Humans and Microbes Since Leeuwenhoek’s discovery of microorganisms in 17 th century led people to...

Humans and Microbes

• Since Leeuwenhoek’s discovery of microorganisms in 17th century led people to suspect they might cause diseases, most research and funding has gone towards understanding pathogens.

• Robert Koch (1876) offered proof of what is now considered germ theory of disease; showed Bacillus anthracis causes anthrax

• Today, we now know that most of the bacteria we associate with are not pathogens, and many are critical for our health.

Bacteria Are Ubiquitous

We contact numerous microorganisms daily• Breathe in, ingest, pick up on skin• Vast majority do not make us sick, or cause infections• Some colonize body surfaces; or slough off with dead

epithelial cells• Most that are swallowed die in stomach or are

eliminated in feces• Relatively few are pathogens that

cause damage

Microbes, Health, and Disease

Most microbes are harmless• Many are beneficial• Normal microbiota (normal flora) are organisms that

routinely reside on body’s surfaces• Relationship is a balance, and some can cause disease

under certain conditions-- opportunistic infections

• Weaknesses in innate or adaptive defenses can leave individuals vulnerable to invasion

– malnutrition, cancer, AIDS or other disease, surgery, wounds, genetic defects, alcohol or drug abuse, and immunosuppressive therapy

The Anatomical Barriers as Ecosystems

Skin, mucous membranes are barriers• Also host complex ecosystem of microorganisms

• Example of symbiosis, or “living together”

• Mutualism: both partners benefit

– In large intestine, bacteria synthesize vitamin K and B’s, which host can absorb; bacteria are supplied with warmth, energy sources

• Commensalism: one partner benefits, other is unharmed

– Many microbes living on skin neither harmful nor helpful, but obtain food and necessities from host

• Parasitism/pathogenicity: one organism benefits at expense of other

– pathogens and parasites

Human commensals and mutalistic microbes

Resident microbiota inhabit sites for extended periods

Transient microbiota inhabit temporarily

• Important to human health• Relatively little is known• Human Microbiome

Project aimed at studyinghttp://en.wikipedia.org/wiki/

Human_Microbiome_Project

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.

NoseStaphylococcusCorynebacterium

MouthStreptococcusFusobacteriumActinomycesLeptotrichiaVeillonella

SkinStaphylococcusPropionibacterium

Large intestineBacteroidesEscherichiaProteusKlebsiellaLactobacillusStreptococcusCandidaClostridiumPseudomonasEnterococcus

UrethraStreptococcusMycobacteriumEscherichiaBacteroides

VaginaLactobacillus

ThroatStreptococcusMoraxellaCorynebacteriumHaemophilusNeisseriaMycoplasma

The Normal Microbiota

The Protective Role of the Normal Microbiota• Significant contribution is protection against pathogens

• Covering of binding sites prevents attachment

• Consumption of available nutrients

• Production of compounds toxic to other bacteria

• When killed or suppressed (e.g., during antibiotic treatment), pathogens may colonize, cause disease

• Some antibiotics inhibit Lactobacillus (predominate vagina of mature females, suppress growth of Candida albicans); results in vulvovaginal candidiasis

• Oral antibiotics can inhibit intestinal microbiota, allow overgrowth of toxin-producing Clostridium difficile


The Protective Role of the Normal Microbiota (continued…)• Stimulation of adaptive immune system-CRITICAL

• Mice reared in microbe-free environment have greatly underdeveloped mucosal-associated lymphoid tissue (MALT); antibodies against normal microbiota bind to pathogens as well

• Important in development of oral tolerance• Immune system learns to lessen response to many

microbes that routinely inhabit gut as well as food

– Basis of hygiene hypothesis, which proposes insufficient exposure to microbes can lead to allergies


The Dynamic Nature of the Normal Microbiota• Healthy human fetus sterile until just before birth

• Exposure during birth and through contact with people, food, and environment lead to microbes becoming established on

• find that families often share similar microbial populations, and important gut microbes are acquired from the mother

• Critical for proper gut development—first colonizers from mom

• Composition of normal microbiota is dynamic• Changes occur over the life of a person. Younger people tend

to have different compositions than older people. • Responses to physiological changes (e.g., hormonal changes),

activities and diet (e.g., consuming food)

Microbiota alter the chemistry of your gutRuth Ley, Peter Turnbaugh, Jeffrey Gordon and colleagues at Washington University link between the microbiota and obesity by studying a special strain-Obese mice had 50% fewer Bacteroidetes and 50% more Firmicutes in their bowels than their lean counterparts.

