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Pathogenic Mechanisms

• Hugh B. FackrellHugh B. Fackrell

• Filename:Filename: PathMech.pptPathMech.ppt

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Outline

• Infection vs DiseaseInfection vs Disease

• PathogenicityPathogenicity

• VirulenceVirulence

• Pathogenic factorsPathogenic factors

• Latency DormancyLatency Dormancy

• CommunicabilityCommunicability

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Saprophyte

• nutrient source is non-livingnutrient source is non-living

• can become parasitecan become parasite

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Parasitism

• host/microorganism interactionhost/microorganism interaction

• MutualismMutualism - both host and parasite benefit. - both host and parasite benefit.

• Commensalism Commensalism - the parasite does no damage - the parasite does no damage to the host.to the host.

• Pathogen Pathogen - the parasite damages the host.- the parasite damages the host.

• OpportunismOpportunism - the parasite takes advantage of - the parasite takes advantage of the weakened condition of the host.the weakened condition of the host.

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Microbial Infection vs Disease

• Infection: colonization of the body with microbeInfection: colonization of the body with microbe– usually non pathogenicusually non pathogenic– indigenous or commensalindigenous or commensal– beneficialbeneficial

• Disease: breach of host defensesDisease: breach of host defenses– microbes infect tissues not normally exposedmicrobes infect tissues not normally exposed

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Infection: Benefits• MetabolitesMetabolites

– E. coliE. coli makes vitamin K makes vitamin K

• Bacterial antagonismBacterial antagonism– E.coliE.coli blocks colonization of gut by blocks colonization of gut by S. aureusS. aureus– evidenceevidence: antibiotic sterilization before abdominal surgery: antibiotic sterilization before abdominal surgery– subsequent Staphylococcal infectionssubsequent Staphylococcal infections– enteritisenteritis

• Encourage immune systemEncourage immune system– axenic animals have poor immunityaxenic animals have poor immunity

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Infection: Adverse Effects

• Staphylococcal infectionStaphylococcal infection– Produces penicillinaseProduces penicillinase– Concurrent infection of Concurrent infection of Neisseria gonorrhaeaeNeisseria gonorrhaeae– Becomes disease gonorrheaBecomes disease gonorrhea

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Microbial Disease

• Microbial disease is the Microbial disease is the exceptionexception

– imbalance favours the microbeimbalance favours the microbe

• 3% of all microbes pathogenic3% of all microbes pathogenic– majority of known microbesmajority of known microbes

• >95% do not cause disease>95% do not cause disease– virtually unknownvirtually unknown

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Location of Microbe in Host • Location often decides outcome of Infection vs Location often decides outcome of Infection vs

disease disease • StreptococcusStreptococcus

– Infection: nasopharynxInfection: nasopharynx– Disease: heartDisease: heart– bacterimiae after tooth extractionbacterimiae after tooth extraction

• E. coliE. coli– Infection gutInfection gut– Disease: cystitis in urinary tractDisease: cystitis in urinary tract

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Contagious Transmission

• can be transmitted from one host to another can be transmitted from one host to another (communicable)(communicable)

• some infections acquired from indigenous some infections acquired from indigenous flora are categorized as communicable.flora are categorized as communicable.

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Communicability• Communicable: spread directly or indirectly Communicable: spread directly or indirectly

from one host to anotherfrom one host to another– chickenpox, measles, tuberculosis, typhoid feverchickenpox, measles, tuberculosis, typhoid fever

• Contagious: Contagious: easilyeasily communicable communicable– eg chickenpox,measles, sore throateg chickenpox,measles, sore throat

• Non communicable: Non communicable: Not spreadNot spread from host to from host to hosthost– tetanustetanus

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Dormancy

• Latency = DormancyLatency = Dormancy: causative microbe : causative microbe remains inactive in the host for some time remains inactive in the host for some time but later becomes active to produce the but later becomes active to produce the signs and symptoms of the diseasesigns and symptoms of the disease

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Carrier State

• Individual infectedIndividual infected– results from a previous disease state (may be results from a previous disease state (may be

temporary)temporary)– the host is a true carrierthe host is a true carrier

• microbe in balance with that individualmicrobe in balance with that individual• No overt signs or symptomsNo overt signs or symptoms• reservoir for infection of othersreservoir for infection of others

–Typhoid Mary Typhoid Mary

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Koch’s PostulatesKoch’s Postulates• The organism should be found in all cases of The organism should be found in all cases of

the disease and its distribution in the body the disease and its distribution in the body should be in accordance with the lesions should be in accordance with the lesions observed.observed.

