Bacterial Pathogenesis 1-2 Past Paper 2024 PDF

Bacterial Pathogenesis 1-2 Prof Dr. Necla Tülek 12 Nov. 2024 make How can they d!sea 2 Learning outcomes To provide information about some definitions of infectious dis...

Bacterial Pathogenesis 1-2 Prof Dr. Necla Tülek 12 Nov. 2024 make How can they d!sea 2 Learning outcomes To provide information about some definitions of infectious diseases, transmission routes, factors related to the agent, host and environment, and general signs and symptoms The pathogenesis of bacterial infection The pathogenesis of bacterial infection includes initiation of the infectious process and the mechanisms that lead to the development of signs and symptoms of disease. Characteristics of bacteria that are pathogens: Transmissibility, Adherence to host cells, Persistence, Invasion of host cells and tissues, Toxigenicity, Ability to evade or survive the host’s immune system.  m!c athegen e morgan Definitions Opportunistic bacteria: An agent capable of causing disease only when the host’s resistance is impaired (ie, when the patient is immunocompromised”). (cause"d!sease only cond!t!on) some !n Pathogenicity:The ability of any bacterial species to cause disease in a susceptible - human host. Pathogen: A microorganism capable of causing disease. Mycobacterium tuberculosis, Yersinia pestis Virulence: A term which presumes pathogenicity, but allows expression of degrees from low to extremely high don't confuse pathogen!ty w!th v!rulence  Definitions Adherence (adhesion, attachment): The process by which bacteria stick to the surfaces of host cells. After bacteria have entered the body, adherence is a major initial step in the infection process. Invasion: The process whereby bacteria, animal parasites, fungi, and viruses enter host cells or tissues and spread in the body. Sheashele know Definitions Know the deference we Colonization refers to the presence of a new organism that is neither a member of the normal flora nor the cause of symptoms Infection: Multiplication of an infectious agent within the body. i.e., it has entered the body of that person Multiplication of the bacteria that are part of the normal flora of the gastrointestinal tract, skin, and so on is generally not considered an infection Infectious disease is caused by damage produced by the bacteria and/or the consequences of innate and immune responses to the infection Carrier: A person or animal with asymptomatic infection that can be transmitted to another susceptible person or animal v!rus corr!erst She asked hepet!t!s  ~ cov!de Many, but not all, infections are communicable (i.e., they are spread from host to host). For example, tuberculosis is communicable (i.e., it is spread from person to person via airborne droplets produced by coughing), but botulism is not, because the exotoxin produced by the organism in the contaminated food affects only those eating that food. contag!ous ~ h!ghly If a disease is highly communicable, the term contagious is applied. Y COVID-19 The infectious dose: ID of an organism required to cause disease varies greatly among the pathogenic bacteria. d!zanter! (bloody d!arrhea) - ↑ - The infectious dose of bacteria depends primarily on their virulence factors (e.g., whether their pili allow them to adhere well to mucous membranes, whether they produce exotoxins or endotoxins, whether they possess a capsule to protect them from phagocytosis, and whether they can survive various nonspecific host defenses such as acid in the stomach) This number varies for each infectious disease. The dose that will cause illness in 50% of the subjects is defined as the infective dose 50 (ID50). Infectious doses vary according to the type of microorganism, for example, 101-2 bacteria for shigellosis, 101for amoebic dysentery, 108 for cholera, 10-50 for tularemia. · prev!ouslhed yr Koch’s Postulates 17 A The microorganism should be found in all cases of the disease in question, and its distribution in the body should be in accordance with the lesions observed. & The microorganism should be grown in pure culture in vitro (or outside the body of the host) for several generations. When such a pure culture is inoculated into susceptible animal species, the typical disease must result. The microorganism must again be isolated from the lesions of such experimentally produced disease.  Molecular Koch’s Postulates The phenotype or property under investigation should be significantly associated with pathogenic strains of a species and not with nonpathogenic strains. Specific inactivation of the gene or genes associated with the suspected virulence trait should lead to a measurable decrease in pathogenicity or virulence. Reversion or replacement of the mutated gene with the wild-type gene should lead to restoration of pathogenicity or virulence.  