The link between the microbiota and obesity became even clearer when Gordon looked at a special strain of mice with no microbiota of their own.

When the team transplanted the microbiota from fat and lean mice into the germ-free strains, those colonized by microbiota from fat donors packed on far more weight than those paired with lean donors.

Comparisons of microbiota of fat and lean mice at a genetic level: --fat mice showed much stronger activation of genes for carbohydrate-destroying enzymes, which break down otherwise indigestible starches and sugars. As a result, these mice were extracting more energy from their food than their lean cousins.

The bacteria were also manipulating the animals’ own genes, --triggered biochemical pathways that store fats in the liver and muscles, rather than metabolize them.

Fat Bacteria Thin bacteriaMore Firmicutes More Bacteroidetes

--break down carbohydrates better

--trigger biochemical pathways to store fat

Principles of Infectious Disease

Key Terms.

Colonization--microbe establishes on body surface internal or external

• Infection usually refers to pathogen• subclinical: no or mild symptoms

• Infectious disease shows noticeable impairment

– 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 developing a secondary infection (e.g., respiratory illness impairing mucociliary escalator)

Fig. 24.1

Oral cavity containingtongue and teethDental cariesPeriodontal disease

Parotid salivary glandMumps

EsophagusEsophagitis

LiverHepatitis

Gallbladder

Small intestineEnteritisDuodenal ulcer

AppendixAppendicitis

Epithelial cells

Microvilli

CapillariesLymphatic vessel Nerve fibers

Smoothmuscle

Lower digestive tractUpper digestive tract

Absorbs some waterand minerals;prepares waste

Largeintestine

Site of most digestionand absorptionof nutrients

Smallintestine

Stores bile untilneeded

Gallbladder

Produces bile to assistin fat digestion

Liver

Secretes digestiveenzymes

Pancreas

Stores food; mechanicaldigestion; breaks downsome proteins

Stomach

Transports food tostomach

Esophagus

Secrete salivaSalivaryglands

Obtains andprocesses food

Oral cavity

FunctionOrgan

Villus

Foodmolecules

RectumAnus

Large intestineDysenteryColitis

PancreasPancreatitis

StomachGastritisGastric ulcer

Salivary glands


Clostridium difficile• Gr+, rod, spore forming, obligate anaerobe.

Produces cytotoxins• Member of gut microbiome, in low

numbers, --It most commonly occurs in patients

in hospitals on antibiotic therapy.

• Can also be acquiredDifficult to kill with disinfectants (spores)

• Mild to severe symptoms including colitis (inflammation of the colon).

• Treatment: Often stopping the antibiotics, if possible, alleviates the problem.

This is a secondary infection

Principles of Infectious Disease

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; E. coli; C. difficile)

• Virulence refers to degree of pathogenicity• Virulence factors are traits that allow microorganism

to cause disease

16.3. Principles of Infectious Disease

Characteristics of Infectious Disease• Communicable or contagious diseases easily spread• Infectious dose is number of microbes necessary to

establish infection• ID50 is number of cells that infects 50% of population

• Shigellosis results from ~10–100 ingested Shigella

• Salmonellosis results from as many as 106 ingested Salmonella enterica serotype Enteritidis

– Difference partially reflects ability to survive stomach acid

Course of Infectious Disease

• Incubation period: time between infection and onset• Illness: signs and symptoms of disease

• May be preceded by prodromal phase (vague symptoms)

• Convalescence: recuperation, recovery from disease• Carriers may harbor and spread infectious agent for

long periods of timeIncubation period ConvalescenceIllness

Acute. Illness is short term because the pathogen is eliminated by the hostdefenses; person is usually immune to reinfection.

Incubation period

Chronic. Illness persists over a long time period.

Incubation period

Latent. Illness may recur if immunity weakens.

Illness Convalescence Latency Recurrence

Illness (long lasting)

• Acute: • Rapid onset

• Short duration

• Persistent/chronic:• May develop slowly,

Continue foryears or lifetime

• May or may nothave symptoms

• Latent infections: never completely eliminated; may reactivate

Acute and Persistent Infections

State of VirusVirus disappearsafter disease ends.

State of VirusAfter initial infection with or without disease symptoms, infectious virus is released from host with no symptoms.

State of VirusAfter initial infection, virus is maintained in neurons in non-infectious state. Virusactivated to produce new disease symptoms.

