【精品】七年级生物上册教案27

1,Viral infections:mechanisms of persistence,Graham Tipples, PhD, FCCM, D(ABMM)National Microbiology LaboratoryGraham.Tipplesphac-aspc.gc.caPhone: 789-6080,Microbial PathogenicityFebruary 3, 2011,2,Lecture Outline,Introduction to persistent infectionsAvoiding the immune systemLatencyVZVHSV-1Chronic infectionsPersistent infection with shedding chronic infectionsPersistent infection without sheddingSummaryBased mainly on “Failure to eliminate microbe” chapter in “Mims Pathogenesis of Infectious Disease”,3,Student seminar topics forpersistent viral infections,Measles virus central nervous system infectionHepatitis B chronic infectionHepatitis C chronic infection,4,Introduction - Persistent Infections - 1,Persistent infections usually represent a secondary event, following on from an initial acute infection.Persistent infections are not usually significant causes of acute illness, but they are important for five reasons:They enable the infectious agent to persist in the communityThey can be activated in immunosuppressed patientsSome are associated with immunopathological diseaseSome are associated with neoplasmsSome are immunosuppressive (HIV) and permit disease caused by other normally harmless persistent microorganismsPersistent infections cannot by definition be acutely lethal, in fact they tend to cause only mild tissue damage or disease in the host,5,2 types of persistent infectionschronic viral infectionscharacterized by continuous shedding of the virus for prolonged periods of time.congenital infections with rubella virus or cytomegalovirus (CMV)chronic infections with HBV or HCVassociated disease may be as a consequence of progressive injury to the host tissues or by immune-mediated destruction of virus-infected cells.latent viral infectionscharacterized by the maintenance of the viral genome in host cells in the absence of viral replication.herpesviruses and retrovirusesassociated disease usually as a consequence of reactivation of productive infection with subsequent cytopathogenicity or alteration of cell-cycle control mechanisms leading to neoplasia.The distinction between chronic and latent infection is not always readily apparent for some viruses e.g. HIV,Introduction - Persistent Infections - 2,6,Viruses causing persistent infections must be able to evade the host immune system and have a mechanism to attenuate their virulence.Preferred sites for establishment of persistent viral infectionsneurons (e.g. HSV, VZV, measles virus, poliovirus, JC virus)liver (e.g. HBV, HCV)lymphocytes or monocytes (e.g. CMV, EBV, HIV, HTLV)CNS can be a preferred site for persistent viral infection since it is not readily accessible by the immune system.,Introduction - Persistent Infections - 3,7,Persistent infections: failure to eliminate microbe,8,Avoiding the immune system - 1,Immune response to an infectious agent:Cell mediated immunityAntibody responsePersistence: failure of the hosts immune response to eliminate the microorganismThere are many strategies that microorganisms have evolved to by-pass or overcome host defenses:toleranceimmunosuppressionantiphagocytic strategiesabsence of suitable target for the immune system“mopping up” antibodiesinterference with immune forcesantigenic variationreduced interferon induction or responsivenessmicrobial presence in inaccessible sites“invade the immune system, evade the immune system”,9,Avoiding the immune system - 2,Tolerance: immunologically specific reduction in the immune response to a given antigen (ie lack of responsiveness)Molecular mimicry - microbial Ag is similar to host Ag so immune response to this Ag is weakImmunosuppression: host shows depressed immune response to antigens unrelated to those of the infecting organism.Infectious agents that multiply in macrophages or lymphoid tissue (e.g. many viruses including measles, mumps, influenza, EBV, CMV, HIV) are especially likely to cause immunosuppression.HIV infects both CD4+ T cells and macrophages resulting in loss of immune reactivity, particularly T helper function.,10,Microbial adaptations to the encounter with the phagocytic cellMicroorganisms first exposed to the phagocytes.Microorganisms which attract, are ingested, and killed by phagocytes fail to cause a successful infection.Most successful microorganisms have evolved to some degree to either avoid phagocytes or interfere with antimicrobial activities of the phagocytes.Most viruses do not infect phagocytes, but the following viruses do multiply in macrophages (entry via endocytosis or fusion, not phagocytosis):Herpes virusesMeasles virusPoxvirus,Avoiding the immune system - 3,11,Phagocytosis and intracellular digestion,12,Antiphagocytic strategies,13,Avoiding the immune system - 4,Absence of suitable target for immune responseIntracellular microorganisms evade immune response within infected cells (e.g. HSV and VZV persistent infection in dorsal root ganglion cells, and EBV in circulating lymphocytes)Direct