Molecular Guidelines for Establishing I Microbial Disease Causation 1.The nucleic acid sequence of a putative pathogen should be present in most cases of an infectious disease and preferentially in anatomic sites where pathology is evident. 2. The nucleic acid sequence of a putative pathogen should be absent from most healthy control participants. If the sequence is detected in healthy control participants, it should be present with a lower prevalence as compared with patients with disease and in lower copy numbers. 3- The copy number of a pathogen-associated nucleic acid sequence should decrease or become undetectable with resolution of the disease (eg, with effective treatment) and should increase with relapse or recurrence of disease. 4. The presence of a pathogen-associated nucleic acid sequence in healthy subjects should help predict the subsequent development of disease. 5. The nature of the pathogen inferred from analysis of its nucleic acid sequence should be consistent with the known biologic characteristics of closely related organisms and the nature of the disease. Bacterial disease production Most bacterial infections are acquired from an external source. However, some bacterial infections are caused by members of the normal flora and, as such, are not te sa transmitted directly prior to the onset of infection. Entry into the human body (or host) s!mes Evasion of primary host defenses such as skin or stomach acid. Find unique niche; avoid, circumvent, or subvert normal host defenses; multiply; and injure the host. Colonization, adhesion, and invasion Pathogenic actions of bacteria Immunopathogenesıs The biochemical, structural, and genetic factors that bacter!al f!gures !mpo play important roles in bacterial pathogenesis role !n bacter!al structures The Chain of Infection & ⑤ & Animals, soil (8 8 I & - * Ir A vectorborne > - What !s rector ? - Transmission The mode of transmission of many infectious diseases is “human-to-human,” but infectious diseases are also transmitted from nonhuman sources such as soil, water, and animals. tocsoplazma > - Animals are also an important source of organisms that infect humans. They can be either the source (reservoir) or the mode of transmission (vector) of certain organisms. Diseases for which animals are the reservoirs are called zoonoses. Fomites are inanimate objects, such as towels, that serve as a source of microorganisms that can cause infectious diseases.  Transmission routes Transmission can occur in various ways. via Respiratory Tract via Digestive Tract (Fecal-Oral Tract) via Skin and Mucosal Contact Sexual transmission via Vertical Infection - from mother to fetus via Blood Transfusion via Vectors Entry into the human body Each of the portals in the body that communicates with the outside world becomes a potential site of microbial entry. The mouth, nose, respiratory tract, ears, eyes, urogenital tract, and anus Human and other animal hosts have various protective mechanisms to prevent microbial entry Bacteria, viruses, and other microbes can also be transmitted from mother to offspring, a process called vertical transmission. Horizontal transmission, by contrast, is person-to-person transmission that is not from mother to offspring. Bacterial Entry into the Body Kolera bacter Canf!no Bar!l My lact!ne Bordetella  Bacterial Disease Production Disease results from tissue destruction, compromised organ function, or host defense responses that produce systemic symptoms (e.g., fever, nasal congestion, headache, lethargy, and loss of appetite). The length of the incubation period is the time required for the bacteria and/or the host response to cause sufficient damage to initiate discomfort or interfere with essential functions. Innate Defenses Against Colonization with Pathogens Human and other animal hosts have various protective mechanisms to prevent microbial entry  Bacterial Virulence Mechanisms Adherence Invasion Products of growth (gas, acid) Toxins Degradative enzymes Cytotoxic proteins Endotoxin Superantigen Induction of excess inflammation Evasion of phagocytic and immune clearance Capsule Resistance to antibiotics Intracellular growth  Colonization, adhesion, and invasion Different bacteria colonize different parts of the body. I mostly !n !nter s!de Colonization: The invasion of a new habitat by a new species. The presence and multiplication of microorganisms without tissue invasion or damage. The colonies develop when a bacterial cell begins reproducing. This may be closest to the point of entry or due to the presence of optimal growth conditions at the site. Colonization of sites that are normally sterile implies the existence of a defect in a natural defense mechanism or a new portal of entry Patients with cystic fibrosis have such defects because of the reduction in their ciliary mucoepithelial function and altered mucosal secretions; as a result, their lungs are colonized by S. aureus