Acute infection (influenza)

Chronic infection (hepatitis B)

Latent infection (cold sores)

YearsTimeDays

Time (days)

Days

(b)

(a)

(c)

Coldsores

ColdsoresVirus

activation

Non-infectious

Time Years

Release of virus

Infectious virionsInfluenza

Hepatitis B

Disease

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pea

ran

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f sy

mp

tom

s an

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viri

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These apply to both viruses and bacteria (Mycobacterium tuberculosis, M. leprae, S. typhae (Typhoid Mary))

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

• Toxemia: toxins circulating in bloodstream

• Viremia: viruses circulating in bloodstream

• Septicemia or sepsis: acute, life-threatening illness caused by infectious agents or products in bloodstream

The microorganism must be present in every case of the disease, but not in healthy hosts.

The microorganism must be grown in pure culture from diseased hosts.

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1

Copyright © The McGraw-Hill Companies, Inc. Permission required for reproduction or display.Koch’s Postulates

The same disease must be produced when a pure culture of the microorganism is introduced

The same microorganism must be recovered from the experimentally infected hosts.

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3

Koch’s Postulates continued

Establishing the Cause of Infectious Disease

Koch’s Postulates (continued…)• There are limitations

• Some organisms don’t grow in lab medium (e.g., causative agent of syphilis)

• Infected individuals do not always have symptoms (e.g., cholera, polio)

• Some diseases are polymicrobial (e.g., periodontal)

• Suitable animal hosts not always available for testing

Molecular Koch’s Postulates (kinda the same but using genes)

• Virulence factor gene or product found in pathogenic strains of organism

• Mutating gene to disrupt function should reduce virulence

• Reversion or replacement of gene should restore

Mechanisms of Pathogenesis—how do pathogens make us sick?

General patterns• Produce toxins that are ingested

• E.g., Clostridium botulinum, Staphylococcus aureus

• Colonize mucous membranes, produce toxins• E.g., Vibrio cholerae, E. coli O157:H7, Corynebacterium

diphtheriae

• Invade host tissues, avoid defenses– E.g., Mycobacterium tuberculosis, Yersinia pestis,

Salmonella enterica

• Invade host tissues, produce toxins• E.g., Shigella dysenteriae, Clostridium tetani

• Pathogens and hosts usually evolve toward balanced pathogenicity (e.g., myxoma virus and rabbits)

Establishing Infection


Receptor

Host cell

Bacterial cell

Pili withadhesins

Adherence• Adhesins attach to host cell receptor• Often on tips of pili (or fimbriae)• Can be component of capsules or various cell wall proteins• Binding highly specific; exploits host cell receptor

Colonization• Growth in biofilms• Siderophores-bind iron• Avoidance of secretory IgA• Rapid pili turnover-shed the IgA,

antigenic variations—avoid detection, IgA proteases—cut IgA

• Compete with normalmicrobiota, tolerate toxins

Invasion—Breaching the Anatomical Barriers

Penetrating the Skin• Difficult barrier to penetrate; bacteria rely on injuries

• Staphylococcus aureus enters via cut or wound; Yersinia pestis is injected by fleas, Lyme’s disease by tick bite

Penetrating Mucous Membranes-respiratory and gut tracts

• CommoneEntry point pathogens• Directed Uptake by Cells

• Pathogen induces cells to engulf via endocytosis

– Salmonella uses type III secretion system to injecteffector proteins; actin molecules rearrange, yieldmembrane ruffling

Courtesy of Mark A. Jepson, from Trends in Microbiology v6, issue 1:359-365, 1 Sept 1998, "Studying M cells and their role in infection"; M.A. Jepson and M.A. Clark, Elsevier Press

M-cell surfaceRuffle

Bacterial cell 10 µm


Borrelia burgdorferi(Lyme’s disease)

Delivering Effector Proteins to Host Cells• Secretion systems in Gram-negatives

• Several types discovered; some can inject molecules other than proteins

• Type III secretion system (injectisome)

– Effector proteins induce changes (e.g., altering of cell’scytoskeleton structure)

– Can induce uptakeof bacterial cells

Effector

Bacterialcytoplasm

Bacterialperiplasm

Host cell

Courtesy of Chihiro Sasakawa, University of Tokyo


Recall from CH 24 pathogensShigella, Salmonella, E. coli

Invasion—Penetrating mucus membranes

Salmonella attach to cells at the end of the small intestine

T3SS injects effectors and the cells are taken into cell in phagosomes.

These are transported across the cell and exported (exocytosis) where they are picked up by macrophage which are often destroyed. The infection remains localized. Inflammatory response results in fluid secretion.

