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C24 Viral infection and immunity 樊晓晖 教授 第24章 病毒的感染与免疫 Section I Mode of viral infection Direct person-to-person spread. Horizontal Transmission vertical infection Relies on PERSISTENCE of the agent to transfer infection from parents to offspring. Transmission and portal of entry • Vertical transmission • Horizontal transmission Several forms of vertical transmission can be distinguished: • 1.Neonatal infection at birth, e.g. gonorrhorea, AIDS. • 2.Infection in utero e.g. syphilis, CMV, Rubella (CRS), AIDS. • 3. Germ line infection - via ovum or sperm. 第24章 病毒的感染与免疫 Section II Types of viral infection Inapparent infection ( Subclinical infection) . 1、 Apparent infection Acute infection 2、 Chronic infection 3、 chronic Persistent Infection latent Slow virus infections 第24章 病毒的感染与免疫 Persistent Infection • ① Chronic Infection :Virus can be continuously detected ; mild or no clinical symptoms may be evident. • ② Latent infection :The Virus persists in an occult, or cryptic, from most of the time. There will be intermittent flare-ups of clinical disease , Infectious virus can be recovered during flare-ups . Latent virus infections typically persist for the entire life of the host • ③ Slow virus infection : A prolonged incubation period, lasting months or years, daring which virus continues to multiply. Clinical symptoms are usually not evident during the long incubation period . 带状疱疹(水痘病毒感染 后潜伏在脊髓后跟N节) Mechanism of Persistent Infection • • • • • Immunity is weak; Viral antigenicity is weak; Viruses is in protective position; Viral variation; Viral genes integration. 第24章 病毒的感染与免疫 •Processes and fates of infections 1. local Infection processes:2. systemic 1. die Infection fates: 2. Subclinical infection 3. Abortive infection 4. Recover •Animal model 第24章 病毒的感染与免疫 Section III Pathogenicity of viruses I. Effects of viral infection on cells • According to the interaction host cells and viruses between cytocidal effect include Steady state infection Apopotosis Transformation Integrated viral infection Formation of inclusion body Cytocidal infection •Severe,cells lyse and die •Occur in non-enveloped virus •Cause Cytopathological effects(CPE) Cells rounding Degeneration, Aggregation Loss of attachments to substrate 上皮细胞epithelial cells – 腺病毒adenovirus uninfected slides from CDC early infection late infection 上皮细胞epithelial cells – 呼吸道合胞病毒respiratory syncytial virus uninfected slides from CDC respiratory syncytial virus 纤维母细胞fibroblastic cells – 单纯疱疹病毒herpes simplex virus uninfected slides from CDC early infection late infection 纤维母细胞fibroblastic cells – 脊髓灰质炎病毒poliovirus uninfected slides from CDC early infection late infection Pathogenicity: Viral early protein •Blocking synthesis of Some cellular protein and nucleic capsid acid destroy •Toxicity of viral protein injury •Affect cellular lysosome •Alter the cellular organ 。 稳定状态感染 Steady state infection •Enveloped viruses, •Without lyses of cells •Release by budding •Change of cell membrane •Formation of auto and fusing of cells antigen Fig A multinucleate giant cell 细胞凋亡 apoptosis HIV Cell transformation, SV40 Integration of viral genes •DNA viruses and retro-viruses •The viral genetic information may become integrated as DNA in the cellular genome or may persist as episomal DNA in these surviving cells. •Oncogenic transformation occur •New antigen appears. Interaction between viruses and hosts • Types of infection. –HBV: steady and integration infection –Herpesviruses: Cytocidal,steady and integration infections. –Most viruses, only one type infection 二、 Effects of virus infection on immune system • Inhibit or destroy immune system • Pathological effects caused by caused by humorol immunity • Pathological effects cellular immunity Inhibit or immune system •HIV •Measle virus destroy Pathological effects by humorol immunity caused • Viruses infect cells, new Ag present on cell membrane →type Ⅱ hypersensitivity damage cells • Viral Ag combines with Ab, precipitate on basic membrane of blood vessel→ type III 型 hypersensitivity damage cells. Pathological effects caused by cellular immunity •Viruses infect cells, new Ag present on cell membrane →recognized by specific CTL) type IV hypersensitivity kills cells Section 4 Anti-virus immunity IFN Innate immunity ( nonspecific) NK cells Humorol immunity Adaptive immunity ( specific) Cellular immunity IFN • Interferons are proteins produced by cells infected with viruses, or exposed to certain other agents, which protect other cells against virus infection or decrease drastically the virus yield