and P. aeruginosa. The first major interaction between a pathogenic microorganism and its host entails attachment to & & a eukaryotic cell surface remain at the site, survive, and obtain food. attachment adherens and ne Adherence to Cell Surfaces Certain bacteria have specialized structures (e.g., pili) or produce substances (e.g., capsules or glycocalyces) that allow them to adhere to the surface of human cells, thereby enhancing their ability to cause disease. These adherence mechanisms are essential for organisms that attach to mucous membranes; mutants that lack these mechanisms are often nonpathogenic. For example, the pili of Neisseria gonorrhoeae and E. coli mediate the attachment of the organisms to the urinary tract epithelium, and the glycocalyx of Staphylococcus epidermidis and certain viridans streptococci allows the organisms to adhere strongly to the endothelium of heart valves. The various molecules that mediate adherence to cell surfaces are called adhesins.  need to memost don't Bacteria may use specific mechanisms to adhere to and colonize different body surfaces Adherence requires the participation g of two factors: an adhesin on the 8 invading microbe and a receptor on the host cell In some instances, pili mediate initial attachment  Bacterial attachment A. The bacterial cell has both adhesive pili and another protein adhesin protruding from its & surface. The pili are binding to a receptor present in material covering the cytoplasmic membrane. B. The pili have pulled the organism into closer contact allowing the second adhesin to bind its receptor, which extends from the cytoplasmic membrane through the surface coating.  Invasion of host cells and tissues For many disease-causing bacteria, invasion of the host’s epithelium is central to the infectious process Invasion is the term commonly used to describe the entry of bacteria into host cells, breaking through tissue barriers and colonizing tissues In many infections, the bacteria produce virulence factors that influence the host cells, causing them to engulf (ingest) the bacteria. The host cells play a very active role in the process Bacterial invasion they can secrete to prote!n rest thenost. A. The bacterial cell has an injection secretion system that is injecting multiple proteins into the host cell. In the cytosol, the bacteria lyse the vacuolar membrane, escape, and move about. B. A bacterial surface protein binds to the cell surface and induces its own endocytosis. Another bacterium is seen invading between cells A and B by disrupting A B intercellular attachment molecules Erz!n  Tissue destruction-injury The successful pathogen must survive and multiply in the face of multiple host defenses. Disease requires some disruption of host function by the organism. One of the two main mechanisms by which bacteria cause disease is invasion of tissue followed by inflammation. The other main mechanism, toxin production, and a third mechanism, immunopathogenesis Several enzymes secreted by invasive bacteria play a role in pathogenesis  Hydrolytic Enzymes Austr!dum , they destryben amangas opportu n!st!c pathogo the Products of bacterial growth, especially fermentation, include acids, gas, and other substances that are toxic to tissue. Many bacteria release degradative enzymes to break down tissue, thereby providing food for the growth of the organisms and promoting the spread of the bacteria. Clostridium perfringens organisms are part of the normal flora of the GI tract but are also opportunistic pathogens that can establish infection in oxygen-depleted tissues and cause gas gangrene. These anaerobic bacteria produce enzymes (e.g., phospholipase C, collagenase, protease, and hyaluronidase), several toxins, and acid and gas from bacterial metabolism, which destroy the tissue. Staphylococci produce many different enzymes that modify the tissue environment; hyaluronidase, fibrinolysin, and lipases. Streptococci also produce enzymes, including streptolysins S and O, hyaluronidase, DNAases, and streptokinases.  Toxins Toxins are bacterial products that directly harm tissue or trigger destructive biologic activities. Toxins and toxin-like activities are degradative enzymes that cause lysis of cells or specific receptor-binding proteins that initiate toxic reactions in a specific target tissue. Exotoxins Exotoxins are proteins that are most often excreted from the cell. However some exotoxins accumulate inside the cell and are either injected directly into the host or are released by cell lysis. Endotoxin and other cell wall components & l!p!d ) /gram negat!ve. Endotoxins are lipid molecules that are components of the bacterial cell membrane. Endotoxins are not actively released from the cell and cause fever, shock, and other generalized symptoms. Both exotoxins and endotoxins by themselves can cause symptoms; the presence of the bacteria