. pneumoniae which causes pneumonia and S. pyogens which causes Scarlet fever, Corynebacterium diphtheriae which causes diphtheria, Haemophilus Influenzae, meningococci, anthrax bacilli and Measles and Mumps viruses. Fomites are another source of infection which can be defined as any porous substance that can absorb and pass on contagion. Nosocomial infections- are infections that were not present or were incubating at the time of admittance to a health care facility. They include infections patients acquire during their stay in a healthcare facility or infections that may manifest after discharge. Patients who undergo surgical procedures have a higher incidence of nosocomial infections than others. Some well known nosocomial infections include: ventilator- associated pneumonia, Methicillin resistant Staphylococcus aureus, Candida albicans, Acinetobacter baumannii, Clostridium difficile, Tuberculosis, etc. ROLE OF ZOONOSIS IN MICROBIAL DISEASES A zoonosis or zoonose is any infectious disease that can be transmitted (in some instances, by a vector) from animals, both wild and domestic, to humans or from humans to non-human animals (the latter is sometimes called reverse zoonosis or anthroponosis). Zoonoses can be caused by a range of disease pathogens such as viruses, bacteria, fungi and parasites. Most human diseases originated in animals; however, only diseases that routinely involve animal to human transmission, like rabies, are considered direct zoonosis. Zoonoses Major modern diseases such as Ebola virus disease and salmonellosis are zoonoses. HIV was a zoonotic disease transmitted to humans in the early part of the 20th century, though it has now mutated to a separate human-only disease. Most strains of influenza that infect humans are human diseases, although many strains of swine and bird flu are zoonoses. Zoonoses Contact with farm animals can lead to disease in farmers or others that come into contact with infected farm animals. Glanders primarily affects those who work closely with horses and donkeys. Glanders, also called Farcy, is a very contagious disease caused by the bacterium Burkholderia mallei. Zoonoses Close contact with cattle can lead to cutaneous anthrax infection, whereas inhalation anthrax infection is more common for workers in slaughterhouses, tanneries and wool mills. Close contact with sheep who have recently given birth can lead to chlamydiosis, or enzootic abortion, in pregnant women. Other examples of zoonoses: 1. Eastern equine encephalitis (EEE) Eastern equine encephalitis (EEE), commonly called Triple E or, sleeping sickness (not to be confused with trypanosomiasis) is a zoonotic alphavirus and arbovirus present in North, Central, and South America and the Caribbean. Zoonosis - Alpha viruses Alphaviruses, such as chikungunya virus, and flaviviruses, such as dengue virus, are (re)-emerging arboviruses that are endemic in tropical environments. Alphavirus infections are spread by insect vectors such as mosquitoes. Once a human is bitten by the infected mosquito, the virus can gain entry into the bloodstream, causing viremia. The alphavirus can also get into the CNS where it is able to grow and multiply within the neurones. This can lead to encephalitis, which can be fatal. Note: - Viremia is a medical condition where viruses enter the bloodstream and hence have access to the rest of the body. It is similar to bacteremia, a condition where bacteria enter the bloodstream. This in contrast to Septicemia/sepsis which is a life- threatening condition that arises when the body's response to infection causes injury to its own tissues and organs. Sepsis develops when the chemicals the immune system releases into the bloodstream to fight an infection cause inflammation throughout the entire body instead. develops when the chemicals the immune system releases into the bloodstream to fight an infection cause inflammation throughout the entire body instead. Primary versus secondary viremia Primary viremia refers to the initial spread of virus in the blood from the first site of infection. Secondary viremia occurs when primary viremia has resulted in infection of additional tissues via bloodstream, in which the virus has replicated and once more entered the circulation. Active versus passive viremia Active viremia is caused by the replication of viruses which results in viruses being introduced into the bloodstream. Examples include the measles, in which primary viremia occurs in the epithelial lining of the respiratory tract before replicating and budding out of the cell basal layer (viral shedding), resulting in viruses budding into capillaries and blood vessels. Passive viremia is the introduction of viruses in the bloodstream without the need of active viral replication. Examples include direct inoculation from mosquitoes, through physical breaches or via blood transfusions. Anthroponotic disease An example is chytridiomycosis which can be spread by humans with the fungus on their skin handling frogs with bare hands. Other examples of anthroponotic diseases include: Leishmaniasis - Both zoonotic and anthroponotic. Other examples of anthroponotic diseases include: Influenza, Measles, pneumonia and various other pathogens - Many primates; and Tuberculosis - Both zoonotic and anthroponotic, with birds, cows, elephants, meerkats, mongooses, monkeys, and pigs known to have been affected. Mycoplasmas – Mycoplasmas – also known as mollicutes- is a genus of bacteria that lack a cell wall. Without a cell wall, they are unaffected by many common antibiotics such as penicillin or other beta- lactam antibiotics that target cell wall synthesis. They can be parasitic or saprophytic. Due to the absence of peptidoglycan layer in the cell wall of both Chlamydia and mycoplasmas, antimicrobial drugs that interfere with protein or nucleic acid synthesis (e.g., tetracyclines, macrolides, and quinolones) are recommended for the treatment. Mycoplasma – Mycoplasmas are widespread in nature as parasites of humans, mammals, reptiles, fish, arthropods, and plants. The list of hosts known to harbor mycoplasmas is continuously increasing, as is the