Lec 6 Mechanisms of Pathogenicity - Bacteria II PDF

11/17/2023 Mechanisms of pathogenicity: bacteria (II) Disease Caused by Bacterial (AB) Exotoxins-Cholera Cholera: Vibrio cholerae 1 11/17/2023 Disease Caused by Bacterial (AB) Exotoxins-Cholera-Cont • V. cholerae releases a toxin (AB) that binds to ganglioside receptors on the surface of i...

11/17/2023 Mechanisms of pathogenicity: bacteria (II) Disease Caused by Bacterial (AB) Exotoxins-Cholera Cholera: Vibrio cholerae 1 11/17/2023 Disease Caused by Bacterial (AB) Exotoxins-Cholera-Cont • V. cholerae releases a toxin (AB) that binds to ganglioside receptors on the surface of intestinal epithelium cells • This toxin is internalized and triggers the production of cAMP within the cell • cAMP activates specific ion channels within the cell membrane, causing an efflux of ions from the cell • The build up of ions in the intestinal lumen draws water from cells and tissues via osmosis – causing acute diarrhea • As water is being removed from body tissues, dehydration will result if left untreated. If left untreated, severe dehydration can lead to shock, coma, and death within hours Disease Caused by Bacterial (AB) Exotoxins-Cholera-Cont Diarrhea Rice water stool • Cholera-related diarrhea comes on suddenly and can quickly cause dangerous fluid loss — as much as a quart (about 1 liter) an hour • Diarrhea due to cholera often has a pale, milky appearance that resembles water in which rice has been rinsed commonly known as “rice water” stool • Although V. cholerae is the causal agent for cholera, it is noteworthy that only a small number of V. cholerae are capable of producing cholera toxin which causes acute diarrhea 2 11/17/2023 I. Exotoxins-Cont TOXICITY I. II. III. Exotoxins: proteins that are released into the surroundings as the pathogen grows (very specific target) Endotoxin: structural component of bacterial cell wall (LPS) Injected toxins: toxin injected directly into a mammalian cell Types of Exotoxins 1. AB exotoxins – composed of two subunits • A subunit – responsible for toxic effect • B subunit – binds to specific target cell 2. Membrane-disrupting exotoxins 3. Superantigens I.2 Membrane Disrupting Toxins Two main subtypes of membrane-disrupting toxins: Pore forming toxins (the most common): Lyse host´s cell by making protein channels in the plasma membrane • Leukocidins: kill leukocytes (neutrophils, T lymphocytes), dendritic cells etc.innate and adaptive immune responsese.g. Staphylococcal leukocidins • Hemolysins: lysis red blood cells Listeriolysin in Listeria Streptolysins in Streptococcus- etc Enzymes that hydrolyze phospholipids: (phospholipases), • Clostridium perfringens α- toxin (phospholipase C) destroys the local population of white blood cells (Gas gangrene), red blood cells etc 3 11/17/2023 Exotoxins Produced By Human Pathogens TOXICITY I. Exotoxins: proteins that are released into the surroundings as the pathogen grows (very specific target) II. Endotoxin: structural component of bacterial cell wall (LPS) III. Injected toxins: toxin injected directly into a mammalian cell IMMUNOPATHOGENESIS • Toxins can even induce disease in the absence of the microorganism that produce them 4 11/17/2023 II. Endotoxin • Lipopolysaccharide (aka endotoxin) in Gram-negative cell wall can be toxic to specific hosts; Toxic component is the lipid portion (lipid A) • Called endotoxin because it is an endogenous (part) of the bacterium • Released when organism lyse; some also released during multiplication or phagocytis etc II. Endotoxin-Cont • Endotoxin is the most important cause of septic shock, which is characterized primarily by fever, hypotension, and disseminated intravascular coagulation • Septic shock is one of the leading causes of death in intensive care units and has an estimated mortality rate of 30-50% • The findings of fever and hypotension are relevant features of septic shock • The endotoxins of Gram-negative bacteria are the best-established causes of septic shock, but surface molecules of Gram-positive bacteria (which do not have