cell to cell spread (not extracellular)HSV spreads in presence of neutralizing AbSome enveloped viruses (corona and flaviviruses) avoid displaying Ags on cell surface by budding into cytoplasmic vesicles - virion release via fusion of vesicle and plasma membrane.Antibodies mopped up by soluble microbial antigensHepatitis B virus - HBsAg is present in serum of carriers at 1013 per mLLocal interference with immune forcesViruses causing latent infections can evade Ab and CMI responses by decreasing viral protein expression.Herpes viruses encode genes which interfere with immune system functionAdenovirus E3/19K protein blocks cell surface expression of MHC class I proteins diminished presentation of viral Ags to cytotoxic T cells.CMV US11 gene product downregulates MHC class I proteins by targeting these molecules to proteosomes for degradation.,14,Avoiding the immune system - 5,Antigenic variationallows escape from neutralizing AbsHIV - persistent infection, shows antigenic variationInfluenza viruses - antigenic shift, antigenic driftReduced interferon induction or responsivenessInterferon - cytokines which influence the function of T cells by increasing the expression of MHC proteins and also have antiviral activity.Viruses are generally sensitive to interferon - evasion by failing to induce IFN production in the host or if they are resistant to action of interferonVaccinia virus - secretes a soluble receptor which binds and inactivates IFNHIV, adenovirus and EBV - produce RNA molecules which bind to PKR (an IFN induced enzyme)Adenovirus - insensitive to IFNHBV - poor IFN inducer,15,Microbial presence in sites inaccessible to the immune responseMany viruses persist in the infected host and are shed to the exterior via the saliva (HSV, CMV), milk (CMV) or urine (polyomavirus in mice) and are therefore only exposed on the lumen of the salivary gland, mammary gland or kidney tubule. It is difficult for T cells and Ab to reach the lumen and eliminate the infection.“Invade the immune system, evade the immune system”Infection of lymphoreticular tissues by viruses exhibiting systemic infection or persistence:Adenovirus (lymphocytes)Epstein-Barr virus (lymphocytes)Cytomegalovirus (macrophages)Measles virus (lymphocytes)Rubella virus (lymphocytes and macrophages)HIV (lymphocytes and macrophages),Avoiding the immune system - 6,16,Ab and CMI in resistence to systemic infections,17,Latency,Any form of persistent infection endows a microorganism with a greatly enhanced ability to remain in the host population as well as in the infected individual.Latency (ie microorganism is present but not apparent) represents an extreme manifestation of persistence.Significance of persistence in latent form evident when measles is compared with chickenpoxMeasles not normally persistentImmune response controls and eliminates the infectionLife long immunitySusceptible hosts required for persistence of virus in the community500,000 is minimum population to maintain in a closed community without outside introduction of virus,18,Latency - Varicella-zoster virus (VZV),VZV causes a persistent infection characterized by latencyPrimary infection typically in children (chickenpox/varicella)Highly infectious for susceptibles in the community.Recovery from infectionVirus disappears temporarily from the communityVirus latent in dorsal root ganglion in non-infectious state kept under control by CMIReactivation of VZV when CMI wanes resulting in shingles or zoster - infectious vesiclesVZV can be maintained in an isolated community with a population of less than 1000Acute infection, apparent recovery (latency) and later in life a second acute infection where virus reappears and is shed to the exterior.,19,Latency - Herpes Simplex Virus 1,Primary infection usually occurs during infancy or early childhood causing a mild acute illness with stomatitis and slight fever.After apparent recovery from initial infection, virus becomes latent in the trigeminal ganglion supplying the mouth.HSV-1 is present in the neurons in a free episomal form.Reactivation of the virus in the ganglion can occur later in life, virus travels down the nerve and causes a vesicular eruption (lips or nostrils) cold sore.The cold sore contains infectious virus.Factors which activate HSV-1 include:coldsfeversmenstruationpsychological factorssunlight probably stimulates the sensory nerves causing viral reactivation, or causing a subclinical spontaneously reactivating lesion to become an overt lesion.,20,21,Latency - HSV-1 latency/reactivation mechanism,Activation of HSV-1 genome transcription depends on the interaction of the virion protein, VP16, with cellular proteins.Latency eitherwhen activating cellular proteins are absent, orrepressor proteins bind to VP16 and/or the activating cellular proteins with the result that normal transcription is inhibited.During latency, there is limited transcription of viral RNAs known as latency-associated transcripts (LATS).Latency is broken by an upregulation of the synthesis of a critical amount of LATS, thus enabling general transcription to start.,22,Latency - HSV-1 latency/reactivation mechanism contd,In a mouse experimental model, virus reactivation is common in ganglion cells, but the immune responses generally suppress the viral replication before the pathogenic sequence occurs.Virus travels down the nerve, infects the dermal cells and then the epidermal cells before a lesion is produced.In this way, a clinial lesion represents the failure to control the growth and spread of reactivating virus.2 stagesspontaneous reactivation in the ganglion (resulting in itching sensations prior to appearance of lesions similar to the “mad itch” in pigs as a result of pseudorabies virus infection).spread of virus from nerve endings to dermal and epidermal cells which is subject to immune control.HSV-1 reactivation can occur in the absence of visible skin or mucosal lesions, which may be a result of the immune system controlling the infection before production of lesions.,23,Persistent infection with shedding chronic infection - 1,During persistent infections, the microorganism can be found continuously in the individual, and in this case are shed continuously, without causing further disease.Epstein-Barr virus and HSV-1 are shed in the saliva, often for long periods after the initial infection. HSV-1 presence in the saliva may or may not correlate with cold sores. Similarly, human herpes viruses 6 and 7 are shed in the saliva in asymptomatic individuals.Hepatitis B virus can persist in the blood for long periodsapproximately 0.1% of apparently normal individuals in northern Europe and North America are carriers (higher is other parts of the world).blood of an HBV carrier is infectious.Significance of persistent infection with sheddingmaintenance of the infection in the community is made easier,24,Persistent infection without shedding chronic infection - 2,Many microorganisms that persist in the body are rarely if ever shed to the exterior. Many are viruses and most give rise to no ill effects.In these cases, the significance is to the individual as opposed to the community.e.g. AdenovirusesMany adenoviruses persist in lymphoid tissues after initial infection, causing no disease, but are still recoverable from normal adenoids or tonsils. There is little or no infectious virus in these tissues.However, when these tissues are removed and placed in culture where immune controls are no longer present, infectious virus grows.Adenoviruses can be recovered from 1/3 of all adenoids and tonsils removed from individuals 10 yrs of age, and they should be regarded as normal microbial flora.Some chronic infections may be problematic if the immune system is weakend, and several can cause cancer (e.g. EBV).CMV is present in leucocytes of 5% of normal people so that infections can result from blood transfusions and organ transplantations.,25,Persistent infection without shedding chronic infection - 3,Retroviruses have an RNA genome which is reverse transcribed into cDNA as part of the replication cycle.cDNA becomes integrated into the host genome. Endogenous retroviruses vertically transmitted ultimate mechanism for parasitism.HIV persistent infection causing chronic disease and shows antigenic variation in the host.Significance of persistent infections without shedding:Persistent infections normally held in check by the immune system can be activated during weakend immune status.AIDSimmunsuppressive therapy during transplantation can result in reactivation of CMV (fever, pneumonitis or hepatitis)Persistent infections induce persistent immune responses, although failing to eliminate the microorganism, can sometimes cause pathological changes (e.g. circulating immune complexes (glomerulonephritis)Induction of tumor formationhuman T cell leukemia viruses 1 and 2 (HTLV-1/2)human papilloma virus (cervical cancer)Burkitts lymphoma and nasopharyngeal carcinoma caused by EBVliver cancer caused by HBV,26,Persistent Infections Summary,Chronic and latent persistent infectionsPersistent infections with or without viral sheddingAvoidance of the immune system is necessaryMany severe infections causing illness and death in communities are not persistent infections and are eliminated from the body after recovery (polio, plague, cholera etc).Persistent infections are important for the microbe for maintenance in small or isolated communities.Persistent infections are typically problematic for vaccine development.Persistent infections can reactivate in immunocompromised or immunosuppressed individuals.Some persistent infections can cause of malignant tumors.,27,IFN antiviral activity,IFN mechanism of antiviral activityInterferon - cytokines which influence the function of T cells by increasing the expression of MHC proteins and also have antiviral activity.IFN-alpha used for treatment of chronic hepatitis, AIDS-related Kaposi