七年级生物上册教案

1、Viral infections:mechanisms of persistenceGraham Tipples, PhD, FCCM, D(ABMM)National Microbiology LaboratoryPhone: 789-6080Microbial PathogenicityFebruary 3, 20211Lecture OutlineIntroduction to persistent infectionsAvoiding the immune systemLatencyVZVHSV-1Chronic infectionsPersistent infection with

2、shedding chronic infectionsPersistent infection without sheddingSummaryBased mainly on “Failure to eliminate microbe chapter in “Mims Pathogenesis of Infectious Disease2Student seminar topics forpersistent viral infectionsMeasles virus central nervous system infectionHepatitis B chronic infectionHep

3、atitis C chronic infection3Introduction - Persistent Infections - 1Persistent 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 th

4、e 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 microorganismsPersiste

5、nt infections cannot by definition be acutely lethal, in fact they tend to cause only mild tissue damage or disease in the host42 types of persistent infectionschronic viral infectionscharacterized by continuous shedding of the virus for prolonged periods of time.congenital infections with rubella v

6、irus 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 t

7、he 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

8、 is not always readily apparent for some viruses e.g. HIVIntroduction - Persistent Infections - 25Viruses 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 infectionsneuro

9、ns (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 - 36Persistent infect

10、ions: failure to eliminate microbe7Avoiding the immune system - 1Immune 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 over

11、come 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 syste

12、m, evade the immune system8Avoiding the immune system - 2Tolerance: 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 depres

13、sed 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 mac

14、rophages resulting in loss of immune reactivity, particularly T helper function.9Microbial 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.Mos

15、t 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 virus

16、esMeasles virusPoxvirusAvoiding the immune system - 310Phagocytosis and intracellular digestion11Antiphagocytic strategies12Avoiding the immune system - 4Absence of suitable target for immune responseIntracellular microorganisms evade immune response within infected cells (e.g. HSV and VZV persisten

17、t 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 re

18、lease 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

19、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 mol

20、ecules to proteosomes for degradation.13Avoiding the immune system - 5Antigenic variationallows escape from neutralizing AbsHIV - persistent infection, shows antigenic variationInfluenza viruses - antigenic shift, antigenic driftReduced interferon induction or responsivenessInterferon - cytokines wh

21、ich 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 solu

22、ble 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 inducer14Microbial presence in sites inaccessible to the immune responseMany viruses persist in the infected host and are

23、 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,

24、evade the immune systemInfection 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 macropha

25、ges)Avoiding the immune system - 615Ab and CMI in resistence to systemic infections16LatencyAny 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 appa

26、rent) 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 viru

27、s in the community500,000 is minimum population to maintain in a closed community without outside introduction of virus17Latency - Varicella-zoster virus (VZV)VZV causes a persistent infection characterized by latencyPrimary infection typically in children (chickenpox/varicella)Highly infectious for

28、 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

29、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.18Latency - Herpes Simplex Virus 1Primary infection usually occurs during infancy or early childhood caus

30、ing 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, vir

31、us 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 sub

32、clinical spontaneously reactivating lesion to become an overt lesion.1920Latency - HSV-1 latency/reactivation mechanismActivation of HSV-1 genome transcription depends on the interaction of the virion protein, VP16, with cellular proteins.Latency eitherwhen activating cellular proteins are absent, o

33、rrepressor 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 criti

34、cal amount of LATS, thus enabling general transcription to start.21Latency - HSV-1 latency/reactivation mechanism contdIn a mouse experimental model, virus reactivation is common in ganglion cells, but the immune responses generally suppress the viral replication before the pathogenic sequence occur

35、s.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 sensati

36、ons 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 m

37、ay be a result of the immune system controlling the infection before production of lesions.22Persistent infection with shedding chronic infection - 1During persistent infections, the microorganism can be found continuously in the individual, and in this case are shed continuously, without causing fu

38、rther 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 c

39、an 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 t

40、he community is made easier23Persistent infection without shedding chronic infection - 2Many 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

41、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

42、 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,

43、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.24Persistent infection without shedding chronic infection - 3Retroviruses have an RNA genome which is reverse transcribed into

44、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 withou

45、t 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,

46、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 car

47、cinoma caused by EBVliver cancer caused by HBV25Persistent Infections SummaryChronic 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 infec

48、tions 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 immu

49、nocompromised or immunosuppressed individuals.Some persistent infections can cause of malignant tumors.26IFN antiviral activityIFN 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 Kaposis sarc