in the host is not required. Exotoxins Exotoxins are proteins that can be produced by gram positive or gram-negative bacteria and include cytolytic enzymes and receptor-binding proteins that alter a function or kill the cell. g In many cases, the toxin gene is encoded on a plasmid ③ tetanus toxin of C. tetani, Heat-labile [LT] and heat-stabile [ST] toxins of enterotoxigenic E. coli, or a lysogenic phage (Corynebacterium diphtheriae and C. botulinum). Cytolytic toxins include membrane-disrupting enzymes, such as the α-toxin (phospholipase C) produced by C. perfringens, which breaks down sphingomyelin and other membrane phospholipids. Hemolysins insert into and disrupt erythrocyte and other cell membranes. Pore-forming toxins, including streptolysin O, can promote leakage of ions and water from the cell and disrupt cellular functions or cell lysis Exotoxins are divided into 3 main groups when these similarities (areas of effect) are taken into account: Enterotoksinler: E. coli (ETEC, VTEC), V.cholerae, S.aureus, C.perfringens, B.cereus, C.difficile (toksin A) Nörotoksinler: C.tetani, C.botulinum Sitotoksinler: C.diphtheriae, P.aeruginosa (ekzotoksin A), C.perfringens (alfatoksin), C.difficile (toksin B), B.pertussis.  dont ned kon I to Because a toxin can be spread systemically through the bloodstream, symptoms may arise at a site distant from the site of infection, such as occurs in tetanus, which is caused by Clostridium tetani L!der A-C, The mode of action of dimeric A-B exotoxins. The bacterial A-B toxins often consist of a two-chain molecule. The B chain binds and promotes entry of the A chain into cells, and the A chain has inhibitory activity against some vital function. ACH, Acetylcholine; cAMP, cyclic adenosine monophosphate. ·  Superantigens - a special group of toxins These molecules activate T cells by binding simultaneously to a T-cell receptor and a major histocomapatibility complex class II (MHC II) molecule on an antigen-presenting cell without requiring antigen. Superantigens activate large numbers of T cells to release large amounts of interleukins (cytokine storm), including IL-1,TNF, and IL-2, causing life- threatening autoimmune-like responses. This superantigen stimulation of T cells can also lead to death of the activated T cells, resulting in the loss of specific T-cell clones and the loss of their immune responses. Superantigens the toxic shock syndrome toxin of S. aureus, staphylococcal enterotoxins, the erythrogenic toxin A or C of S. pyogenes.  wal comparent of ell Endotoxin and other cell wall components - The presence of bacterial cell wall components acts as a signal of infection that provides a powerful multialarm warning to the body to activate the host’s protective systems. The molecular patterns in these structures (pathogen-associated molecular patterns [PAMPs]) bind to Toll- - like receptors (TLRs) and other molecules (CD14) on macrophages, B cells, and other cells, and stimulate the production of acute-phase cytokines release of, such as IL-1, TNF-α, IL-6, and prostaglandins. In some cases, the host response is excessive and may even be life threatening. The lipid A portion of lipopolysaccharide (LPS) produced by gram-negative bacteria is a powerful activator of acute-phase and inflammatory reactions and is termed endotoxin. Weaker, endotoxin-like responses may ocur to gram-positive bacterial structures, including teichoic and lipoteichoic acids. The many activities of lipopolysaccharide (LPS). (develope This bacterial endotoxin activates almost every immune mechanism, as well as the clotting pathway, which together make LPS one of the most powerful immune stimuli known. DIC, Disseminated intravascular coagulation; IFN-γ, interferon-γ; IgE, immunoglobulin E; IL-1, interleukin-1; PMN, polymorphonuclear (neutrophil) leukocytes; TNF, tumor necrosis factor. etoto Kno v S J Main Features of - Exotoxins and Endotoxins compor!sen/d!fference * *  Pathogenicity islands The genes that encode many virulence factors in bacteria are clustered in pathogenicity islands located on the bacterial chromosome or plasmids. For example, in many bacteria, the genes encoding adhesins, invasins, and exotoxins are adjacent to each other on these islands. Nonpathogenic variants of these bacteria do not have these pathogenicity islands. It appears that these large regions of the bacterial genome were transferred as a block via conjugation or transduction. Pathogenicity islands are found in many gram-negative rods, such as E. coli, Salmonella, Shigella, Pseudomonas, and Vibrio cholerae, and in gram positives. Pathogenicity island (PAI) is unique regions exclusively associated with virulence. The major properties of PAIs are as follows: they have one or more virulence genes; they are present in the genome of pathogenic members of species but absent in the nonpathogenic members; they are often found with parts of the genome associated with mobile genetic elements; they often have genetic instability Pathogenicity island (PAI). A. Two bacterial strains are engaged in genetic exchange The recipient (right) has incorporated a large segment of the donor DNA into its chromosome. B. The chemical makeup of the donated segment is different from that of the host chromosome. This PAI contains genes for adhesins, toxins, and a secretion system, regulatory elements all for the production of the same disease. Pathogenicity islands are large genetic regions in the chromosome or on plasmids that contain sets of genes encoding numerous virulence factors that may require coordinated expression.  