General Microbiology 10) Bacterial Pathogenesis PDF

General Microbiology 10) Bacterial Pathogenesis Dr. Lutfi M. Bakar Autumn 2024 Important factors : 1) Host Susceptibility 2) Bacterial Infectivity 3) Host Resistance 4) Genetic and Molecular Basis for Virulence 5) Intracellular Growth...

General Microbiology 10) Bacterial Pathogenesis Dr. Lutfi M. Bakar Autumn 2024 Important factors : 1) Host Susceptibility 2) Bacterial Infectivity 3) Host Resistance 4) Genetic and Molecular Basis for Virulence 5) Intracellular Growth 6) Virulence Factors Basics Infection is the invasion of the host by microorganisms Infection is distinguished from disease, a morbid process that does not necessarily involve infection (e.g. diabetes). Bacteria can cause a multitude of different infections, ranging in severity from inapparent to fulminating Capacity of a bacterium to cause disease reflects pathogenicity. On this basis, bacteria can be organized into three major groups: a. Probable agents of disease b. Opportunistic pathogens are those isolated from patients whose host defence mechanisms have been compromised c. Nonpathogens rarely or never cause disease. But this could change! Virulence is the measure of the pathogenicity. Virulence can be measured experimentally by determining the number of bacteria required to cause animal death, illness, or lesions in a defined period. A lethal dose affecting 50 % of a population of animals (LD50) or an effective dose causing a disease symptom in 50 % of a population of animals (ED50) are useful in comparing the relative virulence of different bacteria Pathogenesis refers both to the mechanism of infection and to the mechanism by which disease develops. Type of infection Description Example Rapid onset (hours or days) Acute Diphtheria brief duration (days or weeks) Prolonged duration (months or Mycobacterial Chronic years) diseases Confined to a small area or to Localized Staphylococcal boil an organ Disseminated to many body Gram-negative Generalized regions (gonococcoernia) bacteremia Staphylococcal and Pyogenic Pus-forming streptococcal infection Microbes ascending in a duct or E. coli urinary tract Retrograde tube against the flow of infection secretions or excretions Airborne Yersinia Infection that occur suddenly Fulminant pestis (pneumonic and intensely plague)  Type of infection Description Example Asymptomatic gonorrhea in Inapparent (subclinical) No detectable symptoms woman and man Dormant (latent) Carrier state Typhoid carrier Anthrax, cryptococcal Zoonosis of environmental Accidental infection, and laboratory or inadvertent exposures exposure, respectively Infection caused by normal flora or transient bacteria Serrati or Candida infection Opportunistic when normal host defenses of urogenital tract are compromised Primary Clinically apparent Shigella dysentery Microbial invasion Bacterial pneumonia Secondary subsequent to primary following viral lung infection infection Two or more microbes Anaerobic abscess (E. coli Mixed infecting the same tissue and Bacteroides fragillis) Host Susceptibility Susceptibility to bacterial infections depends on the physiologic and immunologic condition of the host and on the virulence of the bacteria Development of effective specific immunity (such as an antibody response to the bacterium) may require several weeks. The normal bacterial flora of the skin and mucosal surfaces also serves to protect the host against colonization by bacterial pathogens. In most healthy individuals, bacteria from the normal flora that occasionally penetrate the body (e.g., during tooth extraction or routine brushing of teeth) are cleared by the host's cellular and humoral mechanisms. Bacterial pathogenicity Virulence can be expressed as LD50 Bacteria use a variety of mechanisms to colonize a host, invade tissues, and avoid being destroyed by the host's defense mechanisms Virulence of a bacterium relates to its ability to invade and produce disease in a normal individual Pathogenic bacteria have virulence factors. These factors may be common to all bacteria of a given genus or species, or they may be characteristic of special pathogenic strains. Resistance mechanisms These can be altered by many other processes.: o Aging often weakens defence systems so that they can no longer effectively combat the challenge of bacteria from the environment. o Infants are also especially susceptible to certain pathogens (such as group B streptococci because their immune systems are not yet fully developed and cannot mount a protective immune response to important bacterial antigens. o Genetic defects of the complement system or cellular defences (e.g., inability of polymorphonuclear neutrophils to kill bacteria). o Predisposing disease, such as