number of established mollicute species, close to 180. The primary habitats of human and animal mycoplasmas are the mucous surfaces of the respiratory and urogenital tracts, the eyes, alimentary canal, mammary glands, and joints. The obligatory anaerobic anaeroplasmas have so far been found in the bovine and ovine rumen only. Spiroplasmas and phytoplasmas are widespread in the gut, hemocele, and salivary glands of arthropods. The spiroplasmas and phytoplasmas may be introduced via sap-sucking insects to the phloem tissues of plants, causing disease. Mycoplasma Cell morphology Since mycoplasma cells are bounded by a plastic cell membrane only, their dominating shape is a sphere. However, they exhibit a variety of morphological entities, including pear-shaped cells, flask- shaped cells with terminal tip structures, filaments of various lengths, and helical filaments. An important group of pathogenic mycoplasmas, including M. pneumoniae and M. genitalium, have a flask- or clublike cell shape with a protruding tip or bleb structure. These mycoplasmas attach to eucaryotic cells via the tip structure, serving as an attachment organelle. Classification – order Mycoplasmatales; 2 medically important genera – Mycoplasma – Ureoplasma – Three common clinical isolates – M. pneumoniae, M. hominis, and U. urealyticum Mycoplasmas cause a number of infections in both animals and plants. Human pathogens include: Mycoplasma pneumoniae. Causes upper&lower respiratory infections: tracheobronchytis & atypical pneumonia. Mycoplasmas usually exhibit organ and tissue specificity. Thus, M. pneumoniae is found preferentially in the respiratory tract and M. genitalium is found primarily in the urogenital tract. Extrapulmonary complications involving all of the major organ systems can occur in association with M. pneumoniae infection as a result of direct invasion and/or autoimmune response. Evidence for this organism's contributory role in chronic lung conditions such as asthma is accumulating. Mycoplasma M. genitalium, has been associated with pelvic inflammatory diseases. Genital tract infections - caused by M. hominis and U. ureolyticum which may also be found as part of the natural flora in the genital tract. May cause nongonococcal urethritis, infertility, stillbirth, spontaneous abortion, and acute urethral syndrome. M. bovis, is the causal agent of bovine mycoplasmosis. The clinical signs of bovine mycoplasmosis can be manifested as mastitis, pneumonia, arthritis, skin abscess, meningitis, otitis and reproductive tract infection. Cattle are the most vulnerable animal to M. bovis, all age groups (preweaning, postweaning, neonate and adult) and all cattle sectors such as beef, milk or rearing could be affected. M gallisepticum is commonly involved in the polymicrobial "chronic respiratory disease" in broiler chickens, leading to increased condemnations in the processing plant. In layers and breeders, it is usually subclinical, but causes a reduction in the number of eggs laid per hen over the production cycle. M gallisepticum is transmitted vertically within some eggs (transovarian) from infected breeders to progeny, and horizontally via infectious aerosols and through contamination of feed, water, and the environment, and by human activity on fomites (shoes, equipment, etc.) Pathogenicity factors of mycoplasmas The pathogenicity of mycoplasmas is caused by several factors, e. g. exotoxin, toxic properties of membrane components, exoenzymes, peroxide, and immunological factors. The absence of a rigid cell wall and the small genome tend to influence the interactions between mycoplasmas and host tissue. Mycoplasmas do not have a cell wall and are therefore resistant to the action of the host's lysozymes. They appear in some patients to be immunologically inconspicuous and in other patients they have been reported to have an immuno-suppressive effect. - Mycoplasmas are able to stimulate as well as suppress lymphocytes. Pathogenicity of Mycoplasma The P1 antigen is the primary virulence factor of mycoplasma. P1 is a membrane associated protein that allows adhesion to epithelial cells. The P1 receptor is also expressed on erythrocytes which can lead to autoantibody agglutination from mycoplasma infection. Mycoplasma - Links to cancer Several species of Mycoplasma are frequently detected in different types of cancer cells. These species are: M. fermentans M. genitalium M. hominis Urealyticum M. penetrans Links to cancer Several studies have shown that cells that are chronically infected with the bacteria go through a multistep transformation. The changes caused by chronic mycoplasmal infections occur gradually and are both morphological and genetic. The first visual sign of infection is when the cells gradually shift from their normal form to sickle-shaped. Types of cancer associated with Mycoplasma Colon cancer Gastric cancer Lung cancer Prostrate cancer Renal cancer Rickettsiae Rickettsia is a genus of nonmotile, gram negative, non- sporeforming, highly pleomorphic bacteria that can present as cocci, rods, or thread- like. They differ from true bacteria in that they are obligate intracellular parasites. Rickettsiae Being obligate intracellular parasites, the Rickettsia survival depends on entry, growth, and replication within the cytoplasm of eukaryotic host cells. Because of this, Rickettsia cannot live in artificial nutrient environments and is grown either in tissue or embryo cultures (typically, chicken embryos are used). Rickettsiae R. rickettsii is one of the most pathogenic rickettsia strains. R. rickettsi is the causative agent of rocky Mountain spotted fever. Howard rickets (1871–1910);an associate professor of pathology at the University of Chicago in 1902, was the first to identify and study R. rickettsii. Rickettsiae Rickettsia frequently exhibit a capsule. Despite the similar name, Rickettsia bacteria do not cause rickets, which is a result of vitamin D deficiency. Instead, they are named after Howard Taylor Ricketts. Pathogenic rickettsiae. The rickettsiae are transmitted from animal, animal to man, or man to man through the body of an intermediate arthropod