Mechanisms of anti-viral immunity and immunopathology PDF

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Explain the mechanisms of anti-viral immunity and immunopathology? Viruses cause disease after they break through the natural protective barriers of the body, evade immune control, and either kill cells of an important tissue (e., brain) or trigger a destructive immune and inflammatory response.  ...

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Explain the mechanisms of anti-viral immunity and immunopathology?

 Viruses cause disease after they break through the natural protective barriers of the body, evade immune control, and either kill cells of an important tissue (e.g., brain) or trigger a destructive immune and inflammatory response.  The natural protective barriers consist of biochemical, chemical and physical barrierso Biochem- lysozymes, sebaceous gland secretions, commensal organisms in gut and vagina, spermine in semen o Chemical and physical= mucus, clila lining trachea, acid in stomach, skin  Innate humoral and cellular immune responses are important for antiviral immunity. The longer the virus replicates in the body, the greater the dissemination of the infection, the more rigorous the immune response necessary to control the infection, and the greater the potential for immunopathogenesis.  Interferon and cytotoxic T-cell responses may have evolved primarily as antiviral defense mechanisms  The skin is the best barrier to infection. The orifices of the body (e.g., mouth, eyes, nose, ears, and anus) are protected by mucus, ciliated epithelium, tears, the gastric acid and bile of the gastrointestinal tract, and secreted IgA.  After the virus penetrates these natural barriers, it activates the antigennonspecific (innate) host defenses (e.g., fever, interferon, macrophages, dendritic cells, natural killer [NK] cells), which attempt to limit and control local viral replication and spread.  The hypersensitivity and inflammatory reactions initiated by antiviral immunity can be the major cause of the pathologic manifestations and symptoms of viral disease

 Early responses to the virus and viral infection (e.g., interferon, cytokines) can initiate local inflammatory and systemic responses. For example, interferon and cytokines stimulate the flulike systemic symptoms (e.g., fever, malaise, headache) usually associated with respiratory viral infections and viremias (e.g., arboencephalitis viruses).  These symptoms often precede (prodrome) the characteristic symptoms of the viral infection during the viremic stage.  Some viral infections induce a large cytokine response (cytokine storm), and this can dysregulate immune responses and may trigger autoimmune diseases in genetically predisposed individuals.  Later, immune complexes and complement activation (classic pathway), CD4 T-cell–induced type IV hypersensitivity, and CD8 cytolytic T-cell action may induce tissue damage. These actions often promote neutrophil infiltration and more cell damage

Innate immunity to viruses –  the innate response is triggered by infected cells or against infected cells, and the initial response is more likely to be mediated by interferon and cytokines (flulike symptoms) rather than inflammation mediated by complement and neutrophils.

 Viral molecules, including double-stranded RNA (which is the replicative intermediate of RNA viruses), certain forms of DNA and single-stranded RNA, and some viral glycoproteins, activate type I interferon production and innate cellular responses through interaction with cytoplasmic receptors or the Toll-like receptors (TLRs) in endosomes.  Innate responses prevent most viral infections from causing disease 1. The activity of NK cells is enhanced by IFNs produced by Tc (Cytotoxic t cells) and Th1 cells 2. Cytotoxic t cells specifically recognise surface MHC class 1 + peptide derives from degraded viral proteins and kill the infected cells before the virus replicates  interferon and cytokines – result in the production of o PKR- which leads to apoptosis and blocks viral protein synthesis o 2’5’- olgiodenylate synthetase = which leads to latent endonuclease production and eventually degrades viral mRNA o Mx Protein- that blocks viral transcription  The inflammatory response initiated by cell-mediated immunity is difficult to control and damages tissue.  Infections by enveloped viruses, in particular, induce cell-mediated immune responses that usually produce more extensive immunopathologic conditions. o For example, the classic symptoms of measles and mumps result from the T-cell–induced inflammatory responses rather than from cytopathologic effects of the virus. Adaptive immunity to viruses This involves using antibodies to neutralise virus or kill virally infected cells  Antigen-specific immune responses take several days to be activated and become effective.  The goal of these protective responses is to resolve the infection by eliminating all infectious virus and virus-infected cells from the body.  Antibody is effective against extracellular virus and may be sufficient to control cytolytic viruses because viral replication will eliminate the virion factory within the infected cell.  Antibody is essential to control virus spread to target tissues by viremia.  Cell-mediated immunity is required for lysis of cells infected with a noncytolytic virus (e.g., hepatitis A virus) and infections caused by enveloped viruses.  Extra reading-

