Principles of Infectious Disease PDF

PRINCIPLES OF INFECTIOUS DISEASE • Colonization refers to microbe establishing itself on body surface or mucosal layer. • Term infection can be used to refer to colonization by a pathogen ! ! Can be subclinical: no or mild symptoms Infectious disease or illness = noticeable impairment in a person !...

PRINCIPLES OF INFECTIOUS DISEASE • Colonization refers to microbe establishing itself on body surface or mucosal layer. • Term infection can be used to refer to colonization by a pathogen ! ! Can be subclinical: no or mild symptoms Infectious disease or illness = noticeable impairment in a person ! Symptoms are subjective effects experienced by patient (e.g., pain and nausea) ! Signs are objective evidence (e.g., rash, pus formation, swelling) • Initial infection is “primary infection” ! Damage can predispose individual to “secondary infections” (e.g., measles impairs immune system leading to pneumonia by other microbes) PATHOGENICITY • Primary pathogen is microbe or virus that causes disease in otherwise healthy individual ! Diseases such as plague, malaria, measles, influenza, diphtheria, tetanus, tuberculosis, etc. • Opportunistic pathogen (opportunist) causes disease only when body’s innate or adaptive defenses are compromised or when introduced into unusual location ! Can be members of normal microbiota or common in environment (e.g., Pseudomonas) • Virulence refers to degree of pathogenicity • Virulence factors are traits that allow microorganism to cause disease (e.g. toxins a microbe produces) CHARACTERISTICS OF INFECTIOUS DISEASE • Infectious dose is number of microbes necessary to establish infection – an experimentally derived number ! ! ! ! ID50 is number of microbes sufficient to cause infection in 50% of those people/animals to which the microbes are administered Shigellosis results from ~10–100 ingested Shigella bacteria ! Shigella is a variant of E. coli Salmonellosis requires that as many as 106 Salmonella enterica bacteria be ingested Difference partially reflects ability to survive stomach acid – Shigella is more acid resistant than Salmonella • Communicable or contagious diseases easily spread when they have a low infectious dose CHARACTERISTICS OF INFECTIOUS DISEASE Course of Infectious Disease • Incubation period: time between exposure and onset of symptoms ! ! ! Varies considerably: few days for common cold to even years for Hansen’s disease (leprosy) Depends on growth rate, host’s condition, infectious dose May be preceded by prodromal phase (vague symptoms) • Convalescence: recuperation, recovery from disease • Carriers may harbor and spread infectious agent for long periods of time in absence of signs or symptoms ! Example: typhoid fever (Typhoid Mary) CHARACTERISTICS OF INFECTIOUS DISEASE Course of Infectious Disease Incubation period Illness Convalescence ACUTE. Illness is short term. Symptoms develop quickly but last short time. The pathogen is eliminated by the host defenses. Person is usually immune to reinfection. Incubation period Illness (long lasting) CHRONIC. Symptoms develop slowly and Illness persists over a long time period. Incubation period Illness Convalescence Latency Recurrence LATENT. Infectious agent never completely eliminated, may exist in host tissue without causing symptoms. Illness may recur if immunity weakens. Copyright © The McGraw-Hill Companies, Inc. CHARACTERISTICS OF INFECTIOUS DISEASE Duration of Symptoms • Acute infections: symptoms develop quickly, last a short time (e.g., strep throat) • Chronic infections: develop slowly, last for months or years (e.g., tuberculosis, HIV) • Latent infections: never completely eliminated; microbe exists in host tissues without causing symptoms – not contagious when latent. ! ! ! Decrease in immunity may allow reactivation Chicken pox (acute illness) results from varicella-zoster virus; immune response stops, but virus takes refuge in sensory nerves, can