• The organism should be cultivated outside The organism should be cultivated outside the body of the host, in pure culture, for the body of the host, in pure culture, for several generations of the pathogen.several generations of the pathogen.

• The disease should be reproduced in The disease should be reproduced in susceptible animals.susceptible animals.

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EtiologyEtiology

Science of the causes of diseaseScience of the causes of disease• the nature of the host - speciesthe nature of the host - species• the condition of the hostthe condition of the host• the nature of the disease agentthe nature of the disease agent• the transmission of the agentthe transmission of the agent

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Etiology of Disease (1/2)Etiology of Disease (1/2)

• Specimen from patient containing infectious Specimen from patient containing infectious agent cultured.agent cultured.

• Pure culture obtained and described; identified Pure culture obtained and described; identified if possible.if possible.

• Inoculation and observation of test animal.Inoculation and observation of test animal.

• Many organs removed and cultured.Many organs removed and cultured.

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Etiology of Disease (2/2)

• Isolation and identification of the test Isolation and identification of the test organism.organism.

• Inoculation of a second test animal.Inoculation of a second test animal.

• Culture of second test animal.Culture of second test animal.

• Antibodies in blood of human or animal.Antibodies in blood of human or animal.

• Immunity developed to the infecting agent in Immunity developed to the infecting agent in recently recovered animal.recently recovered animal.

• Animal protected by vaccine or toxoid.Animal protected by vaccine or toxoid.

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Pathogenicity

• Ability or potential to cause disease Ability or potential to cause disease attributed to a genus or speciesattributed to a genus or species

• Dependent on ability toDependent on ability to

– enter the hostenter the host

– adapt and multiply in the hostadapt and multiply in the host

– exit from the hostexit from the host

– transmit to new hosttransmit to new host

Keppie Smith

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Portal of Entry

• May multiply at entry site> lesionMay multiply at entry site> lesion

• Often enters multiplies elsewhereOften enters multiplies elsewhere

• 2/3 Respiratory2/3 Respiratory

• 1/3 intestine, urethra, conjunctiva and skin1/3 intestine, urethra, conjunctiva and skin

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Multiplication in Host

• Rate of multiplication different Rate of multiplication different in vivoin vivo and and in vitro

• time to overt symptoms

• Carrier state

• reservoir gall bladder

• Temperature– viruses– aspirin

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Exit from Host

• Usually by same route a entryUsually by same route a entry

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Bacterial transmission

• DropletsDroplets• FomitesFomites• Direct contactDirect contact

– sexual sexual

– non sexualnon sexual

• BitesBites– insectsinsects

– animalsanimals

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Types of Pathogens

• pathogens characterized as “frank” - pathogens characterized as “frank” - SalmonellaSalmonella

• opportunistic pathogens - opportunistic pathogens - E. coliE. coli in urinary in urinary tracttract

• non-pathogensnon-pathogens - such as - such as Serratia marcescensSerratia marcescens may become infectious agentsmay become infectious agents

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Virulence

• DEGREE of pathogenicity shown by a DEGREE of pathogenicity shown by a specific strain of an organismspecific strain of an organism– C. diptheriaeC. diptheriae > diptheria > diptheria

• variables include:variables include:– number of infecting bacterianumber of infecting bacteria– route of entry into bodyroute of entry into body– specific host defense mechanismsspecific host defense mechanisms– non-specific host defense mechanismsnon-specific host defense mechanisms– virulence factors of the bacteriumvirulence factors of the bacterium

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Virulence Measurement

• Measures the pathogenicity of a isolateMeasures the pathogenicity of a isolate– variable among strainsvariable among strains

• Measure of VirulenceMeasure of Virulence– Median DoseMedian Dose– Minimum Effective DoseMinimum Effective Dose

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Median Dose

Num

ber

Sus

cept

ible

Pathogen

Amount that affects half the population

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Cause of Virulence Variation

• Dose of pathogenDose of pathogen

• Virulence/Pathogenic factorsVirulence/Pathogenic factors

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Dose of Pathogen

• Typhoid FeverTyphoid Fever– S. typhosaS. typhosa contaminated water contaminated water– 1-100 bacteria no effect1-100 bacteria no effect