from such cells. Interferon itself is not directly the antiviral agent, but it is the inducer of one or many anti-viral mechanisms Interferon inducing agents • (1) Viruses. • (2) dsRNA is a potent inducer, both viral intermediates, and synthetic polyI-C. • (4) Certain Bacterial infections, and the production of endotoxin. • (5) Metabolic activators/inhibitors. Mitogens for gamma induction, also a variety of tumor promoters induce IFNs. , in particular PTA-phorbol tetradecanoate acetate, butyrate, dexamethasone Kinds and sources IFNs Kinds INF-α Principal cell source Epithelium and leukocytes IFN-β type I Fibroblasts IFN-γ T lymphocytes typeⅡ IFN IFN Mechanism of action • Release from an initial infected cell occurs • IFN binds to a specific cell surface receptor on an other cell • IFN induces the “antiviral state” : synthesis of protein kinase, 2’5’ oligoadenylate synthetase, and ribonuclease L • Viral infection of the cell activates these enzymes • Inhibition of viral and cellular protein synthesis occurs Application of IFNs •Anti viral infection •Anti tumor treatment •Immuoregulation。 Diseases currently treated with IFN-alpha and IFN-beta • hepatitis C • hepatitis B • papilloma warts and early trials with cervical carcinoma • Kaposi sarcoma of AIDS, • colon tumors • kidney tumors ( usually in combination with other drugs). • Basal cell carcinoma • Breast cancer combined with tamoxifan. Nature killer/ NK cell •NK cells are Activated by IFN-alpha/beta •NK cells are Activated by IFN-alpha and IL-2 and Activate macrophage •NK cells target and kill virus infected cells NK cell Macrophages • Macrophages filter ciral particles from blood • Macrophages inactivate opsonized virus particles • Macrophages present viral antigen to CD4 T cells Complement • Enhancing neutralization of Antibody • Enhancing phagocytosis of virus particles • Lysis 二 Specific immunity •humorol •cellular anti-viral Overview of Specific immunity • specific recognition and selective elimination of foreign molecules. • Involves specificity, diversity, memory, and self/nonself recognition. Humorol immunity • Abs against viruses –NeutrolizationAb:IgG、IgM、IgA –nonneutrolizing: otherantibody • Extracellular viral infections Antibody IgG Function Memory Blood and tissue IgM Primary response Clear viruses in blood - IgA Mucus immunit y C: classic pathway C : C3 pathway +++ - - - + placenta +++ - - ADCC ++ - - Antibody Antibody neutralizes extracellular virue: it blocks viral attachment proteins it destablilizes viral structure Antibody opsonizes virus for phagocytosis Antibody promotes killing of target cell by the complement cascade and antibody-dependent cellular cytotoxicity Antibody resolves lytic viral infections Antibody blocks viremic spread to target tissue IgM is an indicator of recent or current infection IgG is more effective than LgM Secretory IgA is important for protecting mucosal surfaces Neutralization antibody •Neutralization : Neutralization antibody binds virus to terminate the viral infectivity Mechanism of neutralization Ab: • Block viruses to attach and penetrate • Virus combine with Ab to immune complex, facilitate the phygocytosis of macrophage • Ab combines with enveloped virus, activate complement to lyse virus Cellular immunity •Intracellular viral infection •CTL •DTH Maintaining duration of anti-viral immunity •Varied by different viruses, •Factors –Viral antigenecity is single or steady –Viramia –Variation of virus surface Ags. Summary • The ability of viruses to cause disease can be viewed on two distinct levels: (1) the changes that occur within individual cells and (2) the process that takes place in the infected patient. • The fundamental process of viral infection is the viral replication cycle in a host cell. The cellular response to that infection may range from cell death or cancer to no apparent effect. • The host response to an invading virus will depend upon the types of the infectious agent and where it is encountered. • Virus infections may be clinical, sub -clinical, acute, chronic, latent, and delayed. • Interferons (IFNs) are host - coded proteins of the large cytokine family that inhibit viral replication and can modulate humoral and cellular immunity. • Host defenses against viruses fall into two major categories: (1) nonspecific, of which the most important are interferons; and (2) specific, including both humoral and cell-mediated immunity. 复习思考题 何为垂直传播?何为水平传播? 病毒感染的类型有哪些? 病毒对宿主细胞有哪些直接作用? 名词解释: 水平传播(horizontal transmission)潜伏感染(latent infection)整合(integration)包涵 体(inclusion body) • 试简述干扰素的概念、种类、作用及其 抗病毒的主要机制 • • • •