later produce viral particles resulting in shingles Tuberculosis, cold sores, genital herpes also examples CHARACTERISTICS OF INFECTIOUS DISEASE Distribution of Pathogen • Localized infection: microbe limited to small area (e.g., boil caused by Staphylococcus aureus) • Systemic infection: agent disseminated throughout body (e.g., measles) • Suffix -emia means “in the blood” ! ! ! ! Bacteremia: bacteria circulating in blood ! Not necessarily a disease state (e.g., can occur transiently following vigorous tooth brushing) Septicemia or sepsis: acute, life-threatening illness caused by infectious agents or products in bloodstream Toxemia: toxins circulating in bloodstream Viremia: viruses circulating in bloodstream THERE ARE 10 TIMES MORE MICROBIAL CELLS IN YOUR BODY THAN HUMAN CELLS IN YOUR BODY…! ! …SO WHY AREN’T YOU SICK ALL THE TIME? 3 closely related microbes Harmless commensal of humans. 4,643,538 bp E. coli strain HS (O9) E. coli strain EDL933 (O157:H7) Pathogenic - causes fever and diarrhea, produces toxins, hemolytic uremic syndrome Pathogenic - causes fever and diarrhea, produces toxins Salmonella enterica strain 14028s 5,547,323 bp 4,870,265 bp 3 Strain HS Strain EDL933 Strain HS Strain EDL933 Strain HS Strain EDL933 3 closely related microbes Harmless commensal of humans. E. coli strain HS Pathogenic (causes fever and diarrhea, does not invade host tissues E. coli strain EDL933 (O157:H7) Salmonella enterica Causes severe intestinal disease and can spread systemically. 8 Evolu&on(of(enteric(pathogens(has(been(driven(in( large(part(by(acquisi&on(of(new(genes( Pathogenic(4(Can( invade(animal(cells( and(survive(within( macrophages.! Salmonella! Harmless(4(has(co4 evolved(with(humans( and(is(part(of( commensal(flora.! DNA! Enteric(progenitor! E.(Coli(and(Salmonella(diverged( from(their(last(common(ancestor( about(100,000,000(ago.((Since( that(Hme(they(each(have( acquired(and(maintained(about( 2004300(new(blocks(of(genes.! E.(coli(HS! Pathogenic(4(causes( fever(and(diarrhea,( produces(toxins.((Does( not(invade(animal(cells.(! E.(Coli(EDL933! 9( Horizontal (lateral) gene transfer plays a major role in prokaryotic evolution NOTE: “Horizontal” and “lateral” gene transfer are synonomous! Drug resistant, lives in leaf compost, eats dead mango leafs Lineage 1 Pathogenic (causes fever and diarrhea, drug resistant, produces toxins DNA Progenitor Harmless bacteria, lives in apes gut without causing a problem Lineage 2 Still harmless but has co-evolved with humans. = transduction (phage) = conjugation (mobile plasmids) = transformation / DNA uptake Lineage 3 10 Large(blocks(of(newly(acquired(genes(are(called( “genomic!islands”!or,(if(they(are(involved(in(disease,( “pathogenicity!islands”! Genomic! islands! Salmonella! DNA! Ancient(enteric( progenitor! E.(coli(HS! 11( How are new genes acquired? “Competence/Transformation” Some bacteria have energy driven protein complexes in their membrane that actively pump naked DNA from the environment into their cytoplasm. Usually the bacteria wants the DNA as food but sometimes this DNA is incorporated into the genome. “Conjugation” (Jumping plasmids) Some plasmids encode a genes that help them jump from cell to cell. This allows the plasmid to find new hosts. These plasmids are often packed with genes to promote survival of their hosts including drug resistance genes, phage resistance genes, and immune evasion genes. Here it’s not the host that is taking up the DNA but rather the plasmid DNA that is forcing itself into a new host. Phage – “Transduction” Phage (bacteriophage) are viruses that infect bacteria. Before they kill a bacterial cell they pack their virions with copies of their own phage DNA. However sometimes, by accident, a few virions will package a fragment of DNA from their bacterial host. When those virions go and infect the next cell they don’t kill the new cell because they aren’t delivering viral DNA – they’re delivering a