• BoilsBoils– Staphylococcus aureusStaphylococcus aureus– just on surface 7 x 10 just on surface 7 x 10 66cellscells– on suture or scratch ~1000 cellson suture or scratch ~1000 cells– ““stictch abcesses”stictch abcesses”

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“Pathogenic Factors”• Gene mutationGene mutation

– S. pneumoniae- S. pneumoniae- capsulecapsule– Shigella Shigella > dysentery> dysentery

• Lysogeny Lysogeny – scarlet feverscarlet fever– diptheriadiptheria

• CapsulesCapsules– KlebsiellaKlebsiella > polysaccharide > polysaccharide– Anthrax > protein capsuleAnthrax > protein capsule

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“Pathogenic Factors”• Inhibit host metabolismInhibit host metabolism

– M. tuberculosis > M. tuberculosis > tuberculosistuberculosis– mycolic acid mycolic acid blocks lysosomal enzymesblocks lysosomal enzymes

• Resist host metabolismResist host metabolism– stomach acidsstomach acids– bile saltsbile salts– enzymesenzymes– saltsalt

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Invasion FactorsInvasion Factors• usually surface componentsusually surface components• also enzymes - proteasesalso enzymes - proteases• tissue lysinstissue lysins

Adherence factorsAdherence factors

• pili (fimbriae)pili (fimbriae)

• fibronectin receptorsfibronectin receptors

CapsulesCapsules• prevent phagocytosisprevent phagocytosis• opsonizationopsonization

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Adhesion to HostAdhesion to HostAAllows Microbe : more stable foothold at the llows Microbe : more stable foothold at the

portal of entryportal of entry• bind to host cellsbind to host cells• penetrate the epithelial boundarypenetrate the epithelial boundary• become established in the tissuesbecome established in the tissues

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Adhesion Mechanisms

• Fimbriae on bacterial cellsFimbriae on bacterial cells• Adherent capsules, slime layers or other sticky Adherent capsules, slime layers or other sticky

substancessubstances• Viral envelope spikesViral envelope spikes• Pathogen hooks on filaments of target cellsPathogen hooks on filaments of target cells

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Adhesins

• Afimbrial adhesins are proteins that assist in Afimbrial adhesins are proteins that assist in binding bacteria to the host cell.binding bacteria to the host cell.

• F ProteinF Protein::Streptococcus pyogenes Streptococcus pyogenes – assists binding to fibronectin,a protein on host cell assists binding to fibronectin,a protein on host cell

surface. surface.

• M Protein M Protein • Lipoteichoic acidLipoteichoic acid

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Biofilm

• - multilayer bacterial populations embedded - multilayer bacterial populations embedded in a polysaccharide matrix that is attached to in a polysaccharide matrix that is attached to same surface. same surface.

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Siderophores• Iron acquisition : Fe low in human and is bound to Iron acquisition : Fe low in human and is bound to

lactoferrinlactoferrin

transferrintransferrin

ferritinferritin

heminhemin

Bacteria compete for Fe using Bacteria compete for Fe using SiderophoresSiderophores::

Low molecular weight compounds thatLow molecular weight compounds that

chelate ironchelate iron Ex. Enterochelin FeEx. Enterochelin Fe++++++

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Siderophore Competes for Fe3+

Fe3+

Sideriophore

SiderophoreRececeptor

Lactorferrin

Transferrin

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Toxigenicity• Production and release of an extracellular Production and release of an extracellular

microbial product that disrupts the host’s microbial product that disrupts the host’s normal physiologynormal physiology

• Proteins > exotoxinsProteins > exotoxins

• Function away from bacteriumFunction away from bacterium

• Potent poisonsPotent poisons– diptheria toxindiptheria toxin– tetanus toxintetanus toxin– botulism toxinbotulism toxin

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Exotoxins vs EndotoxinsExotoxinsExotoxins• usually Gram +veusually Gram +ve• extracellularextracellular• released from live cellreleased from live cell• proteinprotein• MW 15,000 -100,000MW 15,000 -100,000• Heat labileHeat labile• toxoidtoxoid• Antigenic > vaccineAntigenic > vaccine• extremely potentextremely potent

EndotoxinsEndotoxins• from Gram -vefrom Gram -ve• part of cell wallpart of cell wall• released from dead cellreleased from dead cell• lipopolysaccharidelipopolysaccharide• MW millionsMW millions• heat stableheat stable• no toxoidno toxoid• poorly antigenicpoorly antigenic• less potentless potent