endotoxins) can also cause septic shock 5 11/17/2023 Character Produced by Chemical Nature Exotoxins Mostly Gram positive also some Gram negative bacteria Protein (polypeptide) Secretion Secreted out of the cell Stability to heat Heat labile Enzymes; highly specific in their mechanism and for their host cells Highly immunogenic No Highly toxic, fatal in µg quantities Specificity Immunogenicity Fever Induction Toxicity Endotoxins Gram negative bacteria Lipopolysaccharide Generally not released outside the cell until death of cell Heat stable Not very specific in nature Weakly immunogenic Yes Moderately toxic, fatal in mg quantities General symptoms such as fever, diarrhea, vomiting etc. Effects Specific symptoms Neutralization by Antibodies Can be neutralized Cannot be neutralized Vaccine against diphtheria or tetanus Not possible Tetanus, diphtheria, botulism etc Sepsis by Gram negative bacteria Conversion to Toxoids Diseases caused TOXICITY I. Exotoxins: proteins that are released into the surroundings as the pathogen grows (very specific target) II. Endotoxin: structural component of bacterial cell wall (LPS) III. Injected toxins: toxin injected directly into a mammalian cell IMMUNOPATHOGENESIS 6 11/17/2023 III. Toxins Injected Into Eukaryotic Cells • Toxins are neutralized by specific antibodies (neutralizing antibodies) produced by our immune system • Potential vaccine candidates, Hla (alpha-toxin) in S. aureus Toxins acting on the surface of eukaryotic cells Toxins that have an intracellular target Cytoplasm Toxins injected into eukaryotic cells Cytoplasm Injected toxins cannot be neutralized by antibodies since they are injected directly into eukayotic cells III. Toxins Injected Into Eukaryotic Cells-Cont Injected Toxins • Toxin production and direct injection occur only once bacteria come in contact with the target cell • No dissemination • Not accessible to neutralizing antibodies Many human pathogens Eukaryotic cell Effectors/Toxins T3SS Bacteria 7 11/17/2023 Planktonic vs Biofilm Mode of Growth Biofilm growth is physiologically different from planktonic growth •  May cause chronic infection  Increases virulence  Become less sensitive to antibiotics  Make cells in biofilm more resistant to host defense (“frustrates” phagocytes) Copyright (c) 2017 McGraw‐Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw‐Hill Education. Iron Acquisition System Iron-Siderophore, Hemophore and Bacterioferritin Host transferrin, lactoferrin, etc. Free Fe Fe3+ CSiderophores CFe 3+ C Hemophores (Gram-negatives) HEME (Fe2+) Receptors Hemophores CFe 3+ Biosynthesis (ex. Heme groups) Fe3+ Fe2+ Hydrolysis heme-binding proteins Stored (Bacterioferritin) Wandersman, C. and P. Delepelaire. 2004. Annu. Rev Microbiol 58:611-647. Copyright (c) 2017 McGraw‐Hill Education. All rights reserved. No reproduction or distribution without the prior written consent of McGraw‐Hill Education. 8 11/17/2023 How do Pathogens Cause an Infectious Disease? One example: Food-Borne Diseases • Caused by agents that enter the body through the ingestion of contaminated food/fluids • Occurs when a pathogen or its toxin is consumed • Commonly referred to as food poisoning Food-Borne Infections Versus Food Intoxication Similar symptoms Completely different processes and consequences Different treatment Food-Borne Diseases Food-Borne Infections • • • • • • • • Ingestion of live pathogen (bacteria, virus, parasite) with contaminated food/fluids Colonization and growth of bacteria in the gastrointestinal tract Host tissue invasion Production of virulence/pathogenicity factors Delay in manifestation of signs and symptoms (pathogen are replicating, growing and causing damage) Generally with fever Antibiotics (in some cases) Contagious Food Intoxication • • • • • • • Ingesting food containing toxins formed by bacteria which resulted from the bacterial growth in the food item Ingestion of contaminated food with accumulated toxin Presence of living microorganisms is not required Sudden appearance No fever Antibiotics are not useful Not contagious 9 11/17/2023 