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1、Lecture 8微生物学美国IndianaUniversityPurdueUniversity授课08 Still waters run deep.流静水深流静水深,人静心深人静心深 Where there is life,there is hope。有生命必有希望。有生命必有希望Lecture 8Overall StrategiesDefense against complementSubversion of phagocytosisSubversion of immune responsesBIOL 5332Lecture 8General AspectsPathogen finds i
2、tself in hostile territoryHost fights back and usuallybut not alwayswinsHosts defenses are interrelated and so are organisms countermeasuresBIOL 5333Lecture 8General AspectsGiven organism sometimes has numerous different virulence factorsDoes not have to harm tissue to be called virulence factor,alt
3、hough many doHave to determine precise role of each factor if a large number are involvedNot always sure in vitro situation is same as in disease stateBIOL 5334Lecture 8Defense Against ComplementOverall strategiesInhibit complement activationMask activating substancesCapsuleIgA antibodiesCover up ta
4、rget of complement membrane attack complexBIOL 5335Lecture 8Defense Against ComplementOverall strategies,continuedAppropriate inhibitor to activation to surfaceInactivate complement chemotaxin C5aBIOL 5336Lecture 8Prevent Complement ActivationMasking surface components that activate by the alternati
5、ve pathwayCapsulesMurein of S.aureus good activator,but is covered by capsuleCapsules rich in sialic acid of Group B streptococci and strains of E.coliBIOL 5337Lecture 8Prevent Complement ActivationIgA antibodiesMeningococci get coated with IgA antibodyDoes not activate complementPrevents other Ab t
6、hat can activate from reaching surface of cellBIOL 5338Lecture 8Prevent Complement ActivationCost of having capsule antigenicElicits activation by primary pathwayDefend better against immediate defenses than later onesBIOL 5339Lecture 8Prevent Complement ActivationCover up target of membrane attack
7、complex(outer membrane)Gram,such as Salmonella or E.coli Smooth strains with long 0 antigen polysaccharide chain do not allow access of mac while rough strains(with little or no 0 antigen)doCorrelates with pathogenicityBIOL 53310Lecture 8Subversion of PhagocytosisOverall strategiesInhibition of phag
8、ocyte recruitmentMicrobial killing of phagocytesEscape of ingestionBIOL 53311Lecture 8Subversion of PhagocytosisOverall strategies,continuedSurvival inside phagocytesEscape into the cytoplasmInhibition of lysosome and phagosome fusionResistance to lysosomal enzymesInhibition of phagocyte oxidative p
9、athwayAntibody effects(host counters)BIOL 53312Lecture 8Subversion of PhagocytosisGeneral aspectsBeing inside cell is not necessarily bad for an organismPowerful strategy is to grow within nonphagocytic cellShielded from antibodies and drugsBIOL 53313Lecture 8Subversion of PhagocytosisInhibition of
10、phagocyte recruitmentDirect inhibition of neutrophil motility and chemotaxisBordetella pertussis produces toxinsAdenylate cyclase toxinIncrease cyclic AMP in neutrophilsLeads to paralysisPertussis toxinImpairs migration of monocytesBIOL 53314Lecture 8Subversion of PhagocytosisMicrobial killing of ph
11、agocytesLeukocidins(exotoxins)kill neutrophils and macrophagesCan work at distance or after ingestionTypical producers are highly invasive bacteriaPseudomonas,staphylococci,group A streptococci,gas gangrene clostridiaBIOL 53315Lecture 8Subversion of PhagocytosisEscaping ingestionNaked capsule is eff
12、ective(pneumococci)Opsonized bacteria not as effectiveCountering opsonization by complement components or AbAny mechanism inhibitsActivation of complementSynthesis or activity of AbBIOL 53316Lecture 8Subversion of PhagocytosisEscaping ingestion,continuedCountering opsonization when antibodies are pr