Invasion—Penetrating mucus membranes

Exploiting Antigen-Sampling Processes of the Pyer’s patches (Mucosal-associated lymphoid tissue (MALT) and their M cells)

• Shigella survives phagocytosis bymacrophages; induces apoptosis; binds to base of mucosal epithelialcells and induces uptake. Salmonella typhae also.

• Some invade by alveolar(lung) macro-phages (e.g., Mycobacterium tuberculosis produces surfaceproteins, directs uptake, avoids macrophage activation)

Within an epithelial cell, Shigella cells causethe host actin to polymerize. This propelsthe bacterial cell, sometimes with enoughforce to push it into the next cell.

Mucousmembrane

Shigella cells attach to thebase of the epithelial cellsand induce these cells toengulf them.

Macrophages in the Peyer’s patches engulf material thatpasses through M cells. Shigella cells survive andreplicate, causing the phagocytes to undergo apoptosis.

Lumen of the intestine

Tissue

1

3

2

Macrophages

M cell

Shigella

Avoiding the 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) does the same

Avoiding Killing by Complement System Proteins• Serum resistant bacteria resist


Classical pathwayLectin pathwayAlternative pathway

Antibody

C3b binding to microbial invaders Mannose-binding lectin (MBL) binding to microbial invaders

Antibodies binding to microbial invaders

OpsonizationC3b binds to microbial cells,functioning as an opsonin.Inflammatory response

C3a and C5a induce changes thatcontribute to local vascular permeabilityand attract phagocytes.

C3 Splits C3

C3bC3a

C5

C5a C5b

C3b

C9C9C9

C5b

C6Lysis of foreign cellsC5b combines with complementproteins C6, C7, C8, and C9to form membrane attackcomplexes that insertinto cell membranes.

Combines with C3convertase to form anenzyme that splits C5

C3b MBL

C9C8

C7

Triggered by Triggered byTriggered by

Formation of C3 convertase

The complement system revisited-pathogens have ways to avoid binding to the C3b, deactivating C5a and C5b to avoid attracting phagocytes or being attacked by the membrane attack complex (MACs). The MAC attack.

MAC


Prevent encounterswith phagocytes• C5a peptidase• Cytolytic toxins

Avoid recognitionand attachment• Capsules• M protein• Fc receptors

C3b receptorson phagocyte

Pseudopod

Survive within phagocytes• Escape from the phagosome• Prevent phagosome-lysosome fusion

• Survive within the phagosome

Lysosomes

Digestiveenzymes

Phagolysosome

Phagocyte

Phagosome

C3b

Microbes

C5a

C3b

2

1

3

Avoiding Destruction by PhagocytesPreventing Encounters with Phagocytes

•C5a peptidase: degrades chemoattractant C5a

(Streptococcus pyogenes)•Membrane-damaging toxins: kill phagocytes,

S. pyogenes makes streptolysin O

Avoiding Destruction by Phagocytes

• Avoid 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

Streptococcus pyogenes binds

regulatory protein that inactivates C3b

--So does Neisseria gonorrhoerae.

Regulation of the complement system

Neisseria gonorrhoeae hijacks host system, binds complement regulatory proteins to avoid activation of membrane attack complex

Variableregion

Constantregion

(c)

Heavychain

Antigen-binding site

Lightchain

Fab region

Fc region

(a) (b)


Avoid recognition by antibodies

Fc receptors: bind Fc region of antibodiesStaphylococcus aureus, Streptococcus pyogenes

Opsonization by C3bInflammatory responseLysis of foreign cells

Complementsystem protein

Complement System Activation

Bacterium

Bacterium

Phagocyte

Opsonization

Neutralization

Virus

Toxin

Infected“self” cell

Antibody-Dependent CellularCytotoxicity (ADCC) Natural

killer cell

Cross-LinkingBacterium

Flagellum

Bacterium

Immobilization and Preventionof Adherence

Kills cell

What can happen when antibody binds antigen.