How do Pathogens Cause an Infectious Disease? IMMUNOPATHOGENESIS Immunopathogenesis Disease as a result of host immune response to the pathogen: • Autoantibodies formation (rheumatic fever-Streptococcus, …) • Immune complex formation (glomerulonephritis-Streptococcus, …) • Systemic inflammatory response: septic shock (LPS, superantigens….) Immunopathology Streptococcal pharyngitis (Streptococcus pyogenes) • Common infection called strep throat spread by droplets of saliva or nasal secretions – Infection in throat (pharyngitis) or tonsils – Symptoms of disease not diagnostic because many viral infections have similar presentation Physical manifestations • Redness, edema, exudate and lymph node enlargement in throat Treatment and control: • Antibiotics important for children to lessen chance of complications = poststreptococcal diseases (rheumatic fever and glomerulonephritis) • Control by preventing contact with contaminated materials or infected individuals 10 11/17/2023 Streptococcus pyogenes → Pharyngitis → Post-streptococcal diseases (in some cases; e.g. rheumatic fever, glomerulonephritis, etc) • In rheumatic fever and acute glomerulonephritis, it is not the organism itself that causes the symptoms of disease but the immune response to the presence of the organism=Immunopathogenesis Rheumatic fever • Antibodies against the M protein of S. pyogenes cross-react with joint, heart, and brain tissue • Inflammation results in the arthritis, carditis, etc (characteristic findings in this disease) PostStreptococcal GlomeruloNephritis (PSGN) • The disease is immunological; sequela of pharyngitis or skin infections caused by certain strains of Streptococcus pyogenes; mechanism not fully determined • The body responds to the streptococcal infection by forming immune complexes containing the streptococcal antigen with a human antibody • Damage probably results from the deposition of antigen-antibody complexes, possibly involving the streptococcal M protein, in the glomeruli How do Pathogens Cause an Infectious Disease? ADHERENCE • Capsule • Fimbriae • Biofilm • Flagella • Specific proteins TOXICITY • Endotoxin (LPS) • Exotoxins (released) • Injected toxins IMMUNOPATHOGENESIS EXPOSURE • Polluted air • Splashes, Punctures • Wounds, burns • Fomites, Vectors • Contact/Animals • Mother ‐ Son • Fecal‐Oral/Food • Sexual “INVASION” DISSEMINATION • Lytic enzymes • Collagenase • Hyaluronidase • Proteases • Nucleases INTERACTION WITH IMMUNE SYSTEM • Inflammation • Autoinmune response • Immune disorders immunopathology 11 11/17/2023 Understanding Host-Pathogen Interactions Vibrio cholerae Neisseria meningitidis Chlamydia trachomatis Intracellular Pathogens • Extracellular pathogens: replicate and/or persist on mucosal surfaces or in tissues outside host cells and may rapidly spread or establish an infection • Intracellular pathogens: their cycle in the host includes residence and/or replication inside host cells Understanding Host-Pathogen Interactions-Cont “Noisy” parasite “Silent” parasite Flagella Fimbriae Exoenzymes • No release of host-damaging agents • Not triggering systemic alarms • It has the time to reach the target cell • Intracellular multiplication • Many factors triggering the immune response • Chronic infection • Clearance of the microbe OM Exopolysaccharide Exotoxins 12 11/17/2023 Mechanisms of Bacterial Gene Transfer Very Important for TOXINS, antibiotic resistance etc. Contribution of Horizontal Acquisition of Mobile Genetic Elements to the Evolution of Escherichia coli Pathotypes Plasmids Bacteriophage Pathogeniciy Islands (Transposon) ETEC UPEC EPEC EIEC EHEC • Uptake of mobile genetic elements by commensal E. coli → Acquisition of specific virulence attributes (E. coli pathotype) → Increased ability to adapt to new niches and to cause a broad spectrum of disease (e.g. enteric/diarrhoeal disease, urinary tract infections (UTIs) and sepsis/meningitis) 13 11/17/2023 Lysogenic Conversion Corynebacterium diphteriae toxin Bacteriophage: Lysogenic Conversion Examples of virulence factors carried by phages 14