cancer, or immunosuppressive chemotherapy for organ transplants or cancer (granulocytopenia) Factors affecting host resistance Trauma and diseases Wounds and burns Respiratory illnesses UTI Routine medical procedures Antimicrobial drug therapy Host contact and Vector Some facts about bacteria : High mutation rate of bacteria combined with their short generation time results in rapid selection of the best-adapted strains and species Bacteria can be said to have a single objective: to multiply Only a few of the vast number of bacterial species in the environment consistently cause disease in a given host. From a teleologic standpoint, it is not in the best interest of the pathogen to kill the host, because in most cases the death of the host means the death of the pathogen. The most highly evolved or adapted pathogens are the ones that acquire the necessary nutritional substances for growth and dissemination with the smallest expenditure of energy and least damage to the host. For example, Rickettsia akari Some bacteria that are poorly adapted to the host synthesize virulence factors (e.g., tetanus and diphtheria toxin) so potent that they threaten the life of the host. Genetic and Molecular Basis for Virulence : Virulence factors in bacteria may be encoded on chromosomal DNA, bacteriophage DNA, plasmids, or transposons in either plasmids or the bacterial chromosome. heat-labile enterotoxin (LTI) of E. coli is plasmid encoded, whereas the heat-labile toxin (LTII) is encoded on the chromosome. Other virulence factors are acquired by bacteria following infection by a particular bacteriophage, which integrates its genome into the bacterial chromosome by the process of lysogeny. The transfer of genes for antibiotic resistance among bacteria is a significant medical problem. Transmission of virulence genes among bacteria Conjugation is perhaps the most effective mechanism for transmission of virulence genes. Genetic Elements (Plasmids) carrying virulence genes can be classified as follows: Resistance elements (contain information for resistance to antibiotics) Virulence elements (may code for exotoxins, adhesions, or invasion factors) Adhesion-coding elements ( present in entrotoxigenic E. coli, coding for specific pili known as colonization factors antigens) Portals of Entry 1. Many microorganisms can penetrate mucous membranes of the conjunctiva and the respiratory, gastrointestinal, and genitourinary tracts. 2. Microorganisms that are inhaled with droplets of moisture and dust particles gain access to the respiratory tract. 3. Microorganisms that gain access via the genitourinary tract can enter the body through mucous membranes. 4. Microorganisms enter the gastrointestinal tract by ingestion via food, water, and contaminated fingers. 5. Most microorganisms cannot penetrate intact skin, but may enter hair follicles or sweat ducts. 6. Some microorganisms can gain access to tissues by direct penetration (inoculation) through the skin and mucous membranes in bites, injections, and other wounds. This route of penetration is called the parenteral route. 7. Arthropods and syringes provide a portal of exit for microbes in blood. Transmission of Disease 1. Transmission by direct contact involves close physical contact between the source of the disease and a susceptible host. 2. Transmission by fomites (inanimate objects) constitutes indirect contact. 3. Transmission via saliva or mucus in coughing or sneezing is called droplet transmission. 4. Transmission by a medium such as water, food, or air is called vehicle transmission. 299 5. Airborne transmission refers to pathogens carried on water droplets or dust for a distance greater than one meter. 6. Arthropod vectors carry pathogens from one host to another by both mechanical and biological transmission.  Portals of Exit  Respiratory tract : Coughing and sneezing  Gastrointestinal tract : Feces and saliva  Genitourinary tract : Urine and vaginal secretions  Skin  Blood : Biting arthropods and needles or syringes Pathogenicity : Ability of a pathogen to cause disease by overcoming the host defenses. Virulence : Degree of pathogenicity. ID50 : Infectious dose for 50% of the test population LD50 : Lethal dose (of a toxin) for 50% of the test population Bacillus anthracis Portal of Entry ID50 Skin 10–50 endospores Inhalation 10,000–20,000 endospores Ingestion 250,000–1,000,000 endospores  Adherence Adhesins : surface projections on pathogen, mostly made of glycoproteins or lipoproteins. Adhere to complementary receptors on the host cells. Many bacteria depend on the ability to adhere to cells as a first step in causing disease. Without adhesion factors, many pathogens would be washed away before they could cause disease Adhesion factors