Microbial Mechanisms of Pathogenicity PDF

8/2/2024 Vocabulary Pathogenicity – ability of a microorganism to Microbial Mechanisms of cause disease by overcoming host defenses...

8/2/2024 Vocabulary Pathogenicity – ability of a microorganism to Microbial Mechanisms of cause disease by overcoming host defenses Pathogenicity Virulence – the degree of pathogenicity of a Chapter 15 microorganism BIO 220 1 2 Portals of entry To cause disease, pathogens must... Mucous membranes in respiratory, GI, and 1. Gain access to host genitourinary tracts and conjunctiva 2. Adhere to target tissues Skin 3. Penetrate or evade host defenses Parenteral route – Microbe deposition directly into the tissues beneath the skin or mucous membranes when 4. Damage host tissues (direct or indirect) these barriers are compromised 3 4 1  8/2/2024 Portals of entry Most pathogens have a preferred portal of entry that is a prerequisite to their being able to cause disease If they gain access to the host by another route, disease may not occur – Salmonella typhi, streptococci Some microorganisms can initiate disease from more than one portal of entry – Bacillus anthracis (cutaneous, inhalation, GI) – Yersinia pestis (bubonic, septicemic, pneumonic) 5 6 Numbers of invading microbes Numbers of invading microbes The more microbes that gain access to the The potency of a toxin is often expressed as host, the increased likelihood of disease the LD50, which is the lethal dose for 50% of a The virulence of a microbe can be expressed sample population as the ID50, which is the infectious dose for 50% of a sample population For Bacillus anthracis the ID50 is In mice – Skin, 10-50 endospores – LD50 is 0.03 ng/kg for botulinum toxin – Respiratory, 10,000-20,000 endospores – LD50 is 250 ng/kg for Shiga toxin – GI, 250,000 to 1,000,000 endospores – LD50 is 1350 ng/kg for staphylococcal enterotoxin 7 8 2  8/2/2024 Adherence Adherence The attachment between pathogen and host is accomplished by means of surface molecules Adhesins are usually glycoproteins or on the pathogen called adhesins or ligands lipoproteins that bind to complementary receptors on the – Strains within a species may have different surface of host cells. adhesins Adhesins may be found on the microbe’s glycocalyx, or other structures like pili, Receptors on the host cells are usually sugars fimbriae, and flagella – Can vary between cell types – Streptococcus mutans – glycocalyx – Actinomyces – fimbriae 9 10 Shigellosis How bacterial pathogens penetrate host (bacillary dysentery) defenses Capsules via receptor-mediated endocytosis – Capsule formation increases the virulence of a pathogen Shigella sonnei can escape vesicle Shigella dysenteriae – Capsules resist phagocytosis by preventing attachment of the phagocyte to the microbe – Streptococcus pneumoniae, Haemophilus can polymerize actin to promote influenzae, Bacillus anthracis, Yersinia pestis movement into neighboring cells – Antibodies against the capsule will ultimately result in the destruction of the microbe Dysentery the result of damage to the intestinal wall. Fig. 25.7 11 12 3  8/2/2024 How bacterial pathogens penetrate host How bacterial pathogens penetrate host defenses defenses Cell wall components Extracellular enzymes (exoenzymes) – Streptococcus pyogenes – produces a heat- resistant and acid-resistant protein called the M – Coagulases – coagulate (clot) fibrinogen in protein, which mediates attachment to the host blood, which may protect the bacterium from and helps microbe resist phagocytosis phagocytosis and isolate it from other host – Neisseria gonorrhoeae – uses fimbriae and an defenses outer membrane protein called Opa to attach to Staphylococcus and gain entry to host cells (grows inside epithelial and white blood cells) – Kinases – break down fibrin (blood clots) – Mycobacterium tuberculosis– presence of mycolic Streptococcus pyogenes – streptokinase acids also resist phagocytosis, bacteria can (fibrinolysin) multiply inside phagocytes 13 14 How bacterial pathogens penetrate