host. The most common arthropod vectors are fleas, lice, ticks, and mites. Rickettsiae The rickettsiae are nonpathogenic to the arthropod vectors and, because of their minute size, are capable of being transferred from a parent arthropod to the offspring through a process known as transovarian transmission. Rickettsiae The genus Rickettsia belongs to the α- Proteobacteria and consists of two groups: the typhus group (TG) and the spotted fever group (SFG). E.g., R. prowazekii is the causative agent of louse-borne typhus, which has affected millions of people during periods of hunger, flood and wars. Rickettsia normally multiply directly in the host cell cytoplasm, but some species of the SFG Rickettsia are also capable of dividing in the cell nucleus. Rickettsiae Rickettsia species cause diseases in humans such as typhus, rickettsialpox, african tick bite fever, Rocky mountain spotted fever. Mammals become infectd thro’ bites of infectd arthropods. Rickettsiae ricketsii – Rocky mountian spotted fever, transmitted by infect ticks or dog ticks. Other pathogenic rickettsiae are: R. prowazeki – typhus fever; R. typhi – typhus fever. Baartonella (3 species)-- intracellular parasite which attacks the red blood cells. Pathogen life cycle ] The most common hosts for the R. rickettsii bacteria are ticks. Ticks that carry R. rickettsia fall into the family of Ixodidae ticks, also known as "hard bodied" ticks. Ticks are vectors, reservoirs and amplifiers of this disease. There are currently three known tick specifics that commonly carry R. rickettsii. American dog tick (Dermacentor variabilis) Rocky Mountain wood tick (Dermacentor andersoni) Brown dog tick (Rhipicephalus sanguine). Pathogen life cycle Ticks can contract R. rickettsii by many means. First, an uninfected tick can become infected when feeding on the blood of an infected vertebrate host; such as a rabbit, during the larval or nymph stages, this mode of transmission called transstadial transmission. Once a tick becomes infected with this pathogen, they are infected for life. In addition, an infected male tick can transmit the organism to an uninfected female during mating. Once infected, the female tick can transmit the infection to her offspring, in a process known as transovarian passage. Rickettsiae Transmission in mammals Transmission to mammals can occur in multiple ways. One way of contraction is through the contact of infected host feces to an uninfected host. If infected host feces comes into contact with an open skin wound, it is possible for the disease to be transmitted. Additionally, an uninfected host can become infected with R. rickettsii when eating food that contains the feces of the infected vector. Rickettsiae Another way of contraction is by the bite of an infected tick. After getting bitten by an infected tick, R. rickettsiae is transmitted to the bloodstream by tick salivary secretions. R. rickettsii has also been found to distort the sex ratio of their hosts. This is done by eradicating males and undergoing pathogenesis, this is done primarily via horizontal gene transfer. By eradicating male hosts, female host can pass the R. rickettsii gene to her offspring giving R. rickettsii bacteria yet another way to infect hosts. Rickettssiae - virulence R. rickettsii invades the endothelial cells that line the blood vessels in the hosts body. Endothelial cells are not phagocytic in nature; however, after attachment to the cell surface, the pathogen causes changes in the host cell cytoskeleton that induces phagocytosis. Since the bacteria can now induce phagocytosis the R. rickettsii gene can be replicated and further invade other cells in the hosts body. They are able to avoid lysosomal fusion and oxidative burst by escaping from the phagosome into the cytoplasm where they multiply and spread. CHLAMYDIAS Are coccoid bacteria that lack peptidoglycan in cellwalls. Chlamydia like Rickettsia are obligate intracellular parasites. Like Rickettsia, Chlamydia are small, pleomorphic coccobacillary forms. They require growing cells to remain viable. Chlamydia cannot synthesize its own ATP, and can also not be grown on an artificial medium. They are classified as a type of rickettsiae that do not require arthropods for transmissn to humans. Chlamydia Chlamydia infections are the most common bacterial sexually transmitted diseases in humans and are the leading cause of infectious blindness worldwide. E.g. Chlamydia trachomatis is the most common causative agent of bacterial sexually transmitted disease, being responsible for an estimated 90 million new cases per year worldwide, and is also a leading cause of blindness (trachoma). Chlamydia Chlamydia pneumoniae - is one of the main causative agents of pneumonia, and bronchitis. C. psittaci infects birds but can be transmitted to humans, causing a rare but severe pneumonia. Chlamydia – life cycle All Chlamydia species share a unique developmental cycle during which bacterial multiplication occurs only within a vacuole, called an inclusion, within a host cell. The infectious form of the developmental cycle, called the elementary body (EB), is small, circular and essentially metabolically inactive. After entering epithelial host cells, EBs differentiate within a few hours into a replicating (metabolically active), non- infectious reticulate body. Chlamydia The infectious form – the elementary body (EB) is circular in form is taken into the cell by induced phagocytosis. The elementary body is the dispersal form of the pathogen, and is analogous to the spore. Chlamydia displays a biphasic developmental cycle. The elementary body (EB) form of the bacteria attaches and invades host-epithelial cells. The nascent phagocytic compartment is rapidly modified by Chlamydia-derived proteins to generate a parasitophorous vacuole termed an inclusion. Within the inclusion, the EB differentiates into a reticulate body (RB), the metabolically active and replicative form of the pathogen. RBs divide by binary fission as the inclusion expands and midway through the infectious cycle begin to asynchronously differentiate back into the EB form. chlamydia The reticulate