IgA1 Proteases Some bacteria that cause disease produce enzymes, IgA1 proteases, that split IgA1 and inactivate its antibody activity. IgA1 protease is an important virulence factor of the pathogens N gonorrhoeae, N meningitidis, H influenzae, and S pneumoniae. Production of IgA1 protease allows pathogens to inactivate the primary antibody found on mucosal surfaces and thereby eliminate protection of the host by the antibody  Other virulance factors Antiphagocytic factors Eg. S aureus has surface protein A S pyogenes (group A streptococci) M protein. Intracellular pathogenicity Eg. tuberculosis, Listeria monocytogenes, Antigenic heterogeneity Bacterial secretion systems the roles of the large number of molecular secretion activities used by bacteria to provide nutrients and facilitate their pathogenesis. The requirement for iron  learn Intracellular survival Intracellular survival is an important attribute of certain bacteria that enhances their ability to cause disease. These bacteria are called “intracellular” pathogens and commonly cause granulomatous lesions. The best-known of these bacteria belong to the genera Mycobacterium, Legionella, Brucella, and Listeria. - !ntracelullar bacter!a These organisms can be cultured on microbiologic media in the laboratory and therefore are not obligate intracellular parasites, which distinguishes them from Chlamydia and Rickettsia. The intracellular location provides a protective niche from antibody and neutrophils that function extracellularly. Antigenic heterogeneity The surface structures of bacteria (and of many other microorganisms) have considerable antigenic heterogeneity. Often these antigens are used as part of a serologic classification system for the bacteria. Some bacteria and other microorganisms have the ability to make frequent shifts in the antigenic form of their surface structures in vitro and presumably in vivo. One well-known example is Borrelia recurrentis, which causes relapsing fever. A second widely studied example is N. Gonorrhoeae. that frequent switching of antigenic forms allows gonococci to evade the host’s immune system; gonococci that are not attacked by the immune system survive and cause disease.  Bacterial Secretion Systems The complexity and rigidity of the cell wall structures necessitate mechanisms for the translocation of proteins across the membranes. These secretion systems are involved in cellular functions such as the transport of proteins that make pili or flagella and in the secretion of enzymes or toxins into the extracellular environment. There are at least seven known bacterial secretion systems, protein complexes, or channels that ensure transport of structural and toxigenic proteins through the bacterial cell after translation The Requirement for Iron Iron is an essential nutrient for the growth and metabolismof nearly all microorganisms and is an essential cofactor of numerous metabolic and enzymatic processes. The availability of iron in humans for microbial assimilation is limited because the iron is sequestered by the high-affinity iron-binding proteins transferrin in serum and lactoferrin on mucosal surfaces. The ability of a microbial pathogen to efficiently obtain iron from the host environment is critical to its ability to cause disease. Providing iron therapy during an active infection probably should be delayed because many pathogenic microorganisms can use the small amounts of supplemental iron, resulting in an increase in virulence. gere to there !s no free !ron grow for use of bacter!a So theyuses oreth of them  Biofilm Ex!dental plan A special bacterial adaptation that facilitates colonization, especially of surgical appliances such as artificial valves or indwelling catheters, is a biofilm. Biofilms form especially on foreign bodies such as prosthetic joints, prosthetic heart valves, and intravenous catheters, but they also form on native structures such as heart valves. Biofilms protect bacteria from both antibiotics and host immune defenses such as antibodies and neutrophils. They also retard wound healing, resulting in chronic wound infections, especially in diabetics. Bacteria in biofilms are bound within a sticky web of polysaccharide that binds the cells together and to the surface. Production of a biofilm requires sufficient numbers of bacteria (quorum). When P. aeruginosa determine that the colony size is large enough (quorum sensing) they produce a biofilm. Dental plaque is another example of a biofilm.  