host How bacterial pathogens penetrate host defenses defenses Extracellular enzymes Antigenic variation – Hyaluronidase – hydrolyzes hyaluronic acid, a type – Some pathogens can vary their surface antigens, of polysaccharide that holds together certain cells which may not interact with host-produced in the body, especially in connective tissue, which antibodies can then allow the microbe to spread Neisseria gonorrhoeae has several versions of Clostridium perfringens, Streptococcus the Opa-encoding gene – Collagenase Alphainfluenzavirus Clostridium perfringens Trypanosoma brucei – IgA proteases Neisseria 15 16 4  8/2/2024 How bacterial pathogens penetrate host How bacterial pathogens penetrate host defenses defenses Manipulation of the host cell cytoskeleton facilitates Microbes can survive inside phagocytes uptake of pathogen – L. monocytogenes and Shigella can escape from – When adhesins of microbe bind receptors on host cells, a series of events is triggered that allows entry of the the phagosome before fusion with a lysosome microbe into the host cell – Coxiella burnetii replicates inside phagolysosomes – Salmonella and E. coli inject chemicals (invasins) that promote the rearrangement of target cell actin filaments – M. tuberculosis, Plasmodium, Chlamydia and – Microbe entry is facilitated by the host cell cytoskeleton others can prevent both the fusion of a Some bacterial pathogens use the host cell phagosome with a lysosome AND the proper cytoskeleton for movement acidification of digestive enzymes, allowing for – Shigella and Listeria use actin filaments and cadherins multiplication inside the phagocyte 17 18 How bacterial pathogens penetrate host How bacterial pathogens damage host defenses cells Biofilms 1. Using host’s nutrients – Because of the EPS, pathogens incorporated into biofilms are more resistant to phagocytes and antibiotics than their planktonic counterparts 2. Causing direct damage in the vicinity of invasion 3. Toxin production Fig. 6.6 19 20 5  8/2/2024 Using the host’s nutrients Using the host’s nutrients Some pathogens secrete proteins called siderophores, which bind iron in the human Some pathogens have receptors that bind body iron-transport proteins, resulting in both iron and the binding protein entering the microbial Siderophores can take iron from endogenous cell iron-transport proteins like lactoferrin, transferrin, ferritin, and hemoglobin Iron is transported into microbe to support Some pathogens release toxins when iron vegetative growth and reproduction levels are low, resulting in the death of host cells and subsequent release of iron Fig. 15.3 21 22 Direct damage Toxin vocabulary As pathogens metabolize and reproduce, they Toxins – poisonous substances produced by ultimately cause the host cell to rupture certain microbes Toxigenicity – capacity of microbes to produce When the host cell ruptures, pathogens are toxins released to spread to other tissues Toxemia – presence of toxins in the blood Intoxications – caused by the presence of Most damage is done by microbial toxins toxins, not microbial growth 23 24 6  8/2/2024 Exotoxins Produced inside some bacteria and later secreted by the bacteria into the surrounding medium or released following lysis Can be produced by both Gram (+) and (-) cells Genes for most exotoxins are carried on bacterial plasmids or phages Exotoxins are proteins, usually enzymes, which can be harmful even in low concentrations Fig. 15.4 25 26 Exotoxins Exotoxins Soluble in bodily fluids, so can easily diffuse The body produces antibodies called into the blood and subsequently spread antitoxins that provide immunity to exotoxins throughout the body Work by destroying particular parts of the host’s cells or by inhibiting certain metabolic When exotoxins are inactivated (toxoids), they functions no longer cause disease but can still stimulate Diseases caused by bacteria that produce the body to produce antitoxins exotoxins are often caused by minute amounts of exotoxin, not by bacteria Toxoids are sometimes