segment of DNA from the previously infected cell. That DNA can get incorporated into the genome. How are new genes acquired? Phage encoded genes (lysogeny) Some phage don’t kill their hosts right away but instead choose to integrate their own DNA into the host DNA. This is called “lysogeny”. Some strains of E. coli carry DNA from several different phages scattered around their genomes. The DNA of these latent viruses (“prophages”) stay in the bacterial cell as long as conditions are good. When the host cell gets stressed or damaged the viral DNA is activated and the virus makes more copies of itself. It then kills its host cell – releasing dozens of new viral particles that go and infect more cells. Prophage benefit by keeping the host cell alive – in fact they often encode extra genes to kill off other phages. Sometimes prophages encode toxins or other factors critical for virulence. Phage Encoded Genes Can Alter the Evolutionary Trajectory of a Species The case of cholera Vibrio cholerae is a Gram-negative bacteria somewhat related to E. coli and Salmonella. It is the cause of the disease called cholera. V. cholerae colonizes the small intestine - symptoms often start with stomach cramps and vomiting followed by diarrhea, which may progress to fluid losses of up to 1 liter per hour. These losses result in severe fluid volume depletion and metabolic acidosis, which may lead to circulatory collapse and death. Vibrio cholerae encodes two important disease causing factors: TCP (toxin co-regulated pilus) operon: An operon encoding a pilus that holds the Vibrio cells together and helps it colonize the intestine. The TCP operon is encoded on a pathogenicity island. Cholera toxin (CTX): A toxin secreted from the bacteria that disrupts ion flow in epithelial cells of the intestine. Cholera toxin is encoded on the genome of a phage called CTXφ. CTXφ actually used the TCP as its receptor to enter the bacterial cell! Steps in the evolution of Vibrio cholerae TCP( or Acquire-TCP-island(mechanism-unknown)- DNA( TCP containing Vibrio (can colonize the intestine) Non pathogenic Vibrio TCP CTXφ( Lysogeny with phage CTXφ - this phage infects the cell by binding the TCP Fully virulent Vibrio (can colonize and cause diarrhea) Cholera toxin 16 ESTABLISHING INFECTION Adherence • First-line defense sweep microbes away • Adhesion does not always lead to disease Pili with adhesins Bacterial cell • Adhesins attach to host cell receptor Often located at tips of pili (also called fimbriae) ! Can be component of capsules or various cell wall proteins ! Binding highly specific; exploits host cell receptor ! Dictates type of cell/tissue infected ! Receptor Host cell Copyright © The McGraw-Hill Companies, Inc. ESTABLISHING INFECTION Colonization • Microbe must multiply to colonize ! Growth in biofilms • Must deal with host immunity ! ! ! Siderophores – iron binding Avoidance of secretory IgA ! Rapid pili turnover, antigenic variations, IgA proteases Compete with normal microbiota, tolerate antimicrobial molecules made by other microbes Add#image# Source:#Rachel#Sammons,#PhD# University#of#Birmingham,#Dept.#of#Biomaterials# MECHANISMS OF BACTERIAL PATHOGENESIS Several general patterns • Colonize mucous membranes, produce toxins ! E.g., Vibrio cholerae, E. coli O157:H7, Corynebacterium diphtheriae • Invade host tissues, produce toxins ! E.g., Shigella dysenteriae, Clostridium tetani, Salmonella enterica (food poisoning) , Staphylococcus aureus • Invade host tissues, avoid defenses ! E.g., Mycobacterium tuberculosis, Yersinia pestis (plague), Salmonella typhi (typhoid fever), Listeria • Produce toxins that are ingested, not an infection but poisoning ! E.g., Clostridium botulinum, Staphylococcus aureus PENETRATING THE SKIN • By crossing epithelial barrier, microbes can multiply in nutrientrich environment without competition Staph wound infection • Difficult barrier to penetrate; bacteria rely on skin injuries ! ! ! Staphylococcus aureus enters via cut or wound Yersinia pestis is injected by fleas Borellia (Lyme disease) is injected by ticks. Tick bite (www.cdc.gov) SECRETION SYSTEMS AND EFFECTORS Delivering Toxins (“effector proteins”) directly into Host Cells • Secretion systems in Gramnegatives ! ! ! ! Several types discovered; some can inject molecules other than proteins Type III secretion system (injectisome) Effector proteins induce change in host cell ! E.g. Altering cytoskeleton structure Can induce uptake of bacterial cells Effector Bacterial cytoplasm Bacterial periplasm Host cell Courtesy of Chihiro Sasakawa, University of Tokyo Copyright © The McGraw-Hill Companies, Inc. SECRETION SYSTEMS AND EFFECTORS The LEE pathogenicity island of pathogenic E. coli strains ecnodes a type-3 secretion system and several effector proteins. These proteins allow E. coli to stick tightly to host cells and causes fluid leakage. E. COLI MAKING ACTIN “PEDESTALS” ON HOST CELLS Electron micrograph by Dr. Manfred Rohde, HZI Braunschweig PENETRATING THE MUCOUS MEMBRANE TWO MECHANISMS FOR ENTRY VIA Ruffle THIS ROUTE M-cell surface Directed Uptake by Cells • Pathogen induces non-phagocytic cells to engulf via endocytosis ! ! Salmonella uses type III secretion system to cause actin molecules to rearrange, yield membrane ruffling Enclose bacteria for uptake Bacterial cell 10 µm Courtesy#of#Mark#A.#Jepson,#from#Trends#in#Microbiology#v6,#issue#1:359J365,#1#Sept#1998,#"Studying# M#cells#and#their#role#in#infecMon";#M.A.#Jepson#and#M.A.#Clark,#Elsevier#Press# Copyright © The McGraw-Hill Companies, Inc. PENETRATING THE MUCOUS MEMBRANE 3 Within an epithelial cell, Shigella cells cause the host actin to polymerize. This propels the bacterial cell, sometimes with enough force to push it into the next cell. Exploiting Antigen-Sampling Processes • MALT samples material Lumen of the intestine Mucous membrane Shigella • Some pathogens use M cells to cross intestinal barrier, most are destroyed by macrophages M cell • Some microbes avoid or exploit macrophages ! E.g. Shigella • Some invade by alveolar (lung) macrophages ! Tissue Macrophages 2 Shigella cells attach to the base of the epithelial cells and induce these cells to engulf them. 1 Macrophages in the Peyer’s patches engulf material that passes through M cells. Shigella cells survive and replicate, causing the phagocytes to undergo apoptosis. E.g., Mycobacterium tuberculosis produces surface proteins, directs uptake, avoids macrophage activation Copyright © The McGraw-Hill Companies, Inc. AVOIDING HOST DEFENSES Hiding Within a Host Cell • Allows avoidance of complement proteins, phagocytes, and antibodies ! ! Shigella directs transfer from intestinal epithelial cell to adjacent cells by causing host cell actin polymerization Listeria monocytogenes (meningitis) similar Avoiding Killing by Complement System (MAC) • Bacteria that use this mechanism - serum resistant ! Neisseria gonorrhoeae hijacks host system, binds complement regulatory proteins to avoid activation of membrane attack complex AVOIDING HOST DEFENSES Avoiding Destruction by Phagocytes 1 Prevent encounters with phagocytes • C5a peptidase • Cytolytic toxins C5a Microbes 2 Avoid recognition & attachment • Capsules • M protein • Fc receptors Pseudopod C3b Phagocyte Lysosomes Phagosome C3b Phagolysosome C3b receptors on phagocyte Digestive enzymes 3 Survive within phagocytes • Escape from the phagosome • Prevent phagosomelysosome fusion • Survive within the phagosome Copyright © The McGraw-Hill Companies, Inc. AVOIDING HOST DEFENSES Avoiding Destruction by Phagocytes 1. Preventing Encounters with Phagocytes ! ! C5a peptidase: degrades chemoattractant C5a Membrane-damaging toxins: kill phagocytes, other cells by forming pores in membranes ! E.g., Streptococcus. pyogenes makes C5a peptidase & streptolysin O 1 Prevent encounters with phagocytes • C5a peptidase • Cytolytic toxins C5a Microbes C3b