After bacteria have colonized and multiplied at the portal of entry, they may invade the bloodstream and spread to other parts of the body. b!ndsy Receptors for the bacteria on the surface of cells determine, in large part, the organs affected. For example, certain bacteria or viruses infect the brain because receptors for these microbes are located on the surface of brain neurons. t Receper b!nd!ng  Immunopathogenesis In many cases, the symptoms of a bacterial infection are produced by excessive innate, immune, and inflammatory responses triggered by the infection. When limited and controlled, the acute-phase response to cell wall components is a protective antibacterial response. However, these responses also cause fever and malaise, and when systemic and out of control, the acute-phase response and inflammation can cause life-threatening symptoms associated with sepsis and meningitis Activated neutrophils, macrophage, and complement can cause damage at the site of the infection. Cytokine storms generated by super antigens and endotoxin can cause shock and disruption of body function. Granuloma formation induced by CD4 T cells and macrophages in response to Mycobacterium tuberculosis can also lead to tissue destruction. Autoimmune responses can be triggered by bacterial proteins, such as the M protein of S. pyogenes, which antigenically mimics heart tissue. The anti-M protein antibodies cross-react with and can initiate damage to the heart to cause rheumatic fever. Immune complexes deposited in the glomeruli of the kidney cause poststreptococcal glomerulonephritis.  Microbial Defenses against Host Immunologic Clearance Capsule - prevent phagocytos!s Antigenic mimicry Antigenic masking Antigenic shift Production of antiimmunoglobulin proteases Destruction of phagocyte Inhibition of chemotaxis Inhibition of phagocytosis Inhibition of phagolysosome fusion Resistance to lysosomal enzymes Intracellular replication Different strains of the same bacteria can produce different diseases sagent ofß S. aureus causes inflammatory, pyogenic diseases such as endocarditis, osteomyelitis, and septic arthritis, as well as nonpyogenic, exotoxin- mediated diseases such as toxic shock syndrome, scalded skin syndrome, - and food poisoning. How do bacteria that belong to the same genus and species cause such widely divergent diseases? The answer is that individual bacteria produce different virulence factors that endow those bacteria with the capability to cause different diseases. The different virulence factors are encoded on plasmids, on transposons, on the genome of temperate (lysogenic) phages, and on pathogenicity islands. These transferable genetic elements may or may not be present in any single bacterium, which accounts for the ability to cause different diseases. 5 seorg Typical stages of an infectious disease I (1) The incubation period, which is the time between the acquisition of the organism (or toxin) and the beginning of symptoms (this time varies from hours to days to weeks, depending on the organism). (2) The prodrome period, during which nonspecific symptoms such as fever, malaise, and loss of appetite occur. (3) The specific-disease period, during which the overt characteristic signs and symptoms of the disease occur. Imalag!a feer) ↑ , (4) The recovery period, also known as the convalescence period, during Tr!s which the illness abates and the patient returns to the healthy state. IgG and IgA antibodies protect the recovered patient from reinfection by the same organism.  After the recovery period, some individuals become chronic carriers - of the organisms and may shed them while remaining clinically well. - Others may develop a latent infection, which can recur either in the same form as the primary infection or manifesting different signs and symptoms. Although many infections cause symptoms, many others are subclinical (i.e., the individual remains asymptomatic although infected with the organism). In subclinical infections and after the recovery period is over, the presence of antibodies is often used to determine that an infection has occurred.  d ↓ I 2 ↓ S ! Be Typical stages of an infectious disease. After infection, the patient progresses through four main stages: incubation period, prodrome period, specific disease period, and recovery period. The patient then typically returns to good health and has antibody that protects against reinfection and disease. Latent infection Chronic infection Death  ben Sorular G!ses Koyal may - A- A A A ⑧ ⑳ -  C - D C D Z S ⑧ O 5 ① & B!t