Mini-MedicalMini-Medical SchoolSchool onon InfectiousInfectious DiseasesDiseases SessionSession #1#1 -- BasicBasic ScienceScience “The“The MicrobialMicrobial World”World” MichaelMichael V.V. Norgard,Norgard, Ph.D.,Ph.D., ChairmanChairman DepartmentDepartment ofof MicrobiologyMicrobiology U.T.U.T. SouthwesternSouthwestern MedicalMedical CenterCenter “The“The MicrobialMicrobial World”World”

MichaelMichael V.V. Norgard,Norgard, Ph.D.,Ph.D., ChairmanChairman DepartmentDepartment ofof MicrobiologyMicrobiology U.T.U.T. SouthwesternSouthwestern MedicalMedical CenterCenter OrganismsOrganisms ComprisingComprising thethe MicrobialMicrobial WorldWorld

✦✦ScopeScope ofof thethe Problem:Problem: –– Viruses,Viruses, bacteria,bacteria, protozoa,protozoa, fungi,fungi, andand parasitesparasites –– EnormousEnormous diversitydiversity –– Worldwide,Worldwide, moremore personspersons succumbsuccumb toto microbialmicrobial infectionsinfections thanthan toto cancercancer andand heartheart diseasedisease combined.combined. HierarchyHierarchy ofof MicrobesMicrobes:: [Smallest[Smallest →→ Largest]Largest] ✦✦VirusesViruses ✦✦BacteriaBacteria ✦✦Single-celledSingle-celled EukaryotesEukaryotes (animal-like(animal-like cells):cells): –– ParasiticParasitic protozoaprotozoa –– Fungi/yeastFungi/yeast ✦✦HigherHigher Eukaryotes:Eukaryotes: –– ParasiticParasitic intestinalintestinal wormsworms –– TissueTissue wormsworms DistributionDistribution

✦✦MicrobesMicrobes areare everywhereeverywhere andand inin highhigh numbers.numbers. ✦✦11 gramgram ofof humanhuman fecesfeces containscontains aboutabout 11 trilliontrillion bacteria.bacteria. CommonCommon ClinicalClinical WaysWays ofof CategorizingCategorizing MicrobesMicrobes

✦✦“Avirulent”“Avirulent” oror “nonpathogenic”“nonpathogenic” -- harmless.harmless. ✦✦“Virulent”“Virulent” oror “pathogenic”“pathogenic” -- capablecapable ofof causingcausing disease.disease. CommonCommon ClinicalClinical WaysWays ofof CategorizingCategorizing MicrobesMicrobes

✦✦ NormalNormal floraflora -- microbesmicrobes thatthat colonizecolonize thethe bodybody andand usuallyusually dodo notnot causecause disease.disease. ✦✦ OpportunisticOpportunistic pathogenspathogens -- microbesmicrobes thatthat normallynormally dodo notnot causecause disease,disease, butbut maymay underunder certaincertain circumstances.circumstances. ✦✦ FrankFrank pathogenspathogens -- microbesmicrobes thatthat alwaysalways causecause disease.disease. ✦✦ OtherOther -- diseasesdiseases causedcaused mostlymostly byby thethe ingestioningestion ofof preformedpreformed toxinstoxins oror whenwhen toxinstoxins areare producedproduced fromfrom bacteriabacteria duringduring infection.infection. ConceptConcept ofof "Pathogenesis""Pathogenesis"

✦✦PathogenesisPathogenesis -- thethe coursecourse ofof thethe infectiousinfectious process.process. ✦✦"Virulence""Virulence" factorsfactors oror "pathogenicity""pathogenicity" factorsfactors -- –– MicrobesMicrobes whichwhich cancan causecause diseasedisease areare thoughtthought toto carrycarry outout thethe processprocess byby utilizingutilizing oneone oror moremore propertiesproperties calledcalled virulencevirulence factorsfactors oror pathogenicitypathogenicity factors.factors. ✦✦ THETHE STUDYSTUDY OFOF MICROBIALMICROBIAL VIRULENCEVIRULENCE FACTORSFACTORS ISIS AA MAJORMAJOR EMPHASISEMPHASIS ININ MICROBIOLOGYMICROBIOLOGY ANDAND INFECTIOUSINFECTIOUS DISEASEDISEASE RESEARCH.RESEARCH. ✦✦ UNDERSTANDINGUNDERSTANDING THETHE MOLECULARMOLECULAR MECHANISMSMECHANISMS BYBY WHICHWHICH PATHOGENSPATHOGENS EXERTEXERT THEIRTHEIR VIRULENCEVIRULENCE PROPERTIESPROPERTIES WILLWILL LEADLEAD TOTO NEWNEW ANTIBIOTICSANTIBIOTICS ANDAND VACCINES.VACCINES. TheThe WorldWorld fromfrom thethe Microbe'sMicrobe's PerspectivePerspective