bodies finally reorganize into a new generation of elementary bodies prior to infecting a new series of host cells, thereby completing the developmental cycle. Newly formed EBs are eventually released by cell lysis and/or extrusion to initiate new rounds of infection. The bacterium induces its own endocytosis upon contact with potential host cells - After attachment, chlamydiae are internalized into the cell by an unknown mechanism resembling endocytosis. EBs continue to survive and replicate so long as they are able to synthesize proteins to actively modify the inclusion membrane. Chlamydia The most dangerous thing about chlamydia when transmitted sexually is that 75% of women and 50% of men are asymptomatic, and are completely unaware that they are infected. Chlamydia infection is a major cause of infertility, not only in women, but in men as well. Women are subject to pelvic inflammatory disease (PID), and ectopic pregnancy. Viroids, Virusoids, & Prions (virus-like agents) Viroids are autonomously replicating, small single-stranded circular RNA pathogens that do not code for proteins and may cause diseases in infected, in man and susceptible plants. Viroids In 1971, Theodor Diener, a pathologist working at the Agriculture Research Service, discovered an acellular particle that he named a viroid, meaning “virus- like.” The first viroid discovered was found to cause potato tuber spindle disease, which causes slower sprouting and various deformities in potato plants. Host Range and Host Specificity:- Viroids are the etiologic agents of a number of diseases affecting economically important herbaceous and ligneous plants including potato, tomato, cucumber, hop, coconut, grapevine, several subtropical and temperate fruit trees (avocado, peach, apple, pear, citrus, and plum). Viroids Tomato planta macho viroid (TPMVd) infects tomato plants, which causes loss of chlorophyll, disfigured and brittle leaves, and very small tomatoes, resulting in loss of productivity in this field crop. Avocado sunblotch viroid (ASBVd) results in lower yields and poorer-quality fruit. ASBVd is the smallest viroid discovered thus far that infects plants. Peach latent mosaic viroid (PLMVd) can cause necrosis of flower buds and branches, and wounding of ripened fruit, which leads to fungal and bacterial growth in the fruit. Coconut cadang-cadang viroid (CCCVd) and Coconut tinangaja viroid (CTiVd) infect monocotyledons, whereas the others infect dicotyledons. Symptoms: viroids have destructive consequences, as illustrated by CCCVd that has killed millions of coconut trees in the Philippines, whereas others affect leaves (chlorosis in spots or covering the whole blade, epinasty, rugosity, and necrosis), stems (pitting, internode shortening, and dwarfing), bark (scaling, cracking, cankers), flowers (size reduction, etc.). Absence of symptoms is common in naturally infected wild plants, which can act as reservoirs. Cross-Protection The phenomenon of cross-protection refers to observations that the ability of viroids to infect a host may be influenced by previous infections by other strains of the same or closely related viroid. Cross-protection: - when a plant pre- infected with a mild viroid strain is challenge-inoculated with a severe strain of the same viroid, the typical symptoms of the second strain and the accumulation level of its RNA are blocked or attenuated for a certain time. Transmission of viroids Viroids may be spread via vegetative propagules, mechanical damage, seed, pollen, or biological vectors. They can also be transmitted during agricultural or horticultural practices in which contaminated instruments are used. Viroids do not code for any protein because they cannot produce mRNA. When viroids infect plants, they induce symptoms in plants through the phenomenon known as RNA silencing. Most known plant viruses and viroids contain RNA genomes and replicate via dsRNA intermediates, thereby serving as potent inducers and targets of RNA silencing; i.e., RNA silencing provides a multi-layer defense system which protects plants from invasion by exogenous RNA replicons such as viruses and viroids. Viroids Two rounds of rolling circle replication are used by viroids to replicate themselves. Upon entry into a plant cell, the circular, positive single-stranded RNA uses the plant RNA polymerase to make a minus strand. The polymerase continues to make multiple copies using the rolling circle mechanism. RNA silencing performs crucial roles, regulating gene expression, maintaining genome stability and defending plants against invasive agents. Transcriptional and post- transcriptional gene silencing (TGS and PTGS, respectively) are set off by double-stranded (ds) RNAs. VIRUSOIDS The only human disease known to be caused by a viroid is hepatitis D. This disease was previously ascribed to a defective virus called the delta agent. However, it now is known that the delta agent is a viroid enclosed in a hepatitis B virus capsid. Hepatitis D viroid causes liver cell death. The HDV helper virus is the hepatitis B virus (HBV). Co-infection with HBV and HDV results in more severe pathological changes in the liver during infection, which is how HDV was first discovered. HDV will only replicate in cells that are simultaneously infected with HBV. Infection of humans by HDV can either occur by simultaneous infection with both HB and D viruses, or by superinfection with HDV of a person who is chronically infected by HBV. Since HDV depends on HBV for its propagation, control of HDV is dependent on control of HBV. HBV is controlled through vaccination. Virusoids Most known virusoids/satellites are associated with plant viruses, but hepatitis delta satellite virus is associated with a human helper virus, hepatitis B virus. RNA replication of virusoids is similar to that of viroids but, unlike viroids, virusoids require that the cell also be infected with a specific “helper” virus. The human hepatitis delta virus, replicates autonomously through a rolling-circle mechanism mediated by ribozymes, but depends on hepatitis virus B for transmission. VIRUSOIDS Virusoids are found in viruses belonging