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Toxins: Biological Functions

• ExotoxinsExotoxins• CytotoxicCytotoxic• NeurotoxicNeurotoxic• EnterotoxicEnterotoxic

– enteron = gutenteron = gut

• EndotoxinsEndotoxins• cause fevercause fever• changes in blood changes in blood

pressurepressure• inflammationinflammation• lethal shocklethal shock

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Infection ProcessInfection Process

Host Physiology Protects

Infectious Agent Successful

Infection Rejected = no disease

Infection Moderate = subclinical disease

Host (human, animal, plant)

Infectious AgentInfectious Agent

Infection Established

Infection Established = disease

• an infection develops into disease when the balance between microbial pathogenicity and host resistance is tipped toward the agent.

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Host Susceptibility

• Humoral Defense MechanismsHumoral Defense Mechanisms

• Cellular Defense MechanismsCellular Defense Mechanisms

• Inflammation - a combination of humoral Inflammation - a combination of humoral and cellularand cellular

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Resistance to Bacterial Infections

– PhagocytosisPhagocytosis– Immune responseImmune response– Non-specific mechanismsNon-specific mechanisms

2. Bacteria2. Bacteria– multiplymultiply– objective not to destroy the hostobjective not to destroy the host

3. Host - Mediated Pathogenesis3. Host - Mediated Pathogenesis– for example, tuberculosis - tissue damage results for example, tuberculosis - tissue damage results

from toxic mediators released by lymphoid cells.from toxic mediators released by lymphoid cells.

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Non-Specific Physiological Host Defense Mechanisms

• Innate or Natural ImmunityInnate or Natural Immunity

• an individual is born with certain an individual is born with certain mechanisms of resistance to infectious mechanisms of resistance to infectious agentsagents

• also called racial or inherent immunity.also called racial or inherent immunity.

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Mechanisms of Microbial Antagonism• attachment site occupiedattachment site occupied with indigenous flora with indigenous flora

(commensals); usually bacteria(commensals); usually bacteria

• bacteriocinsbacteriocins - proteins secreted by the indigenous - proteins secreted by the indigenous flora that inhibit the growth of other bacteriaflora that inhibit the growth of other bacteria

• competitive competitive deletion of essential nutrientsdeletion of essential nutrients

• production of production of toxic by-productstoxic by-products – genitourinary tract - at menarche, tissues of vagina and genitourinary tract - at menarche, tissues of vagina and

cervix become populated with Lactobacilli which lower cervix become populated with Lactobacilli which lower the pH to 4.4-4.6; inhibitory to gram negative enterics.the pH to 4.4-4.6; inhibitory to gram negative enterics.

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Physical Barriers & Chemical Agents• Intact Skin:Intact Skin:

• acid pHacid pH

• epithelial surfaceepithelial surface

• Staphylococcus aureus (pathogen); also carried as indigenous Staphylococcus aureus (pathogen); also carried as indigenous floraflora

• Mucous membranes:Mucous membranes:

• vaginavagina

• bowelbowel

• respiratory tractrespiratory tract

• more easily penetrated than the intact skinmore easily penetrated than the intact skin

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Mucous:

• motion of ciliamotion of cilia

• coughing/sneezingcoughing/sneezing

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Physical Barriers & Chemical Agents

• Eyes:Eyes:

• flushing action flushing action

• lysozymelysozyme

• Outer ear canal:Outer ear canal:

• waxwax

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Alimentary canal

• saliva (antibodies)saliva (antibodies)

• some protection from stomach acid (over rated)some protection from stomach acid (over rated)

• indigenous floraindigenous flora

• diarrheadiarrhea

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Genitourinary

• urine flushes out pathogensurine flushes out pathogens

• vaginal pH prevents some bacteria from vaginal pH prevents some bacteria from growinggrowing

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Physical Barriers

• Phagocytic cells:Phagocytic cells:– Ingests and destroys pathogensIngests and destroys pathogens

• Ciliated cells:Ciliated cells:– sweep pathogens away from other cellssweep pathogens away from other cells

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Chemical Agents

Lysozyme:Lysozyme:• dissolves peptidoglycandissolves peptidoglycan

Fatty acids:Fatty acids:• prevents bacterial growthprevents bacterial growth• sebaceous glandssebaceous glands