✦✦ MicrobesMicrobes cannotcannot think;think; theythey simplysimply exploitexploit thethe humanhuman environmentenvironment solelysolely forfor growthgrowth andand survival.survival. MISSION:MISSION: SURVIVESURVIVE ANDAND MULTIPLYMULTIPLY TOTO ENSUREENSURE SURVIVALSURVIVAL OFOF THETHE SPECIES.SPECIES. FindFind thethe BestBest PlacePlace forfor thethe TroopsTroops toto InvadeInvade

✦✦ConceptConcept ofof Site:Site: PathogenPathogen CombinationsCombinations

– Staph infection: invasion through compromised skin. – Tuberculosis: inhalation into lung. – Strep infection: streptococci bind to throat epithelial cells. – Urinary tract infection: E. coli enter at urethral orifice. – Gastritis: stomach lining acceptable to Helicobacter pylori. InitialInitial InvasionInvasion (Infection)(Infection)

✦✦ SubtleSubtle InfiltrationInfiltration inin thethe QuietQuiet ofof NightNight andand OftenOften WithWith CamouflageCamouflage – Streptococcus pyogenes – Streptococcus pneumoniae and Neisseria meningitidis ✦✦ MassiveMassive invasioninvasion toto overwhelmoverwhelm thethe oppositionopposition – Some of the invaders can escape stomach acid (e.g., E. coli, Salmonella) EstablishingEstablishing aa "Beach"Beach Head"Head" (Colonization)(Colonization)

✦✦EnsuringEnsuring thethe availabilityavailability ofof foodfood andand waterwater (scavenging(scavenging ofof nutrients).nutrients). ✦✦EstablishingEstablishing aa goodgood defensedefense (armor;(armor; barriers)barriers) againstagainst anan offensiveoffensive (immune)(immune) attack.attack. TakingTaking thethe OffensiveOffensive (Invasion/Spread)(Invasion/Spread)

✦✦MovingMoving outout fromfrom thethe initialinitial sitesite toto moremore distantdistant sitessites thatthat offeroffer moremore territoryterritory andand moremore opportunitiesopportunities forfor survivalsurvival andand expansion.expansion. ExpandExpand toto NeighboringNeighboring EnvironmentsEnvironments

✦✦InfectInfect otherother individuals.individuals. ExamplesExamples ofof MicrobialMicrobial PathogenesisPathogenesis StrategiesStrategies -- VirusesViruses

✦ Viruses take over our cells and use them as "factories" to make new virus particles: – Budding - slow release; eventually stresses and kills the cell. – Lysis - rapid, complete destruction of the cell by explosion. – Latent infection - more protracted, insidious infection that may or may not lead to destruction of the infected cell or may lead to cancer. BacteriaBacteria

✦✦BacteriaBacteria exploitexploit aa widewide spectrumspectrum ofof parasiticparasitic strategies.strategies. StaphStaph InfectionsInfections

✦ Staphylococci are part ofof ourour normalnormal skinskin floraflora butbut cancan bebe highlyhighly infectious under appropriate circumstances (e.g., compromised skin). – Principal virulence factors are a combination of potent toxins:

• coagulase (makes fibrin clots on surface of bacterial cell). • other enzymes that digest tissue. • exfoliative toxin; "scalded skin syndrome." • toxic-shock syndrome toxin. • enterotoxins; classic "food poisoning." ShigellosisShigellosis (Bacillary(Bacillary Dysentery)Dysentery)

✦✦ToxinToxin -- causescauses severesevere diarrheadiarrhea andand cancan affectaffect centralcentral nervousnervous system.system. ✦✦EfficientEfficient invasioninvasion ofof cellscells inducedinduced byby ShigellaShigella surfacesurface proteins-proteins- intracellularintracellular residenceresidence (a(a goodgood "hiding""hiding" place!).place!). ✦✦SpreadSpread toto adjacentadjacent cellscells viavia aa cleverclever mechanismmechanism (without(without everever leavingleaving itsits intracellularintracellular residence).residence). ✦✦MassiveMassive tissuetissue inflammationinflammation andand destructiondestruction (blood(blood andand pus).pus). TuberculosisTuberculosis

✦✦MycobacteriumMycobacterium tuberculosistuberculosis entersenters thethe lunglung (via(via microdroplets).microdroplets). ✦✦AlsoAlso needsneeds toto taketake upup anan intracellularintracellular residence:residence: trickstricks cellscells intointo thinkingthinking itit isis somethingsomething thatthat shouldshould bebe takentaken upup (coats(coats itselfitself withwith aa hosthost protein).protein). ✦✦Chronic,Chronic, slow-progressingslow-progressing infectioninfection forfor yearsyears oror decades.decades. EscherichiaEscherichia colicoli

