Infection Chapter 9 Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of...

InfectionInfection

Chapter 9Chapter 9

Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

2Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.Mosby items and derived items © 2010, 2006 by Mosby, Inc., an affiliate of Elsevier Inc.

OverviewOverview Eradication effortsEradication efforts

Successes and failuresSuccesses and failures Infection is 3rd leading cause of death in U.S.Infection is 3rd leading cause of death in U.S.

Leading cause of death globallyLeading cause of death globally Emergence of new infectionsEmergence of new infections Increasing prevalence of known infectionsIncreasing prevalence of known infections

Drug resistanceDrug resistance


Microorganism/Human RelationshipMicroorganism/Human Relationship

Mutual relationshipMutual relationship Normal floraNormal flora Relationship can be breached by injuryRelationship can be breached by injury

• Leave their normal sites and cause infection elsewhereLeave their normal sites and cause infection elsewhere

Opportunistic microorganismsOpportunistic microorganisms


InfectionInfection

ColonizationColonization Pathogens present: may infect othersPathogens present: may infect others

InvasionInvasion Attaches to host cells via adhesion molecules and Attaches to host cells via adhesion molecules and

receptors: cell injury, alteration in function, or deathreceptors: cell injury, alteration in function, or death MultiplicationMultiplication

Uses host nutrients/environment: tissue damage, Uses host nutrients/environment: tissue damage, disease symptomsdisease symptoms

SpreadSpread Migration through tissue, circulatory, or lymph Migration through tissue, circulatory, or lymph

systems: diseasesystems: disease


Normal Colonization Normal Colonization

Produce enzymes that help digestionProduce enzymes that help digestion Produce antibacterial factorsProduce antibacterial factors

Prevent colonization by pathogensPrevent colonization by pathogens Produce metabolitesProduce metabolites

Vitamin KVitamin K B vitaminsB vitamins

Maintained by system integrity/immune systemsMaintained by system integrity/immune systems Pathogens if system integrity compromisedPathogens if system integrity compromised Problem if immunocompromised/opportunisticProblem if immunocompromised/opportunistic


InfectionInfection

Factors influencing disease developmentFactors influencing disease development Entry portal: spread is easy through blood and lymph Entry portal: spread is easy through blood and lymph

systemssystems Mechanism of action: how does it damage cells?Mechanism of action: how does it damage cells? Infectivity: ability to enter and replicateInfectivity: ability to enter and replicate Pathogenicity: ability to produce diseasePathogenicity: ability to produce disease Virulence: speed of replicationVirulence: speed of replication Toxigenicity: production of toxinsToxigenicity: production of toxins


ClassificationClassification EndemicEndemic

Diseases with relatively high, but constant, rates of Diseases with relatively high, but constant, rates of infection in a particular population infection in a particular population

EpidemicEpidemic Number of new infections in a particular population Number of new infections in a particular population

greatly exceeds the number usually observedgreatly exceeds the number usually observed PandemicPandemic

An epidemic that spreads over a large area (a An epidemic that spreads over a large area (a continent or worldwide) continent or worldwide)


Clinical Course: Stages of Clinical Course: Stages of InfectionInfection

IncubationIncubation ProdromalProdromal InvasionInvasion ConvalescenceConvalescence


Clinical Manifestations of Clinical Manifestations of Infectious DiseaseInfectious Disease

Variable depending on the pathogenVariable depending on the pathogen Directly caused by the pathogen or indirectly caused Directly caused by the pathogen or indirectly caused

by its productsby its products Fatigue, malaise, weakness, loss of concentration, Fatigue, malaise, weakness, loss of concentration,

generalized aching, loss of appetite generalized aching, loss of appetite FeverFever

Resetting the hypothalamusResetting the hypothalamus• Exogenous pyrogensExogenous pyrogens

• Endogenous pyrogensEndogenous pyrogens


Classes of Infectious Classes of Infectious MicroorganismsMicroorganisms

VirusesViruses ChlamydiaChlamydia RickettsiaRickettsia MycoplasmaMycoplasma BacteriaBacteria FungiFungi ProtozoaProtozoa HelminthsHelminths


Pathogenic Defense MechanismsPathogenic Defense Mechanisms

Compete with normal floraCompete with normal flora Produce toxinsProduce toxins Produce enzymes: avoid phagocytosis, Produce enzymes: avoid phagocytosis,

opsonization, destroy connective tissuesopsonization, destroy connective tissues Avoid lysis: stop complement cascade by Avoid lysis: stop complement cascade by

degrading C3bdegrading C3b Paralyze cilliary activityParalyze cilliary activity


Antigenic VariationAntigenic VariationAltering the Surface MoleculesAltering the Surface Molecules