to the Sobemoviruses; Nepoviruses and Poleroviruses and more. Virusoids get encapsidated by the capsid protein of the helper virus of which the virus is a satellite. Thus, transmission occurs by conventional virus-means, and virusoids may have arisen from viroids that evolved a mechanism for packaging using a helper virus. Virusoids There are currently only five described types of virusoids and their associated helper viruses. The helper viruses are all from the family of Sobemoviruses. An example of a helper virus is the subterranean clover mottle virus, which has an associated virusoid packaged inside the viral capsid. Once the helper virus enters the host cell, the virusoids are released and can be found free in plant cell cytoplasm, where they possess ribozyme activity. Virusoids The helper virus undergoes typical viral replication independent of the activity of the virusoid. A virusoid genome does not code for any proteins, but instead serves only to replicate virusoid RNA. Virusoids Virusoids belong to a larger group of infectious agents called satellite RNAs, which are similar pathogenic RNAs found in animals. Unlike the plant virusoids, satellite RNAs may encode for proteins; however, like plant virusoids, satellite RNAs must coinfect with a helper virus to replicate. Virusoids Satellite genomes may be single- stranded RNA or DNA or circular RNA, and are replicated by enzymes provided by the helper virus. The origin of satellites remains obscure, but they are not derived from the helper virus. In plants, satellites and satellite viruses may attenuate or exacerbate disease caused by the helper virus. Plant diseases caused by satellites Examples of disease include necrosis and systemic chlorosis, or reduced chlorophyll production leading to leaves that are pale, yellow, or yellow-white. The symptoms induced by satellite RNAs are thought to be a consequence of silencing of host genes. For example, the Y-satellite RNA of cucumber mosaic virus causes systemic chlorosis in tobacco. This syndrome is caused by production of a small RNA from the Y-satellite RNA that has homology to a gene needed for chlorophyll biosynthesis. Production of this small RNA leads to degradation of the corresponding mRNA, causing the bright yellow leaves. The giant DNA viruses including Acanthamoeba polyophaga mimivirus, and others are associated with much smaller viruses (sputnik and mavirus, respectively) that depend upon the larger viruses for reproduction. PRIONS Prions are infectious proteins. The infectious prion protein is made by the host, and its amino acid sequence is identical to a normal host protein. The prion and normal forms of the protein are indistinguishable in their postranslational modifications. The only difference between them appears to be in their folded three-dimensional structure. The misfolded prion protein tends to aggregate, and it has the remarkable capacity to cause the normal protein to adopt its misfolded prion conformation and thereby to become infectious. This ability of the prion to convert the normal host protein to misfolded prion protein is equivalent to the prion's having replicated itself in the host. If eaten by another susceptible host, these newly- misfolded prions can transmit the infection. Prion Pathogenesis Pathogenesis - A prion is an infectious agent composed entirely of protein material, called PrP (short for prion protein), that can fold in multiple, structurally distinct ways, at least one of which is transmissible to other prion proteins, leading to disease that is similar to viral infection. Prions may propagate by transmitting their misfolded protein state: When a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the misfolded prion form. When a prion enters a healthy organism, it induces existing, properly folded proteins to convert into the misfolded prion form. In this way, the prion acts as a template to guide the misfolding of more proteins into prion form.In These refolded prions can then go on to convert more proteins themselves, leading to a chain reaction resulting in large amounts of the prion form. Therefore all known prions induce the formation of an amyloid fold, in which the protein polymerises into an aggregate consisting of tightly packed beta sheets. The protein that prions are made of (PrP) is found throughout the body, even in healthy people and animals. However, PrP found in infectious material has a different structure and is resistant to proteases, the enzymes in the body that can normally break down proteins. The infectious isoform of PrP, known as PrPSc, is able to convert normal PrPC proteins into the infectious isoform by changing their conformation, or shape; this, in turn, alters the way the proteins interconnect. PrPSc always causes prion disease. Aggregations of these abnormal isoforms form highly structured amyloid fibers, which accumulate to form plaques. Prion aggregates are extremely stable and accumulate in infected tissue, causing tissue damage and cell death.On the light-microscopic level spongiform changes in the brain, degeneration of neurons and astrocytosis are histopathological indications of prion diseases. Prions cause neurodegenerative disease (Alzeimer’s, Scrapie, Lewy body dementia etc.) by aggregating extracellularly within the central nervous system to form plaques known as amyloid, which disrupt the normal tissue structure. This disruption is characterized by "holes" in the tissue with resultant spongy architecture due to the vacuole formation in the neurons. Prion diseases All known prion diseases, collectively called transmissible spongiform encephalopathies (TSEs), are untreatable and fatal. While the incubation period for prion diseases is relatively long (5 to 20 years), once symptoms appear the disease progresses rapidly, leading to brain damage and death. Neurodegenerative symptoms can include convulsions, dementia, ataxia (balance and coordination dysfunction), and behavioural or personality changes. Prions PrP and long-term memory- scientific evidence suggestes that PrP may have a normal function in maintenance of long-term memory. PrP and stem cell