13、esentStaphylococci and streptococciMake surface component(protein A)Binds to IgG molecules by the wrong end(Fc region)Cannot act as opsonins because Fc region not free to bind to Fc receptors on phagocytic cellsNot known if antiphagocytic defense is relevant to disease processBIOL 53317Lecture 8Subv
14、ersion of PhagocytosisSurvival inside phagocytesEscape into cytoplasmRickettsia(Rocky Mountain Spotted Fever)or trypanosomes of Chagas disease cross membrane of phagosome to enter cytoplasmSince lysosomes do not secrete contents into cytoplasm,organism is safeHow they enter cytoplasm is not known fo
15、r certainPossess surface-bound phospholipase,which may weaken membraneBIOL 53318Lecture 8Subversion of PhagocytosisSurvival inside phagocytes,continuedInhibition of lysosome and phagosome fusionExamplesbacteria that cause:TuberculosisPsittacosisLegionnaires diseaseBIOL 53319Lecture 8Subversion of Ph
16、agocytosisMechanism of tuberculosisInduced by complex glycolipids(sulfatides)not certainFacts:Inhibition must be due to modification of phagosome membraneMicroorganism might contribute by compounds secreted or present on the surfaceBIOL 53320Lecture 8Subversion of PhagocytosisSurvival inside phagocy
17、tes,continuedResistance to lysosomal enzymessurvive in phagolysosome(pH as low as 4)Leishmania(protozoa)resistance may be due to:Resistant cell surfacesExcretion of enzyme inhibitorsBIOL 53321Lecture 8Subversion of PhagocytosisSurvival inside phagocytes,continuedInhibition of phagocytes oxidative pa
18、thwayBacillus of Legionnaires diseaseInhibits hexose-monophosphate shunt and oxygen consumption in neutrophilsReduces respiratory burst for killing microbesStaphylococciproduces catalase that degrades hydrogen peroxide necessary for oxidative killingBIOL 53322Lecture 8Subversion of PhagocytosisSurvi
19、val inside phagocytes,continuedAntibody effects:host counters parasiteSometimes help host guard against microbial survival measuresAntibodies do not prevent entry into cells,but inhibit subsequent effectsRickettsia coated with antibody cannot pass through membrane into cytoplasmAntibodies against Le
20、gionnella prevent inhibition of phagolysosomal fusionBIOL 53323Lecture 8Subversion of Immune ResponseImmunosuppression:general aspectsHost becomes susceptible to other infections and survival probability is lessenedBIOL 53324Lecture 8Subversion of Immune ResponseAIDSinfects T4 inducer-helper lymphoc
21、ytesDepletion of cells leads to collapse of immune systemReduction in circulating lymphocytesImpaired delayed hypersensitivityDefective responses of T cells to AgReduction in T-cell numbers cytotoxic for tumor cells and virus infected cellsBIOL 53325Lecture 8Subversion of Immune ResponseB cell funct
22、ion is also impairedReduced production of specific IgIncreased chaotic production of nonspecific IgBIOL 53326Lecture 8Subversion of Immune ResponseOther immunosuppressive viruses:MeaslesTuberculosis more common after widespread measles outbreaksInfected T cells in vitro do not dieLose certain functi
23、ons,including ability to mount delayed hypersensitivity responseBIOL 53327Lecture 8Subversion of Immune ResponseInfected B cells in vitroStop synthesizing and releasing IgPrimary effect on B cellsNot secondary to action of virus on T cells or macrophageBIOL 53328Lecture 8Subversion of Immune Respons
24、eOther immunosuppressive viruses:Hepatitis B and influenzaImpair function of lymphoid cells without causing major structural damageImmune suppression as a result of inhibition of synthesis of lymphokinesLeishmanias(protozoa)BIOL 53329Lecture 8Subversion of Immune ResponseLeishmanias(protozoa)when gr
25、own in macrophageSuppress secretion of interleukin-1Important for initiating series of inflammatory and immunological reactions important for the eradication of the organismAlso explains T cell unresponsivenessSuppresses capacity of macrophage to make class I and class II products of major histocomp
