(病毒學(xué)教學(xué)課件）Viral pathogenesis

1、( (病毒學(xué)教學(xué)課件病毒學(xué)教學(xué)課件Viral Viral pathogenesispathogenesisDefinition: Viral pathogenesis is a process by which viruses produce disease in a host.Two levels of study- Within a host organism viral entry, spread, pathogenesis and diseases, immune responses, immune escaping - At the population level transmis

2、sion and spread among individuals, host susceptibility and resistance, vaccine protectionTools to study viral pathogenesisEpidemiology-Define pattern of disease and infection- Define the mode of transmission between hosts- Define relationship between infection, immunity and disease-Link to a virus t

3、o a specific disease-Formulate questions related to viral pathogenesise.g. HIV-1 and InfluenzaAnimal models for human viral diseasesA. Human viruses in animal models- Human viruses can replicate and cause diseases in animals without adaptation- Human viruses can replicate and cause diseases in anima

4、ls through a series of adaptation- The animals are genetically engineered to allow analysis of a human virus (such as transgenic and humanized SCID mice)-The animals are genetically engineered to express virus as a transgeneTools to study viral pathogenesis (contd)B. Animal viruses in animal models

5、that resemble human infection e.g. MCMV, HV68, SIV, FIV, EIAVCell culture and virus propagationPatient cohortsPathogens- Human pathogens- Veterinary pathogens- Wild type, variants, chimeras, recombinants and re-assortantsInoculation and Sampling (virology, immunology and pathology)Direct in vivo ima

6、gingVirologic, immunologic and pathophysiologic measurements At the organism level- viral entry- spread- pathogenesis and diseases- immune responses- immune escaping Outcomes of virus infection of a hostVirulence The virulence of a virus is its capacity, when compared with other closely related viru

7、ses, to produce disease in a host. Factors that influence virulence:- dose of virus- entry route- hosts age, sex, immune status and speciesRoutes of virus entryViral transmission Mode of transmissionExample/CommentAerosol/salviaRespiratory or salivary spread Influenza virusTransmission is difficult

8、to control EBV Measles Mumps Fecal/Oral spreadPolioControllable by public health measures Rotavirus Hepatitis A Venereal spreadHSVControllable by appropriate precautions HIV HPV Zoonoses Insect/human, Animal/human, Animal/insect/human Dengue, Rabies,Lassa, Hanta, Yellow feverHuman infection can be c

9、ontrolled by controlling vectors (insects) and/or by controlling animal infection. No (or rare) human to human transmission. Sources of viral transmission Respiratory, enteric, or genitourinary secretions Arbovirus infection through an arthropod vector Contaminated blood, body fluids and blood produ

10、cts Skin - HSV, HPV, and chickenpox Milk CMV, HIV, mumps, rubella, HBV, HCV, flavivirus Maternal-child transmission (vertical spread) HIV, HBV, HCV, HSV, and CMV Organ transplantation CMV, EBV, HIV, HTLV-1Factors that influence the transmission The amount of material transmitted (virus titers) and t

11、he route of transmission Host genetic factors and other physiologic determinantsInitiate infection via skin, conjunctiva and genital tract Site of infectionMethod of infectionVirus familyExamplesSkinMinor breaks/cutsHepadnaviridaeHepatitis B HerpesviridaeHerpes simplex 1 PapovaviridaePapillomavirus

12、PoxviridaeVaccinia Animal biteHerpesviridaeHerpes monkey B RhabdoviridaeRabies Vector biteBunyaviridaeRift Valley fever FlaviviridaeYellow fever, Dengue ReoviridaeColorado tick fever Togaviridae Eastern encephalitis InjectionFlaviviridaeHepatitis C HepadnaviridaeHepatitis B HerpesviridaeCytomegalovi

13、rus RetroviridaeHIV, HTLV I/II Conjunctiva ContactAdenoviridaeAdenovirus PicornaviridaeEnterovirus 70 Genital tractContactFlaviviridaeHepatitis C HepadnaviridaeHepatitis B HerpesviridaeHerpes simplex 2 PapovaviridaePapillomavirus RetroviridaeHIV Initiate infection via the respiratory tract Localizat

14、ion of diseaseVirus familyExampleUpper respiratory tractAdenoviridaeAdenovirus PicornaviridaeRhinoviruses, some enteroviruses Lower respiratory tractBunyaviridaeSin Nombre CoronaviridaeCoronavirus OrthomyxoviridaeInfluenza ParamyxoviridaeParainfluenza, RSV Generalized systemic disease without initia

15、l respiratory symptomsArenaviridaeLassa fever BunyaviridaeHantaan virus HerpesviridaeVaricella, CMV PapovaviridaeBK and JC viruses ParamyxoviridaeMumps, measles PoxviridaeSmallpox (extinct) TogaviridaeRubella Initiate infection via the alimentary tract Site of infectionVirus familyExampleMouth/oroph

16、arynxHerpesviridaeHSV, EBV, CMV Intestinal tract Producing enteritisAdenoviridaeAdenovirus 40, 41 AstroviridaeAstrovirus CaliciviridaeNorwalk agent ReoviridaeRotavirusProducing generalized disease usually w/o enteric illnessPicornaviridaePoliovirus, Hepatitis A Usually no symptomAdenoviridaeSome ade