renewal – A 2006 article from the Whitehead Institute for Biomedical Research indicates that PrP expression on stem cells is necessary for an organism's self- renewal of bone marrow. The study showed that all long-term hematopoietic stem cells express PrP on their cell membrane and that hematopoietic tissues with PrP-null stem cells exhibit increased sensitivity to cell depletion. Prions – effect of insomnia recent research in animal and human studies suggests that the sleep–wake cycle itself may influence Alzheimer’s disease onset and progression. Chronic sleep deprivation increases amyloid plaque deposition, and sleep extension results in fewer plaques in experimental models. PATHOGENS AND MICROBIAL INTELLIGENCE Bacterial pathogens have developed mechanisms which result in damage or death of particular hosts. Each pathogenic bacterium not only has evolved its individual cellular sensing and behavior, but also collective sensing, interbacterial communication, distributed information processing, joint decision making, dissociative behavior, and the phenotypic and genotypic heterogeneity necessary for their success as pathogens. Bacterial cells are exquisitely sensitive to the local environment, making intricate adjustments of their behavior in adaptation to the ever-changing environment. The concept microbial intelligence encompasses complex adaptive behaviour shown by single cells, and altruistic and/or cooperative behavior in populations of like or unlike cells mediated by chemical signalling that induces physiological or behavioral changes in cells and influences colony structures. Examples of microbial intelligence Quorum sensing: The formation of biofilms requires joint decision by the whole colony. Under nutritional stress bacterial colonies can organise themselves in such a way so as to maximise nutrient availability. Bacteria reorganise themselves under antibiotic stress. Bacteria can swap genes (such as genes coding antibiotic resistance) between members of mixed species colonies. Other examples of microbial intelligence Under rough circumstances, some bacteria transform into endospores to resist heat and dehydration. A huge array of microorganisms have the ability to overcome being recognized by the immune system as they change their surface antigens so that any defense mechanisms directed against previously present antigens are now useless with the newly expressed ones. Quorum sensing The opportunistic bacteria Pseudomonas aeroginosa also uses quorum sensing to coordinate the formation of biofilms, swarming, motility, exopolysaccaride production, and cell aggregation. These bacteria can grow within a host without harming it, until they reach a certain concentration. Then they become aggressive, their numbers sufficient to overcome the host's immune system, and form a biofilm, leading to disease within the host. Determinants of Pathogenicity Pathogenicity depends on the following factors: a) Number of organisms present b) virulence of pathogen/virulence factors c) Ports of entry d)Bacterial adherence, e) Invasiveness/Dissemination f) Pathological damage g) Host defenses or degree of resistance h) Siderophore production i) Plasmids j) Bacterial vaccines. Roles of plasmids in Pathogenicity and host specificity Plasmids found in pathogenic bacteria promote the dissemination of a variety of traits. These include pathogenicity and host specificity, toxin and hormone production, and resistance to bactericides such as copper and antibiotics, and to UV irradiation. The genes involved in pathogenicity and host specificity comprise two main groups, those termed avirulence (avr) and virulence (vir) genes, and those involved with a type III protein secretion system (chromosomally located). The type III secretion system, also present animal pathogens, determines the production of a pilus-like structure, which used to deliver certain protein products, including Avr proteins, inside plant cell. In contrast, those avr genes are evenly divided between plasmid and chromosomal locations. Avr genes always correspond to hosts that carry a matching gene for resistance (R), the so- called gene-for-gene theory. Pathogenicity Islands Are large segments of DNA that carry virulence genes acquired during evolution of pathogen by horizontal gene transfer VIRULENCE FACTORS OF BACTERIA Virulence Factor - is a characteristic that enables bacteria to cause DISEASE -may be common to all bacteria -can be species-species specific or strain-specific (genetically determined ) Some examples of virulence factors are: Attachment factors/ Adhesins Anti-phagocytic factors Spreading factors and enzymes Toxins; exotoxin and endotoxin VIRULENCE FACTORS OF BACTERIA 1). Attachment factors/ Adhesins: Bacteria produce various adhesins and a wide variety of other surface proteins to attach to host tissue. Different microorganism utilizes different structure for attachment. For examples; Staphylococcus mutans attaches to the surface of teeth by its sticky capsule. Adhesins Immune response inhibitors – secretion of proteases by some bacteria. E.g. Immunoglobulin (Ig) proteases Other bacteria such as coli, Neisseria spp, Shigella attaches with the help of pilli. Some examples of adhesions are: Capsule Pili Hemagglutinin spike of viruses Lipoteichoic acid Biofilm producing glycocalyx Attachment factors/ Adhesins: Immunoglobulin (Ig) proteases - are a group of virulence factors possessed by bacteria. Immunoglobulins are antibodies expressed and secreted by hosts in response to an infection. These immunoglobulins play a major role in destruction of the pathogen through mechanisms such as opsonization. Some bacteria, such as streptococcus pyogenes, are able to break down the host's immunoglobulins using proteases. Lipoteichoic Acids: Lipoteichoic acids as membrane teichoic acids are polymers of amphiphitic glycophosphates with the lipophilic glycolipid and anchored in the cytoplasmic membrane. They are antigenic, cytotoxic and adhesins (e.g., Streptococcus pyogenes). Attachment factors/ Adhesins: 5). PILI – Relatively short pili are important in the recognition of receptors on the surface of