Phagocyte Lysosomes Pseudopod C3b receptors on phagocyte C3b Phagosome Phagolysosome Digestive enzymes Copyright © The McGraw-Hill Companies, Inc. AVOIDING HOST DEFENCES Avoiding Destruction by Phagocytes 2. Avoiding Recognition and Attachment ! ! ! Capsules: interfere with opsonization; some bind host’s regulatory proteins that inactivate C3b (E.g., Streptococcus pneumoniae) M protein: cell wall of S. pyogenes binds regulatory protein that inactivates C3b Fc receptors: bind Fc region of antibodies, interfere with opsonization ! E.g., Staphylococcus aureus, Streptococcus pyogenes Microbes 2 Avoid recognition and attachment • Capsules • M protein • Fc receptors Pseudopod C3b receptors on phagocyte C3b Phagocyte Lysosomes C3b Phagosome Phagolysosome Digestive enzymes Copyright © The McGraw-Hill Companies, Inc. AVOIDING HOST DEFENCES Avoiding Destruction by Phagocytes 2. Avoiding Recognition and Attachment ! ! ! Capsules: interfere with opsonization; some bind host’s regulatory proteins that inactivate C3b (E.g., Streptococcus pneumoniae) M protein: cell wall of S. pyogenes binds regulatory protein that inactivates C3b Fc receptors: bind Fc region of antibodies ! E.g., Staphylococcus aureus, Streptococcus pyogenes Bacterium Fab region of the antibody (binds to antigen) Antibody (a) Fc receptor on bacterium (binds the Fc region of an antibody) Fc region of the antibody (phagocytes recognize and bind this region as an initial step in phagocytosis) (b) Copyright © The McGraw-Hill Companies, Inc. AVOIDING HOST DEFENCES Avoiding Destruction by Phagocytes 3. Surviving Within Phagocytes ! Escape from phagosome: prior to lysis with lysosomes ! ! Prevent phagosome-lysosome fusion: avoid destruction ! ! Shigella species lyse phagosome prior to fusion with lysosomes Salmonella sense ingestion by macrophage, blocks fusion process Survive within phagolysosome: ! Coxiella burnetii can withstand; delays fusion, allows time to equip itself to survive Microbes C3b Phagocyte Lysosomes Pseudopod C3b Phagosome Phagolysosome C3b receptors on phagocyte 3 Survive within phagocytes • Escape from the phagosome • Prevent phagosomelysosome fusion • Survive within the phagosome Digestive enzymes Copyright © The McGraw-Hill Companies, Inc. AVOIDING HOST DEFENSES Avoiding Antibodies • IgA protease: cleaves IgA, found in mucus, secretions ! Neisseria gonorrhoeae and others produce • Antigenic variation: alter structure of surface antigens, stay ahead of antibody production ! Neisseria gonorrhoeae varies antigenic structure of pili • Mimicking host molecules: cover surface with molecules similar to those found in host cell, appear to be “self ” ! Streptococcus pyogenes form capsule from hyaluronic acid, a polysaccharide found in tissues DAMAGE TO THE HOST • Direct or indirect effects ! ! Direct (e.g., toxins or secreted effectors) Indirect (e.g., immune response) • Damage may help pathogen to exit and spread • Damage may allow microbe to better extract nutrients • Not all pathogens are well adapted to cause disease in every situation and in some cases it appears that their ability to cause disease in some hosts is not part of their true lifecycle. ! Legionella uses a type 4 secretion system to colonize and kill amoebae in its natural environment (water). However this system and its effectors also allow Legionella to survive within macrophages. BACTERIAL TOXINS • Protein toxins (exotoxins) produced by microbes usually bind to cell surface or enter the cell to perturb cellular function. • Toxin can enter host cells via endocytosis or the microbe can inject them directly into the host cell in which case they are more typically called “effectors”, not exotoxins. Cholera toxin – O’Neal et al. (2004) Biochemistry 43: 3772-3782 EXOTOXINS • Proteins with specific damaging effects ! Often major cause of damage during infection • Secreted by bacteria or leak into tissue following bacterial lysis ! ! ! Pathogen must usually