used in vaccines themselves (exotoxins produce symptoms) – i.e. Diphtheria and tetanus 27 28 7  8/2/2024 Types of exotoxins (A-B exotoxins) A-B Exotoxins Most exotoxins are of this type Consist of two parts (A and B) which are polypeptides A is the active (enzymatic) component B is the binding component Fig. 15.5 29 30 Genotoxins Exotoxins ( Membrane-disrupting toxins) A-B toxins Cause lysis of host cells by disrupting PM via Produced by some Gram (-) bacteria including forming protein channels or disrupting the Haemophilus ducreyi, Helicobacter, and phospholipid bilayer Salmonella – S. aureus forms protein channels – C. perfringens disrupts phospholipids Causes damage to cellular DNA, resulting in mutations, disruption to cellular division, and Cause the death of host cells (esp. potentially cancer phagocytes) and aid the escape of bacteria from vesicles into the host cytoplasm 31 32 8  8/2/2024 Exotoxins ( Membrane-disrupting toxins) Exotoxins ( Membrane-disrupting toxins) Leukocidins – membrane-disrupting toxins that Hemolysins – destroy erythrocytes kill phagocytic leukocytes (i.e. macrophages) – Staphylococcus and Streptococcus – Form protein channels – Streptolysins are hemolysins produced by... – Mostly produced by Staphylococcus and i.e. Streptolysin O, streptolysin S Streptococcus Can cause lysis of other body cells as well – Trypanosoma cruzi and Listeria monocytogenes secrete toxins that lyse phagolysosome and plasma membranes 33 34 Types of exotoxins (Superantigens) Antigens (bacterial proteins) that provoke a very intense immune response Superantigens stimulate the proliferation of T cells, which then release enormous amounts of cytokines Cytokines regulate immune responses and mediate cell-to-cell communication Symptoms include fever, nausea, diarrhea, etc. 35 36 9  8/2/2024 Endotoxins Endotoxins Released during bacterial multiplication and Produced by Gram (-) bacteria when cells die and cell walls lyse Lipid A of LPS is the endotoxin Antibiotics can lyse cell walls, causing the release of these toxins and an immediate worsening of symptoms Endotoxins stimulate macrophages to release cytokines in high concentrations, which are toxic at these concentrations Chills, fever, weakness, generalized aches, and in some cases shock, death and miscarriage Fig. 4.13 37 38 Endotoxins Endotoxins and the pyrogenic response Endotoxins activate blood-clotting proteins, causing the formation of small blood clots which can obstruct capillaries, potentially resulting in tissue death Disseminated intravascular coagulation (DIC) Bacterial cell death caused by lysis or antibiotics can also produce fever. Medications like aspirin and acetaminophen reduce fever by blocking prostaglandin formation. Fig. 15.6 39 40 10  8/2/2024 Endotoxins Endotoxins Shock – life-threatening decrease in bp Endotoxins do not promote the formation of Septic shock – shock caused by bacteria effective antitoxins Gram (-) bacteria cause endotoxic shock – Phagocytosis of these bacteria causes macrophages to release tumor necrosis factor (TNF) Antibodies that are produced do not counter Damages capillaries, which allows fluid loss and reduces the effect of the toxin blood pressure – Haemophilus influenzae type B causes the release of IL-1 and TNF, which affects the integrity of the blood-brain-barrier Lets phagocytes and more bacteria enter nervous system 41 42 Limulus amebocyte lysate (LAL) assay This is a test to identify the presence of endo- toxins in drugs, medical devices, and body fluids Blood of Limulus polyphemus contains WBCs called amebocytes, which have large amounts of a protein that causes clotting. In the presence of endotoxins, amebocytes lyse, liberate their clotting protein and cause a gel-clot (precipitate) 43 44 11  8/2/2024 Portals of exit Portals of exit relate to the infected part of the body, with microbes tending to use the same portal for both entry and exit Portals of exit include the respiratory, GI, and genitourinary tracts, skin, wounds, biting insects Fig. 15.9 45 46 12