a host cell and the subsequent attachment to the receptor. These are also known as fimbriae. The pili contain chemical compounds called adhesins which allow the cell to bind to specific receptors on various human tissues. This binding gives rise to organ specificity of some bacterial strains. PILI b. Type I and type II pili promote adhesion to human host cells with these results: a). Binding of platelets and fibrin around the bacterial cell to evade phagocytosis. c). Binding of bacterial cells to epithelial adhesion receptors which results in interactions which may kill the human cell. For example, Neisseria gonorrhoeae is avirulent if it lacks pili. Attachment factors/ Adhesins: Capsule (K –antigen) - A fundamental requirement for most pathogenic bacteria that enter the human body is to escape phagocytosis. The most common means utilized by bacteria to avoid phagocytosis is an antiphagocytic capsule. The capsule is a major virulence factor, e.g. all of the principal pathogens which cause pneumonia and meningitis, have polysaccharide capsules on their surface. Non-encapsulated mutants of these organisms are avirulent. Capsule The capsule serves a diversity of functions in disease including: i. Antiphagocytosis - the smooth nature of the capsule prevents the phagocyte from adhering to and engulfing the bacterial cell. Furthermore, opsonins are prevented from binding to the cell and the process of opsonization is hindered. ii. Prevention of neutrophil killing of engulfed bacteria - lysosome contents do not have direct access to the interior of the bacterial cell and thus cannot kill the cell. iii. Prevention of complement-mediated bacterial cell lysis. iv. Prevention of polymorphonuclear (pmn) leukocyte migration to the site of infection. Capsule v. Toxicity to the host cell - this takes many forms depending on the chemical nature of the capsule. One example is the capsule of B. fragilis which induces abscess formation. vi. Adhesion to the host cell. vii. Protection of anaerobes from oxygen toxicity. Capsule viii. Enhancement of the pathogenicity of other species in a mixed infection. ix. Receptors for bacteriophage. x. Induction of antibody synthesis - this is the basis for: a. Serological diagnosis. b. Vaccine production. Capsule - serotypes A given species of bacteria may give rise to several serotypes based on the capsular antigen. For example, Streptococcus pneumonia produces over 70 capsular serotypes which have the structure of teichoic acid-like polymers. Glycocalyx/biofilm Other bacteria produce slime materials to attach themselves to a surface or substrate. Bacteria may attach to surface, produce slime, divide and produce microcolonies within the slime layer, and construct a biofilm, which becomes an enriched and protected environment for themselves and other bacteria. Polysaccharide films that may inevitably be present on the surfaces of bacterial cells, but which cannot be detected visually, are called glycocalyx. Biofilm A classic example of biofilm construction in nature is the formation of dental plaque mediated by the oral bacterium, Streptococcus mutans. The bacteria adhere specifically to the pellicle of the tooth by means of a protein on the cell surface. The bacteria grow and synthesize a dextran capsule which binds them to the enamel and forms a biofilm some 300-500 cells in thickness. Dental plaque The bacteria are able to cleave sucrose (provided by the animal diet) into glucose plus fructose. The fructose is fermented as an energy source for bacterial growth. The glucose is polymerized into an extracellular dextran polymer that cements the bacteria to tooth enamel and becomes the matrix of dental plaque. The dextran slime can be depolymerized to glucose for use as a carbon source, resulting in production of lactic acid within the biofilm (plaque) that decalcifies the enamel and leads to dental caries or bacterial infection of the tooth. 2. Antiphagocytic factors: In order to survive and cause disease microorganisms must resist killing by phagocytosis. Capsule is an important antiphagocytic factor for some bacteria. For example capsulated Pneumococcus is virulent and causes pneumonia but non-capsulated Pneumococcus is non-virulent. Production of Siderophoes Another important nutrient is iron. Under physiological conditions, ferric iron (Fe3+) is the dominant state. Ferric iron is hardly soluble, which limits its bioavailability. This is intensified on host mucosal surfaces by the secretion of the iron-binding molecule lactoferrin. To overcome iron limitation, bacteria secrete siderophores. Siderophores have a very high affinity for Fe3+. The iron-complexed forms are taken up by bacterial cells via ABC transporters. In general, iron- saturated siderophores can be acquired by all members of a community since siderophore acquisition solely depends on the expression of an appropriate receptor Superoxide dismutase and other enzymes: Some bacteria produces superoxide dismutase and other enzyme that prevent from phagocytic killing. 3. Spreading factors and enzymes: After infection microorganism needs to spread locally or generally to whole body but host defense mechanism i.e blood clot prevent spreading of microorganism. Pathogenic microorganisms such as Streptococcus spp produces fibrinolysin that dissolve clot and helps in spread of bacteria. Spreading Factors and Extracellular enzymes Other examples Extracellular enzymes – Hyaluronidase dissolves connective tissue – Collagenase is produced by Costridium, hydrolyses collagen in muscle connective tissue, which facilitates gas gangrene due to these organisms. – Streptokinase lyses blood clots – Phospholipases damage cell membranes – Lecithinase damages cell membranes Other examples Hemolysins lyse erythrocytes and white blood cells by lysis. Neuraminidase is produced by intestinal pathogens such as Vibrio cholerae and Shigella dysenteriae. It degrades neuraminic acid (also called sialic acid) p , an intercellular cement of the epithelial cells of the intestinal mucosa. Some exotoxins insert into membranes, form pores Phospholipases hydrolyze phospholipids of membrane. 