Antigenic drift = mutation Antigenic drift = mutation Mutation of genes that express surface molecules Mutation of genes that express surface molecules Unrecognized by B and T cellsUnrecognized by B and T cells Can happen quickly, even during an infectionCan happen quickly, even during an infection

Antigenic shiftAntigenic shift Recombination (i.e., a human virus + chicken virus) Recombination (i.e., a human virus + chicken virus)

into a new virusinto a new virus Gene switchingGene switching

Different genes turn on and off at different timesDifferent genes turn on and off at different times


Bacterial Virulence and InfectivityBacterial Virulence and Infectivity Bacteria must have iron to multiplyBacteria must have iron to multiply

Siderophores (iron receptors)Siderophores (iron receptors) Presence of polysaccharide capsulesPresence of polysaccharide capsules Suppression of complement activationSuppression of complement activation Bacterial proliferation rates can surpass Bacterial proliferation rates can surpass

protective responseprotective response


Bacterial Virulence and InfectivityBacterial Virulence and Infectivity Toxin productionToxin production

ExotoxinsExotoxins• Enzymes released during growth causing specific Enzymes released during growth causing specific

responsesresponses• ImmunogenicImmunogenic

Antitoxin productionAntitoxin production

EndotoxinsEndotoxins• Lipopolysaccharides contained in the cell walls of gram-Lipopolysaccharides contained in the cell walls of gram-

negative organismsnegative organisms• Pyrogenic effectsPyrogenic effects


ToxinsToxins Kill, damage, or alter cell functionKill, damage, or alter cell function Exotoxin: released from living microbeExotoxin: released from living microbe

NeurotoxinsNeurotoxins Stimulate antibody productionStimulate antibody production Can be converted to toxoidCan be converted to toxoid

Endotoxin: from lysed gram-negative bacteriaEndotoxin: from lysed gram-negative bacteria Activates inflammatory responseActivates inflammatory response


Bacterial Virulence and InfectivityBacterial Virulence and Infectivity

Bacteremia or septicemiaBacteremia or septicemia Presence of bacteria in the blood due to a failure Presence of bacteria in the blood due to a failure

of the body’s defense mechanismsof the body’s defense mechanisms Usually caused by gram-negative bacteriaUsually caused by gram-negative bacteria Toxins released in the blood cause the release of Toxins released in the blood cause the release of

vasoactive peptides and cytokines that produce vasoactive peptides and cytokines that produce widespread vasodilationwidespread vasodilation


Viral InfectionViral Infection

Viruses are intracellular parasitesViruses are intracellular parasites Do not have organelles necessary for Do not have organelles necessary for

reproductionreproduction Replicate by “taking over” the metabolic systems Replicate by “taking over” the metabolic systems

of host cellof host cell May kill cell, coexist with cell, be killed by immune May kill cell, coexist with cell, be killed by immune

systemsystem


Viral InfectionViral Infection

Attaches to host cell via protein receptorsAttaches to host cell via protein receptors Penetrates host cellPenetrates host cell Releases genetic information into host Releases genetic information into host

cytoplasmcytoplasm RNA viruses enter host nucleusRNA viruses enter host nucleus

• Produce mRNA (new viral material)Produce mRNA (new viral material)

• May produce provirus DNA (retroviruses: HIV)May produce provirus DNA (retroviruses: HIV)

DNA viruses enter host nucleusDNA viruses enter host nucleus• May integrate into host DNA; may make mRNAMay integrate into host DNA; may make mRNA


Viral ReplicationViral Replication Translation of mRNA results in the production Translation of mRNA results in the production

of viral proteinsof viral proteins New virions are released through buddingNew virions are released through budding Viral DNA that is integrated in host cell; DNA Viral DNA that is integrated in host cell; DNA

is transmitted to daughter cells by mitosisis transmitted to daughter cells by mitosis


Viral Infection and ReplicationViral Infection and Replication


Cellular Effects of VirusesCellular Effects of Viruses

Inhibition of host cell DNA, RNA, or protein Inhibition of host cell DNA, RNA, or protein synthesissynthesis

Disruption of lysosomal membranesDisruption of lysosomal membranes Promotion of apoptosisPromotion of apoptosis Fusion of infected, adjacent host cellsFusion of infected, adjacent host cells Alteration of antigenic propertiesAlteration of antigenic properties Transformation of host cells into cancerous Transformation of host cells into cancerous

cellscells Promotion of secondary bacterial infectionsPromotion of secondary bacterial infections