are surface structures, such as : * Pili or fimbriae(as colonization factor antigens), * M protein (Streptococcus pyogenes) and may be * flagella  Capsules  One of the most common virulence factors possessed by bacteria  Encapsulated strains of many bacteria are more virulent and more resistant to phagocytosis and intracellular killing than are nonencapsulated strains (e.g., pneumococci) Overcoming Host Defenses Capsules: inhibition or prevention of :  Cell Wall Proteins: e.g. M protein of S. pyogenes  Penetration into the Host Cell Cytoskeleton: Salmonella and E. coli produce invasions, proteins that cause the action of the host cell’s cytoskeleton to form a basket that carries the bacteria into the cell. Invasiveness  The Ability to Invade Host Cells  Some bacteria produce adhesion molecules called invasions enabling bacterial entry into the cell  As an example, invasins of Shigella , Listeria monocytogenes, Streptococcus pneumoniae Penetration into the Host Cell Cytoskeleton  Invasins Salmonella alters host action to enter a host cell  Use actin to move from one cell to the next ◦ Listeria Exoenzymes Many bacteria produce and secrete enzymes These enzymes may play an important pathogenic role by a variety of mechanisms. Examples are :  coagulase - causes blood to clot  kinase - dissolves blood clots  hyaluronidase - dissolves intercellular cementing material (hyaluronic acid)  lecithinase - breaks-down lecithin (another intercellular cementing material)  hemolysins - destroy red blood cells  collagenases -break-down collagen (a protein of connective tissue)  proteases - break-down proteins Toxins Membrane-Disrupting Toxins Lyse host’s cells by : 1. Making protein channels into the plasma membrane, e.g. S. aureus 2. Disrupting phospholipid bilayer, e.g. C. perfringens Examples: Hemolysin (e.g. Streptolysin) : RBCs lysis  Exotoxins  Are protein toxins released from viable bacteria but also released upon bacterial lysis  Exotoxins can be grouped into several categories (e.g., neurotoxins, cytotoxins, and enterotoxins)  There are three main types of exotoxins: 1. superantigens (Type I toxins) Special type of Exotoxin, Nonspecifically stimulate T-cells. Cause intense immune response due to release of cytokines from host cells. Fever, nausea, vomiting, diarrhea, shock, and death. 2. A-B toxins and other toxin that interfere with host cell function (Type III toxins), and 3. exotoxins that damage host cell membranes (Type II toxins).  The body's major defense against exotoxins is the production of antitoxin antibodies.  The exotoxins of Clostridium perfringens. This bacterium produces several significant exotoxins that play a role in the pathogenesis of gas gangrene.  Exotoxin B, produced by rare invasive strains of group A beta streptococci (Streptococcus pyogenes)  Pneumolysin, produced by Streptococcus pneumoniae,  Shiga toxin  Anthrax toxins, produced by Bacillus anthracis Botulinal and Tetanus exotoxin. Exotoxins Source : Gram +ve and Gram -ve Relation to microbe : By-products of growing cell Chemistry : Protein Fever? No Neutralized by antitoxin? Yes LD50 : Small Circulate to site of activity. Affect body before immune response possible. Exotoxins with special action sites: Neuro-, and enterotoxins  Endotoxins They are comprised of toxic lipopolysaccharide components of the outer membrane of Gram-negative bacteria. Endotoxin exerts profound biologic effects on the host and may be lethal. The term endotoxin was coined in 1893 by Pfeiffer to distinguish the class of toxic substances released after lysis of bacteria from the toxic substances (exotoxins) secreted by bacteria. Biologic Activity of Endotoxin : 1. mitogenic effects on B lymphocytes that increase resistance to viral and bacterial infections 2. induction of gamma interferon production by T lymphocytes, which may enhance the antiviral state, promote rejection of tumor cells, and activate macrophages and natural killer cells 3. activation of the complement cascade with the formation of C3a and C5a 4. induction of the formation of interleukin-1 by macrophages and interleukin-2 and other mediators by T lymphocytes. Toxin Examples Portal of Entry ID50 Botulinum (in mice) 0.03 ng/kg Shiga toxin 250 ng/kg Staphylococcal enterotoxin 1350 ng/kg  Characteristics of bacterial endotoxins and classic exotoxins Property ENDOTOXIN EXOTOXIN Lipopolysaccharide Protein (mw = 50 - Chemical Nature (mw = 10kDa) 1000kDa) RELATIONSHIP Part of outer Extracellular, diffusible TO membrane DENATURED BY No Usually BOILING ANTIGENIC Yes Yes TOXOID No Yes Relatively low POTENCY Relatively high (1 ug) (>100ug) SPECIFICITY Low degree High degree ENZYMATIC No Usually ACTIVITY PYROGENICITY Yes Occasionally Thank you For your Attention And Goodbye