Complement:Complement:• Mediates phagocytosisMediates phagocytosis

Perspiration:Perspiration:• lactic acid lowers pHlactic acid lowers pH

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Mucosal Surfaces - Chemical Agents

• LysozymeLysozyme

• breaks the N-acetylmuraminic acid and N-acetyl glucosamine link breaks the N-acetylmuraminic acid and N-acetyl glucosamine link in gram positive bacteria (i.e. tears)in gram positive bacteria (i.e. tears)

• LactoferrinLactoferrin

• iron binding protein competes with microbes for ironiron binding protein competes with microbes for iron

• LactoperoxidaseLactoperoxidase

• milk and salivamilk and saliva

• Secretory IgASecretory IgA

• inferfers with the attachment and microbial mobility, agglutinate inferfers with the attachment and microbial mobility, agglutinate the microorganismsthe microorganisms

• neutralize exotoxinsneutralize exotoxins

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Mucosal Surfaces - Chemical Agents• pH and Peristalsis in Gastrointestinal SystempH and Peristalsis in Gastrointestinal System

• pH of the stomach during digestion drops to 2-4pH of the stomach during digestion drops to 2-4

• Peristalsis - intestinePeristalsis - intestine

• Respiratory MucosaRespiratory Mucosa– particles greater than 5 µm are moved by ciliaparticles greater than 5 µm are moved by cilia– particles smaller than 5 µm are phagocytized by alveolar particles smaller than 5 µm are phagocytized by alveolar

macrophagesmacrophages

• Urinary TractUrinary Tract– acidic pH has a flushing actionacidic pH has a flushing action

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Bacteria as Disease Agents• Depend onDepend on• the structure and function of the organism i.e. the structure and function of the organism i.e.

How metabolism and growth characteristics relate How metabolism and growth characteristics relate to the disease state and diagnosisto the disease state and diagnosis

• host defense mechanisms and host/ parasite host defense mechanisms and host/ parasite interactionsinteractions

• mechanism of pathogenicitymechanism of pathogenicity– toxinstoxins

– invasive factorsinvasive factors

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Diagnosis of Bacterial Disease

• Clinical Clinical - signs and symptoms, history, - signs and symptoms, history, exposure, epidemiologyexposure, epidemiology

• Laboratory -Laboratory - specimens sent to laboratory specimens sent to laboratory

Both not always necessary but preferableBoth not always necessary but preferable

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Bacterial Defense Mechanisms

• Cell EnvelopeCell Envelope– CapsuleCapsule– PeptidoglycanPeptidoglycan– Cytoplasmic membraneCytoplasmic membrane

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Capsules

– usually seen only in direct smear of clinical usually seen only in direct smear of clinical materialmaterial

– prevents phagocytosisprevents phagocytosis

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Peptidoglycan

– simulates endogenous pyrogensimulates endogenous pyrogen– osmotic regulationosmotic regulation– leucocyte chemoattractantleucocyte chemoattractant– anticomplementaryanticomplementary

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Cytoplasmic Membrane

– osmotic barrierosmotic barrier– regulates transportregulates transport

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Growth Patterns of Bacterial Pathogens

• Obligate intracellular pathogensObligate intracellular pathogens

• Faculative intracelular pathogensFaculative intracelular pathogens

• extracellular pathogensextracellular pathogens

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Obligate IntracellularBacterial Pathogens

• RickettsiaRickettsia spp spp• CCoxiella burnetiioxiella burnetii• ChlamydiaChlamydia spp spp

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Facultative Intracellular Bacterial Pathogens

SalmonellaSalmonella spp spp

ShigellaShigella spp spp

Legionella pneumophilaLegionella pneumophila

Invasive Invasive Escherichia coliEscherichia coli

NeisseriaNeisseria spp spp

MycobacteriumMycobacterium spp spp

Bordetella pertussisBordetella pertussis

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Predominantly Extracellular Bacterial Pathogens

MycoplasmaMycoplasma spp spp Pseudomonas aeruginosaPseudomonas aeruginosa

Enterotoxigenic Enterotoxigenic Escherichia coliEscherichia coliVibrio choleraeVibrio choleraeStaphylococcus aureusStaphylococcus aureusStreptococcus pyogenesStreptococcus pyogenesHaemophilus influenzaeHaemophilus influenzaeBacillus anthracisBacillus anthracis