Acquired Immunodeficiency Acquired Immunodeficiency Syndrome (AIDS)Syndrome (AIDS)

Syndrome caused by a viral diseaseSyndrome caused by a viral disease HIVHIV Depletes the body’s Th cellsDepletes the body’s Th cells IncidenceIncidence

• WorldwideWorldwide 5 million per year5 million per year

• United StatesUnited States About 31,000 cases per yearAbout 31,000 cases per year 400,000 currently living with AIDS400,000 currently living with AIDS


AIDSAIDS HIV-1HIV-1

Cause of HIV in Western Hemisphere and EuropeCause of HIV in Western Hemisphere and Europe HIV-2HIV-2

Cause of HIV in Africa and Southeast AsiaCause of HIV in Africa and Southeast Asia


AIDSAIDS Effective antiviral therapies have made AIDS Effective antiviral therapies have made AIDS

a chronic diseasea chronic disease EpidemiologyEpidemiology

Blood-borne pathogenBlood-borne pathogen Increasing faster in women than menIncreasing faster in women than men


Mechanism of InjuryMechanism of Injury RNA virus (retrovirus)RNA virus (retrovirus)

Stores genetic material on single-stranded RNA Stores genetic material on single-stranded RNA rather than usual double-stranded DNArather than usual double-stranded DNA

Carries an enzyme Carries an enzyme reverse transcriptasereverse transcriptase that that creates a double-stranded DNA version of the creates a double-stranded DNA version of the virusvirus

New DNA becomes part of cell’s genetic material New DNA becomes part of cell’s genetic material and accelerates apoptosisand accelerates apoptosis


HIVHIV StructureStructure

gp120 protein binds to the CD4 molecule found gp120 protein binds to the CD4 molecule found primarily on the surface of helper T cellsprimarily on the surface of helper T cells• CD4+ Th cellsCD4+ Th cells

Typically 800 to 1000 cells/mmTypically 800 to 1000 cells/mm33

Reverses CD4:CD8 ratioReverses CD4:CD8 ratio

Co-receptorsCo-receptors• CXCR4 and CCR5CXCR4 and CCR5

Strains can be selective for these receptors; influences the Strains can be selective for these receptors; influences the tropism of the target cellstropism of the target cells


HIV Life Cycle and Target PointsHIV Life Cycle and Target Points


HIVHIV Clinical manifestationsClinical manifestations

Serologically negative, serologically positive but Serologically negative, serologically positive but asymptomatic, early stages of HIV, or AIDSasymptomatic, early stages of HIV, or AIDS

Window periodWindow period Th cells <200 cells/mmTh cells <200 cells/mm33

Diagnosis of AIDS is made in association with Diagnosis of AIDS is made in association with various clinical conditionsvarious clinical conditions• Atypical or opportunistic infections and cancerAtypical or opportunistic infections and cancer


Phases of DiseasePhases of Disease Early phaseEarly phase

Lasts about 2 weeksLasts about 2 weeks Headaches, fever, flu-like symptomsHeadaches, fever, flu-like symptoms High level of virus in bloodHigh level of virus in blood

Middle phaseMiddle phase Lasts months to yearsLasts months to years Few symptomsFew symptoms Virus dormant in host DNAVirus dormant in host DNA Few virus in blood but many Abs. Basis of testing.Few virus in blood but many Abs. Basis of testing. Continuous infection, death, and replacement of Continuous infection, death, and replacement of

CD4+ T cells likely by own Tc (CD8+ cells)CD4+ T cells likely by own Tc (CD8+ cells)


Progression to AIDSProgression to AIDS Late phaseLate phase

Rapid decline in CD4+ T cellsRapid decline in CD4+ T cells If <400/cubic ml (normal, 1000), start treatmentIf <400/cubic ml (normal, 1000), start treatment

Patient weak, opportunistic infections beginPatient weak, opportunistic infections begin• Herpes, varicella, Herpes, varicella, MycobacteriumMycobacterium (Tb), fungi, (Tb), fungi, PneumocystisPneumocystis

When CD4+ <200/cubic ml:When CD4+ <200/cubic ml: LymphomaLymphoma Cancer (Kaposi sarcoma)Cancer (Kaposi sarcoma) Often fatal within a yearOften fatal within a year


TreatmentTreatment

HAART (highly active antiretroviral therapy)HAART (highly active antiretroviral therapy) 3 or more drugs: usually 2 that target reverse 3 or more drugs: usually 2 that target reverse

transcriptase (fools DNA into incorporating it into new transcriptase (fools DNA into incorporating it into new strand, then halts DNA synthesis) and 1 that targets strand, then halts DNA synthesis) and 1 that targets viral protease (can’t cleave apart precursor proteins viral protease (can’t cleave apart precursor proteins so can’t make new viral proteins)so can’t make new viral proteins)