colonize tissue to produce enough toxin Foodborne intoxication results from consumption – produced in food Destroyed by heating; most exotoxins heat-sensitive • Can act locally or systemically • Proteins, so immune system can generate neutralizing antibodies ! ! ! Many toxins fatal before immune response mounted Vaccines therefore critical - toxoids are inactivated toxin Antitoxin is suspension of neutralizing antibodies EXOTOXINS Exotoxins grouped into categories based on tissues they affect • Neurotoxins damage nervous system ! E.g. Clostridium botulinum – Flaccid paralysis - Interfere or block neurotransmitter release, thus preventing signal to muscles • Enterotoxins cause intestinal disturbance ! E.g. Cholera– diarrheal disease – affects regulatory protein in intestinal cells resulting in continuous electrolyte and water secretion • Cytotoxins damage variety of cell types ! E.g. Shiga toxin – produced by some strains of E. coli O157:H7 and Shigella – inactivates the eukaryotic ribosome 60S subunit to block protein synthesis. Can cause hemolytic uremic syndrome (HUS). EXOTOXINS • Neurotoxins: damage nervous system • Enterotoxins: cause intestinal disturbance • Cytotoxins: damage variety of cell types (continued) Copyright © The McGraw-Hill Companies, Inc. EXOTOXINS Categories for general structure and mechanism A-B Toxins • A-B toxins have two parts ! ! A subunit is toxic, usually an enzyme B subunit binds to cell, dictates delivery to cell type • Structure allows novel approaches for vaccines and therapies ! Can use B subunit to deliver medically useful proteins to specific cell type Active subunit Binding subunit A B Binding site 1 B subunit binds to a specific molecule on the host cell. 2 Toxin is taken up by endocytosis. 3 Toxin subunits separate allowing the A subunit to enter the cytoplasm. Copyright © The McGraw-Hill Companies, Inc.. BACTERIAL SECRETED EXOTOXINS • Cholera toxin is a classic AB toxin. • It is imported into the cell via “retrograde transport” to the Golgi apparatus - then the endoplasmic reticulum. At this point it is exported to the cytoplasm. • There, the A subunit of the toxin activates a host enzyme (adenlyate cyclase) to generate cyclic AMP. This ultimately opens a chloride ion channel in the membrane causing leakage of water and ions out of the cell. From: Viswanathan, et al., Nature Reviews Microbiology (2009) Volume 7, pages 110-119 Clostridial toxins • Botulism toxin – Produced by Clostridium botulinum – On a per weight basis it is the most potent biological neurotoxin known – A protease that inhibits the release of acetylcholine from excitory neurons to muscle cells. – Muscles fail to work causing “flaccid paralysis” • Tetanus toxin (a.k.a Tetanospasmin) – Produced by Clostridium tetani – the second most potent biological neurotoxin known – Binds inhibitory interneurons in the spinal cord and prevents release of inhibitory neurotransmitters necessary for muscle relaxation. – Causes “spastic paralysis” – Tetanus is also called “lockjaw” Botulism vs. Tetanus Flaccid paralysis - loss of muscle contraction due to botulism Spastic paralysis - excessive muscle contraction due to tetanus A cow dying from botulism. A soldier dying from tetanus. (From: “Botulism in cattle associated with poultry litter” by Seamus Kennedy, Veterinary Record 2011;168:638-639) (Painting by Charles Bell (1808) - in the Royal College of Surgeons, Edinburgh.) Botulinum toxin has medical uses Dolly Parton The Queen of Country Music (born 1946, picture from 2009) Botox was first used to treat strabismus (crossed eyes) and was later adapted to be a treatment for a variety of conditions involving muscle spasms (back pain, overactive bladder, prostate issues). More recently it has been used to treat excessive sweating. The effects of the toxin last 3 - 6 months. EXOTOXINS Categories for general structure and mechanism Membrane-Damaging Toxins • Cytotoxins that disrupt plasma