✦✦ E.E. colicoli -- PartPart ofof ourour normalnormal intestinalintestinal floraflora -- usuallyusually notnot harmful.harmful. –– EntericEnteric infectionsinfections –– UrinaryUrinary tracttract infectioninfection –– SepsisSepsis -- bloodblood infections.infections. –– MeningitisMeningitis -- infectioninfection ofof thethe centralcentral nervousnervous system.system. AnthraxAnthrax

✦✦AnthraxAnthrax -- actuallyactually aa diseasedisease ofof farmfarm animals;animals; humanshumans areare infectedinfected onlyonly rarelyrarely.. However,However, humanhuman infectioninfection isis veryvery destructivedestructive.. ✦✦ Organism:Organism: BacillusBacillus anthracisanthracis –– CutaneousCutaneous anthraxanthrax (organisms(organisms [spores][spores] enterenter thethe skin).skin). –– InhalationInhalation anthraxanthrax (from(from dust,dust, wool,wool, oror debrisdebris fromfrom hides);hides); hashas implicationsimplications forfor bioterrorism.bioterrorism. –– AA three-componentthree-component toxintoxin isis veryvery potent.potent. HelicobacterHelicobacter pyloripylori

✦ Stomach ulcers from Helicobacter pylori - A huge clinical problem: – Ingestion of organism. – Resistant to stomach acid; bacterium attaches to mucosal epithelial cells. – Organisms are below the mucous layer; they produce ammonia to neutralize stomach acidity. – Organisms create a slow (years to decades) inflammatory response. – Persons with H. pylori gastritis have 3- to 12-fold increased risk of stomach cancer. ParasitesParasites

✦ Malaria (several protozoan species of Plasmodium) - transmitted to humans by bite of female Anopheles mosquitoes. – A major global health problem in tropical developing countries. – Plasmodium is a model intracellular parasite - carries out a key part of its life cycle inside the human red blood cell. – Produces enzymes that breakdown hemoglobin of red blood cell as a key nutrient source. – Complex life cycle; partly in humans and partly in mosquitoes. – Phase in humans can be cyclic and thus give rise to relapses over several years. Treatment is difficult and resistance to drug therapy is highly problematic. HookwormHookworm-- anan IntestinalIntestinal RoundwormRoundworm.. LifeLife Cycle:Cycle: Penetrate skin Immature worms Heart and lungs

Eggs mature Coughed up

Eggs in soil Swallowed

Eggs excreted Small intestine

Eggs in feces Larvae mature Lay eggs ComparisonComparison ofof VirusesViruses andand BacteriaBacteria

VirusesViruses BacteriaBacteria ✦✦ SizeSize 10-100 times larger

✦✦ ReplicateReplicate onon theirtheir own?own? NoNo YesYes ✦✦ StructureStructure SimpleSimple ComplexComplex cellcell (Genetic material +protein coat only) ✦✦ MetabolicMetabolic FunctionsFunctions NoNo YesYes ✦✦ SusceptibleSusceptible toto classicalclassical NoNo YesYes antibiotics?antibiotics? Summary/Take-HomeSummary/Take-Home LessonsLessons

1.1. TheThe “Microbial“Microbial World”:World”: viruses,viruses, bacteria,bacteria, protozoa,protozoa, fungi,fungi, andand otherother parasites.parasites. 2.2. MicrobesMicrobes areare everywhereeverywhere inin thethe environment;environment; humanshumans areare heavilyheavily colonized!colonized! 3.3. InIn humans,humans, therethere areare “avirulent”:“avirulent”: (e.g.,(e.g., normalnormal floraflora whichwhich areare beneficial)beneficial) microbesmicrobes vs.vs. thosethose whichwhich areare “opportunistic”“opportunistic” oror “pathogenic.”“pathogenic.” 4.4. SoleSole missionmission ofof microbes:microbes: GetGet byby andand multiply!multiply! Summary/Take-HomeSummary/Take-Home LessonsLessons

5.5. VirusesViruses “take“take over”over” ourour cellscells andand useuse themthem asas “factories”“factories” toto makemake newnew viruses.viruses. 6.6. BacteriaBacteria andand parasitesparasites havehave evolvedevolved highlyhighly ingeniousingenious strategiesstrategies toto evadeevade ourour immuneimmune responsesresponses andand toto exploitexploit diversediverse environmentsenvironments withinwithin thethe humanhuman body.body. 7.7. BacteriaBacteria andand parasitesparasites relyrely onon traitstraits (“virulence(“virulence factors”)factors”) toto makemake themthem “pathogenic”.“pathogenic”. 8.8. StudiesStudies ofof microbialmicrobial “virulence“virulence factors”factors” willwill provideprovide novelnovel insightsinsights forfor developingdeveloping newnew antibioticsantibiotics andand vaccines.vaccines.