4). Toxins Toxins - are divided into two groups: endotoxins and exotoxins. Exotoxins are classified as a toxin that is released by bacteria into the surrounding environment, and endotoxins, are a toxin kept "within" the bacterial cell and released only after destruction of the bacterial cell wall. Exotoxin: Toxins which are released outside the bacterial cell is called exotoxins Exotoxin is protein in nature. In general, exotoxins are highly toxic and lethal dose is low. Both Gram Positive and Gram Negative bacteria produces exotoxin. Endotoxin Lipopolysaccharides: One of the major components of the outer membrane of Gram-negative bacteria is lipopolysaccharide (endotoxin), a complex molecule consisting of a lipid A anchor, a polysaccharide core, and chains of carbohydrates. Sugars in the polysaccharide chains confer serologic specificity. Some examples of exotoxins are: Neurotoxin: Botulinum toxin; produced by Clostridium botulinum, tetanus toxin; produced by Clostridium tetani Enterotoxin: cholera toxin; produced by Vibrio cholerae Cytotoxin: Dephtheria toxin; produced by Corynebacterium dephtheriae Hemolysin: lyse RBCs; Leucosidin: lyse WBCs Exotoxins Another potent exotoxin is the tetanus toxin (tetanospamin) secreted by C. tetani. Exotoxins are also produced by some fungi as a competitive resource. The toxins, named mycotoxins, deter other organisms from consuming the food colonised by the fungi. 5). FLAGELLA FLAGELLA - This is the source of the H antigen which is used in serologic diagnosis. It is also the motility organ and possibly an organ for attachment to a human cell. It is considered a virulence factor. Flagella are involved in bacterial pathogenicity not just by conferring motility but also through other pathways. Flagella influence bacterial pathogenicity also by promoting adherence by acting as bacterial adhesions and by providing force-generating motility promoting bacterial biofilm formation supporting pathogen survival in vivo, translocating virulence proteins into host cells via, and triggering host pro-inflammatory responses through the Toll-like receptor signaling pathway. Virulence factors 6). ENDOSPORE - May have an endospore within the cytoplasm. This is a body that allows the organism to resist adverse conditions. The production of resistant spores by certain pathogenic bacterial species contributes to their transmission and difficulties in preventing their reoccurrence. Virulent factors 7). Destructive enzymes - Some bacteria pathogens produce a variety of enzymes which cause damage to host tissues. Enzymes include hyaluronidase, which breaks down the connective tissue component hyaluronic acid; a range of proteases and lipases; Dnases, which break down DNA, and hemolysins which break down a variety of host cells, including red blood cells. Virulent factors Effector Protein - Bacterial effectors are proteins secreted by pathogenic bacteria into the cells of their host. Effector proteins may have many different activities, but usually help the pathogen to invade host tissue, suppress its immune system, or otherwise help the pathogen to survive. Virulent factors 8). CELL WALL The Gram-positive bacterial cell wall is distinguished by having multiple layers of peptidoglycan sheets and is thus up to ten times the thickness of a Gram-negative bacterial cell wall.The glycan backbone of the peptidoglycan molecule can be cleaved by an enzyme called lysozyme that is present in animal serum, tissues and secretions, and in the phagocytic lysosome. CELL WALL The function of lysozyme is to lyse bacterial cells as a constitutive defense against bacterial pathogens. Some Gram-positive bacteria are very sensitive to lysozyme and the enzyme is quite active at low concentrations. Gram- negative bacteria are less vulnerable to attack by lysozyme because their peptidoglycan is shielded by the outer membrane. Gram negative cellwall The peptidoglycan of the Gram-negative cell is chemically similar to but not identical with the peptidoglycan of the Gram-positive cell wall. The outer membrane of the Gram-negative cell wall function as follows: A). A barrier to noxious environmental compounds. The barrier effect is seen most clearly in enteric bacteria that must cope with bile salts and digestive enzymes such as phospholipases and lysins. Gram negative cell wall B). A molecular sieve for small water-soluble molecules. C). An absorption site for bacteriophage D). An absorption site for cellular conjugation E). A reservoir for proteases, other enzymes and toxins Protoplasmic Membrane The protoplasmic membrane does not play a major role in disease pathogenesis. The only known role of the plasma membrane in pathogenesis is that it is the source of lipoteichoic acid which protrudes through the peptidoglycan of the Gram-positive cell and presents as a surface marker. Specifically the lipoteichoic acid, during the disease process, causes: lipoteichoic acid, during the disease process, causes: Dermal necrosis (Shwartzman reaction) Induction of cell mitosis at the site of infection Stimulation of specific immunity Stimulation of non-specific immunity Adhesion to the human cell Complement activation Induction of hypersensitivity (anaphylaxis) Treatment It is difficult to treat gram-negative bacteria in comparison to gram- positive bacteria due to following reasons. 1. The outer membrane present around the cell wall of gram-negative bacteria increases the risk of toxicity to the host. Treatment 2. Porin channels are present in gram-negative bacteria which can prevent the entry of harmful chemicals and antibiotics like penicillin. These channels can also expel out antibiotics making much more difficult to treat in comparison to gram-positive bacteria. treatment 3. The risk of resistance against antibiotics is more in Gram-negative bacteria due to the presence of external covering around the cell wall. 4. Gram-negative bacteria possess both exotoxins and endotoxins but in case of gram-positive bacteria there are only exotoxins. Differences between bacterial endotoxins and exotoxins Many bacteria produce toxins, enz

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