26、atibility locus(MHC)Potential for marked suppression of cell-mediated immunityBIOL 53330Lecture 8Subversion of Immune ResponseFinal thoughtsInfection of lymphocytes is not immuno-suppressive in natureLarge number of organisms infect lymphoreticular tissues,but do not cause global disturbances to hos
27、t immunityBacteria that cause typhoid fever or brucellosis live in lymph nodes for long period of timeDo not induce noticeable immune suppressionBIOL 53331Lecture 8Subversion of Immune ResponseFrequent changing of antigenic coats(antigenic variation)Examples of bacteria,viruses,and protozoaTrypanoso
28、mes(protozoa)GonococciBorrelia(recurrent fever)Influenza virusesBIOL 53332Lecture 8Subversion of Immune ResponseTrypanosoma brucei(causative agent of sleeping sickness)Infects blood of interstitial fluids of animals and manExposed to circulating AbBIOL 53333Lecture 8Subversion of Immune ResponseTryp
29、anosoma brucei,continuedCovered with thick protein coat(variable surface glycoprotein)Undergoes antigenic shifts during infectionHave several hundred genes that encode different antigens,but express only one at a timeBIOL 53334Lecture 8Subversion of Immune ResponseTrypanosoma brucei,continuedWhen an
30、tibodies against one type are made:Number of parasites in blood dropsSoon replaced by new antigenic typeCan be many successive waves of antigenic changes in a single hostProtective immunity does not function wellBIOL 53335Lecture 8Subversion of Immune ResponseGonococcus and its adhesinPeriodic chang
31、e inPilin(protein fimbriae;attach to cells)Major outer membrane proteinsBIOL 53336Lecture 8Subversion of Immune ResponseAntigenic variation among influenza virusesmajor obstacle to effective vaccine(year after year)DefinitionsAntigenic driftminor changes that occur every 2 to 3 yearsAntigenic shiftm
32、ajor changes that occur about every 10 yearsBIOL 53337Lecture 8Subversion of Immune ResponseAntigenic variation,continuedMechanism involves two proteinsHemagglutinin-binds to cell receptorsNeuraminidase-changes receptorsBIOL 53338Lecture 8Subversion of Immune ResponseProteolysis of antibodiesMake ex
33、tracellular proteases that inactivate secretory IgA antibody(major Ab type on human mucosal surfaces;subclasses I and II)Cleave only subclass I at hinge region to leave complete by inactive peptide fragmentsExamples:Gonococci,meningococci,Haemophilus influenzae,and some pathogenic dental streptococc
34、iBIOL 53339Lecture 8Subversion of Immune ResponseProteolysis of antibodies,continuedSpecificity of IgA1 proteases from different bacteriaHighly specific for subclass IBiochemical and genetic differences that suggest property evolved independentlyPresence in fluids and tissuesActive form in infected
35、tissues and fluidsBIOL 53340Lecture 8Subversion of Immune ResponseProteolysis of antibodies,continuedPossible relationship to pathogenicity;suggested,not provenNonpathogeic relatives lack these proteasesFabulation(cleavage with Fab fragment attached)Ag unavailable for binding with intact antibody mo
36、leculesMay serve to protect some organisms against AbBIOL 53341Lecture 8Subversion of Immune ResponseOther viral survival strategies:general aspectsChronic infectionevade host defenses longerBIOL 53342Lecture 8Subversion of Immune ResponseHerpes infectionDo not usually enter extracellular fluid,but
37、pass among cells through cytoplasmic bridgesCan also be latent(reside within nerve cells but do not multiply)In these circumstances,not affect by antibodies,cell-mediated immunity,or interferonSurvive for long periods of time,then later reactivate(perhaps when defenses are lower)BIOL 53343Lecture 8Lecture 8Questions?Comments?Assignments.BIOL 53344