Not a cure; instead slows progressionNot a cure; instead slows progression Expensive: $7000 to $10,000 per yearExpensive: $7000 to $10,000 per year Many side effects unpleasantMany side effects unpleasant


PreventionPrevention Vaccines so far not very effectiveVaccines so far not very effective Reduce risk behaviorsReduce risk behaviors


ResearchResearch

Fusion inhibitorsFusion inhibitors Interferes with fusion of HIV and CD4+ cellsInterferes with fusion of HIV and CD4+ cells

Integrase inhibitorsIntegrase inhibitors Worked in monkeys to slow disease progression; Worked in monkeys to slow disease progression;

have undergone clinical trialshave undergone clinical trials Entrance inhibitors (co-receptor binding Entrance inhibitors (co-receptor binding

inhibition)inhibition) Uses monoclonal antibodies to inhibit binding to co-Uses monoclonal antibodies to inhibit binding to co-

receptorsreceptors


Pediatric HIV and AIDSPediatric HIV and AIDS Presence of passive maternal antibody limits Presence of passive maternal antibody limits

the use of HIV antibody testing in infants up the use of HIV antibody testing in infants up to 15 months of ageto 15 months of age

CNS particularly vulnerableCNS particularly vulnerable Developmental delaysDevelopmental delays Impaired brain growth or acquired microcephaly Impaired brain growth or acquired microcephaly Motor deficits Motor deficits


Fungal Infection and InjuryFungal Infection and Injury Large microorganisms with thick cell wallsLarge microorganisms with thick cell walls EukaryotesEukaryotes Exist as single-celled yeasts, multicelled Exist as single-celled yeasts, multicelled

molds, or bothmolds, or both PathogenicityPathogenicity

Adapt to host environmentAdapt to host environment• Wide temperature variations, digest keratin, low oxygenWide temperature variations, digest keratin, low oxygen

Suppress the immune defensesSuppress the immune defenses


Fungal Infection and InjuryFungal Infection and Injury Diseases caused by fungi: mycosesDiseases caused by fungi: mycoses

Superficial, deep, or opportunisticSuperficial, deep, or opportunistic Fungi that invade the skin, hair, or nails are Fungi that invade the skin, hair, or nails are

known as dermatophytesknown as dermatophytes Diseases produced are Diseases produced are tineas tineas (ringworm)(ringworm)

• Tinea capitis, tinea pedis, and tinea crurisTinea capitis, tinea pedis, and tinea cruris

Deep fungal infections are life threatening Deep fungal infections are life threatening and are commonly opportunisticand are commonly opportunistic


Fungal Infection and InjuryFungal Infection and Injury


Infection: CountermeasuresInfection: Countermeasures

Vaccines: prevent initiation of diseaseVaccines: prevent initiation of disease Primary response short livedPrimary response short lived Boosters provide multiple secondary responsesBoosters provide multiple secondary responses

• Increased memory cellsIncreased memory cells

• Increased antibodyIncreased antibody

• Increased T cellsIncreased T cells


Viral VaccinesViral Vaccines

Attenuated: weakened live virus (MMR, Attenuated: weakened live virus (MMR, varicella, polio/oral)varicella, polio/oral)

Inactivated: killed virus (hepatitis A, Inactivated: killed virus (hepatitis A, polio/injected, influenza)polio/injected, influenza)


Bacterial VaccinesBacterial Vaccines

Dead bacteria (pneumococcal pneumonia)Dead bacteria (pneumococcal pneumonia) Not very immunogenic in childrenNot very immunogenic in children

Conjugated (to carrier proteins)Conjugated (to carrier proteins) Increased immunogenicityIncreased immunogenicity Haemophilus influenzaeHaemophilus influenzae type B (Hib) type B (Hib)

ToxoidsToxoids Vaccine against bacterial toxins (DTaP, DT)Vaccine against bacterial toxins (DTaP, DT)


CountermeasuresCountermeasures

AntimicrobialsAntimicrobials Inhibit synthesis of cell wallInhibit synthesis of cell wall Damage cytoplasmic membraneDamage cytoplasmic membrane Alter metabolism of nucleic acidAlter metabolism of nucleic acid Inhibit protein synthesisInhibit protein synthesis Modify energy metabolismModify energy metabolism

AntiviralsAntivirals Less successful because viruses use host Less successful because viruses use host

enzymesenzymes

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