Fc receptor onbacterium (bindsthe Fc region ofan antibody)

Fab region of the antibody(binds to antigen)

(b)

Fc region of the antibody(phagocytes recognizeand bind this region asan initial step in phagocytosis)

(a)

Bacterium

Antibody


Fc receptors: bind Fc region of antibodiesStaphylococcus aureus, Streptococcus pyogenes

Avoiding Destruction by Phagocytes

• Surviving Within Phagocytes• Escape from phagosome: prior to fusion with lysosomes

Listeria monocytogenes -- pores in membrane;

Shigella species lyse phagosome• Prevent phagosome-lysosome fusion: Salmonella produce

protein that blocks fusion process• Survive within phagolysosome: few can survive destructive

environment.• Coxiella burnetii (Q fever)

Lysosomes

Digestiveenzymes

Phagolysosome

Phagocyte

Phagosome

Capsules and biofilms also help bacteria hide from the immune syetem

Avoiding Destruction by Phagocytes, continued…

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 (recall the gene swapping that N. gon. does through transformation by DNA uptake)

• 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

Exotoxins: proteins with damaging effects• Secreted or leak into tissue following bacterial lysis

• Foodborne intoxication results from consumption (Botulism)

• Destroyed by heating; most exotoxins heat-sensitive

• Can act locally or systemically• Proteins, so immune system can generate antibodies

• Many fatal before immune response mounted

• Vaccines therefore critical: toxoids are inactivated toxin

• Antitoxin is suspension of neutralizing antibodies to treat

• Neurotoxins damage nervous system• Enterotoxins cause intestinal disturbance• Cytotoxins damage variety of cell types

Damage to the Host

Direct or indirect effects• Direct (e.g., toxins produced)• Indirect (e.g., immune response)

Three main categories of Exotoxins based on structure and mechanisms (Table 16.1 lists many examples)

1) A-B toxins

2) Membrane damaging toxins

3) Superantigens

Exo- vs Endotoxin : Exotoxin is a protein made by the cell in the cytoplasm, may be exported.

Endotoxin refers to the part of the cell membrane of Gram Negative bacrteria—usually the lipid A

16.8. Damage to the Host


Exotoxins (continued…)• A-B toxins have two parts

• A subunit is toxic, usually an enzyme

• B subunit binds to cell, dictates cell type to be infected

– Structure allows novel approaches for vaccinesand therapies; can use B subunit to deliver medically useful compounds to specificcell type


Active subunit

AB

Binding site

Binding subunit

B subunit binds to aspecific moleculeon the host cell.

Toxin is taken upby endocytosis.

Toxin subunits separateallowing the A subunitto enter the cytoplasm.

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RECALL these from intestinal diseases-CH 24


© VeronikaBurmeister/Visuals Unlimited

A

A

B

10 µm

1

2

3

5

4

V. choleraebacterium

Water follows electrolytesout of the cell by osmosis.

The A subunit locks a G proteinin the “active” mode, turning onadenylate cyclase.

The A-B toxin’s B subunit attachesto receptors on cell membrane;the A subunit enters the cell.

Plasma membraneof intestinal cell

cAMP activates ion transportchannels in the membranecausing Cl– and other electrolytesto pour out of the cell.

Adenylate cyclase causes theconversion of ATP to cAMP.

cAMP

H2O

HCO3–

Na+

K+

Cl–

G protein ONOFF

ATP

Adenylatecyclase

●

A-B toxin

B binds to cellA enters


Exotoxins (continued…)• 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 Streptococcus pyogenes

• Phospholipases hydrolyze

phospholipids of membranes

– α-toxin of Clostridium perfringens

(gas gangrene)

Exotoxins (continued…)

• Superantigens: simultaneously bind MHC class II and T-cell receptor

• T-cell interprets as antigen recognition

• Toxic effect is from massive cytokine release from TH

• Include toxic shock syndrome toxin(TSST) and severalby Staphylococcusaureus, Streptococcuspyogenes

Antigen-presenting cell Antigen-presenting cell

Peptide notrecognized byT-cell receptor

MHC class IImolecule

Peptiderecognized byT-cell receptor

T-cellreceptor

Helper T cell Helper T cell

Superantigen

Helper T cell that does not recognizepeptide is activated because of superantigen;it proliferates and releases cytokines.

Helper T cell that recognizes peptide isactivated; it proliferates and releasescytokines.

a b


Adapted from Arousing the Fury of the Immune System, 1998 Howard Hughes Medical Institute.

Effector functions of Cytotoxic T cells

Exotoxins (continued…)

• 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

Damage to the Host

Endotoxin, Other Bacterial Cell Wall Components• Endotoxin is lipopolysaccharide (LPS)

• Lipid A triggers inflammatory response

– When localized, response helps clear

– When systemic, causes widespread response: septic shock or endotoxic shock

• Lipid A typically released following cell lysis

– Phagocytosis, MAC formation, certain antibiotics

• Activates innate and adaptive defenses

– 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

• Peptidoglycans, other components also trigger

Damaging Effects of the 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

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