membranes, lyse cells ! Hemolysins lyse red blood cells • Some insert into membranes, form pores ! E.g., Streptolysin O from S. pyogenes • Phospholipases hydrolyze phospholipids of membrane ! E.g., -toxin of Clostridium perfringens (gas gangrene) Pore forming toxin from Streptococcus mitis EXOTOXINS Categories for general structure and mechanism Superantigens Antigen-presenting cell Antigen-presenting cell MHC class II molecule Peptide recognized by T-cell receptor Peptide not recognized by T-cell receptor Superantigen T-cell receptor Helper T cell Helper T cell Copyright © The McGraw-Hill Companies, Inc.. a Helper T cell that recognizes peptide is activated; it proliferates and releases cytokines. b Helper T cell that does not recognize peptide is activated because of superantigen; it proliferates and releases cytokines. Adapted'from'Arousing)the)Fury)of)the)Immune)System,'1998'Howard'Hughes'Medical'Ins<tute.' EXOTOXINS Categories for general structure and mechanism Superantigens Antigen-presenting cell • Toxic effect is from massive cytokine release from TH ! ! Antigen stimulates 1 in10,000 TH cells Superantigen can stimulate as much as 1 in 5 • Leads to fever, nausea, diarrhea and vomiting ! ! Peptide not recognized by T-cell receptor Organ failure, circulatory collapse, even death Immune suppression and autoimmunity • Include toxic shock syndrome toxin (TSST) and several by Staphylococcus aureus, Streptococcus pyogenes Superantigen Helper T cell b Helper T cell that does not recognize peptide is activated because of superantigen; it proliferates and releases cytokines. Adapted'from'Arousing)the)Fury)of)the)Immune)System,'1998'Howard'Hughes'Medical'Ins<tute.' Copyright © The McGraw-Hill Companies, Inc.. EXOTOXINS Other Toxic Proteins • Some damaging proteins are not A-B toxins, membrane-damaging toxins, or superantigens • E.g., Exfoliatin from Staphylococcus aureus causes scalded skin syndrome ! ! Destroys material that binds together skin layers Bacteria may be growing in small lesion, but toxin spreads systemically • Various hydrolytic enzymes including proteases, lipases, and collagenases break down connective tissue ! Destroy tissues, some help bacteria spread ENDOTOXINS • Endotoxin is lipopolysaccharide (LPS) • Name implies location “inside cells” – not true - outer layer of gram-negative outer membrane. • However the “toxin” is part of the cell rather than secreted outside of the cell. • The toxic component is the lipid A portion. ENDOTOXINS • Lipid A triggers inflammatory response ! ! When localized, response helps clear infection When systemic, causes widespread response: septic or endotoxic shock • Lipid A typically released following cell lysis ! Phagocytosis, MAC formation, certain antibiotics • Activates innate and adaptive defenses by variety of mechanisms ! Toll-like receptors (monocytes, macrophages, others) induce cytokine production; also T-independent antigen response of B-cells at high concentrations • Heat-stable; autoclaving does not destroy DAMAGING EFFECTS OF IMMUNE RESPONSE • Damage Associated with Inflammation ! Phagocytic cells can release enzymes and toxic products • Damage Associated with Adaptive Immunity ! ! Immune complexes: antigen-antibody complexes can form, settle in kidneys and joints, and activate complement system leading to inflammation ! E.g., acute glomerulonephritis following skin, throat infections of S. pyogenes Cross-reactive antibodies: may bind to body’s own tissues, promote autoimmune response ! E.g., acute rheumatic fever following S. pyogenes infection TOXINS Exotoxins' Protein'factors' secreted'outside' bacterial'cells'that' target'specific' host'proteins'or' pathways.' Effectors' Proteins'injected' directly'into'host' cells'by'complex' secre<on'systems' (e.g.)Type)3) secre8on).' Endotoxins' Components'of' bacterial'cells'that' are'recognized'by' the'innate' immune'system.' ' DAMAGE TO THE HOST Comparison of Exotoxins and Endotoxin