17、noviruses PicornaviridaeEnterovirus ReoviridaeReovirus Relationship between initial site of viral infection and disease production Site of infectionLocal SystemicOropharynx CMV, EBV, HSV Respiratory tractInfluenza virusMeasles RSVMumps RhinovirusRubella Varicella Lassa Intestinal tractNorwalkHepatit

18、is A RotavirusPolio Genital tractPapillomavirusHepatitis B Hepatitis C HIV Virus spread in a hostLocalized versus systemic infection Route of infection (contact, inhalation, arthropod vector bite, needle)Cell tropism (enveloped versus non-enveloped viruses)Apical versus basolateral release of virus

19、in polarized epithelial mucosal cells (entry and budding sites in polarized cells; viral determinants and cell transport proteins) Hematogenous spreadPrimary replication in primary siteRegional lymph nodesEfferent lymphaticsThoracic ductSystemic circulation (blood-brain barrier) (or direct inoculati

20、on of virus into the bloodstream arthropod vector)Secondary sitesPrimary versus secondary viremiaInside nerve (poliovirus and HSV)Pathogenesis of flavivirus infectionHemorrhagic fever YFV and DHFVEncephalitits syndrome JEV and SLEVFever, arthralgia and rash DFV and WNVHepatitis - HCVPathogenesis (ec

21、tromelia) of mouse poxvirusThe magnitude and duration of viremia the dynamic relationship between virus and hostReplication at the primary and secondary sites and circulating blood cells such as HIV in CD4 T cells provide a continuing source of virus input into the circulation Macrophages in the RES

22、, serum antibody and complement act in concert to facilitate viral clearance (the size and net charge of virus particles, other pathogen)Replicated in macrophages (HSV, CMV, togavirus, flavivirus, poxvirus, lentiviruses, coronaviruses, arenaviruses, reovirus, piconavirus, rhabdoviruses, myxo- and pa

23、ramyxoviruses)- circumvent antiviral defense of macrophages: HLA down-regulation and inhibition of antiviral molecule production such as nitric oxide (NO)Replicated in vascular endothelial cells that may be a factor for their organ-specific tropismA correlation between the capacity of blood-borne ne

24、urotropic viruses to generate a high-titer viremia and their neuroinvasivenessTissue invasion Blood and brain barrier: tight junctions (zona occludens) join capillary cells of the cerabral microvasculature and an underlying dense basement membrane, with a notable exception of choroid plexus Transend

25、othelial transport of free viruses across capillary endothelial cells such as piconavirus, togavirus, bunyavirus, parvovirus, retrovirus Transendothelial transport of cell-associated viruses such as HIV inside macrophage Neural spread such as HSV, rabies virus, piconavirus, reovirus, coronavirus, ps

26、eudorabies virus, Borna disease virus and arbovirus Blood borne viruses enter into the CNSTropismThe pattern of systemic illness produced during an acute viral infection depends in large part on the specific host organs infected and in many cases on the capacity of viruses to infect (entry, replicat

27、ion, spread, etc) discrete populations of cells within these organs.Patterns of viral infectionAcute infection: symptomatic or asymptomatic; reactivationPersistent infection Reduced CPELimit or restrict apoptosisBalance between lytic versus non-lytic infection such as CMV nonproductive versus produc

28、tive infection in monocytes and macrophages, respectivelyThe generation defective interfering (DI) particles to modulate wild type virus infectionRestrict gene expression such as EBV in B cells, HSV in sensory neuron and papillomavirus in basal skin cellsMaintain viral genome in dividing versus non-

29、dividing cellsEvasion of the immune responseLatency such as HSVPrivileged sitesEscape mutants such as HIV1.Decrease in MHC expressionAdaptive Immune ResponsesImmunopathgenesisIn some cases, the balance between the protective and harmful effects of immunity shifts to immunity being the primaty cause

30、of tissue pathology and even death of the host. In these cases, virus-induced tissue damage is referred to as immunopathogenesis.Immunopathogenesis of HBV infectionClearance of HBV DNA is largely mediated by antiviral cytokines produced by cells of the innate and adaptive immune response. In particu

31、lar, interferon (IFN)-g, tumor necrosis factor (TNF)-a and IFN-a/b.In particular, the appearance of CD8+ T-cells that mediate cytolytic activity against HBV-infected hepatocytes coincide with an increase in alanine transaminase (ALT) detected in serum.Both a combination of cytolytic and antiviral cy

32、tokine activity is required to prevent infection of new hepatocytes and clear infected hepatocytes.Following clearance of the virus and a reduction in ALT, HBV-specific antibodies are detected, including antibodies to core, precore and surface. The presence of HBV envelope-specific antibody (HBsAb)

33、together with HBV-specific memory T-cells will protect the infected individual from recurrence or reinfection with HBV.Immunopathogenesis of HIV infectionImmune Evasion At the population level - transmission- spread among individuals- host susceptibility and resistance- vaccine protectionMode of transmissionAerosol/salviaRespiratory or salivary spread Influenza virusTransmission is difficult to cont