o Prior immunity delivers antigen-specific immunity much sooner and more effectively than during a primary infection. o It may not prevent the initial stages of infection but, in most cases, does prevent disease progression. o On rechallenge, cell-mediated responses are more effective at limiting the local spread of virus, and serum antibody can prevent viremic spread of the virus. o Memory immune responses can be generated by prior infection or vaccination. o Antigenic variation over the course of several years (antigenic shift and drift) by influenza or during the lifetime of the infected individual by HIV limits the antiviral efficacy of antibody. o Failure to resolve the infection may lead to persistent infection, chronic disease, or death of the patient.  The presence of large amounts of antigen and antibody in blood during viremias or chronic infections (e.g., HBV infection) can initiate the classic type III immune complex hypersensitivity reactions.  These immune complexes can activate the complement system, triggering inflammatory responses and tissue destruction. o These immune complexes often accumulate in the kidney and cause glomerulonephritis.  Role of regulatory cells in adaptive immunity to viruses Over the last few years, it has become evident that regulatory T cells (Treg cells) may play an important role in the suppression of virus specific immune responses. Indeed, several studies suggest a role of diverse populations of Treg cells in the natural course of HCV and HBV infections.  Regulatory T cells are divided into a natural CD4+CD25+ Treg cell population and diverse populations of induced or adaptive Treg cells.  In the majority of HCV and a significant amount of HBV infections the immune system fails to eliminate the virus and viral persistence is established.  The virus specific T cell responses of the host may also cause tissue damage and autoimmune reactions in the liver, especially in the setting of chronic viral infection.  Extra reading – o Children generally have a less active cell-mediated immune response (e.g., NK or natural killer T [NKT] cells) than adults

and therefore usually have milder symptoms during infections by some viruses (e.g., measles, mumps, Epstein-Barr, and varicella-zoster viruses). o However, in the case of HBV, mild or no symptoms correlate with an inability to resolve the infection, resulting in chronic disease.

Viruses and malignant transformation Changes occur when tumour viruses cause transformation of cultured cells  Many of these changes are relevant for tumour production In vivo  Thes eani malv i r us esdonotgener al l yc aus edi s eas ei mmedi at el y f orc er t ai nani malc el l s .  I ns t ead,ani malc el l sar eper s i s t ent l yi nf ect edwi t hs uchv i r us es , t heDNAofwhi c h( pr ov i r us)i si nt egr at edi nt ot hec hr omosomal DNAoft hehos tc el l .  I ngener al ,c el l swi t hi nt egr at edpr ov i r alDNAar ec onv er t ed i nt oc ancerc el l s ,aphenomenonk nownasmal i gnant t r ans f or mat i on  Thehal l mar koft hes et r ans f or medani malc el l si s o t hatt hei rgr owt hi suncont r ol l abl e; unl i k enor malc el l s , o t hei rgr owt hi snoti nhi bi t edbyc ont actwi t hot herc el l s , o andt heyl oset hei rc apaci t yt oadher e( anc hor )t oc er t ai n s ur f ac es .

Gr owt hofnor malt i s s uesandor gansi sal s ocont r ol l edbya genet i cphenomenonc al l edpr ogr ammedc el ldeat h,orapopt osi s , i nwhi chac er t ai nnumberofc el l swi l ldi eandbeel i mi nat edaf t era fi ni t enumberofdi v i s i ons .  Mal i gnantt r ans f or mat i oncani mpedepr ogr ammedcel ldeat h,t hus al l owi ngt hec el l st ogr owuncont r ol l edandr es ul t i ngi ncanc er . 

Extra reading- (asked before in exam q even though not mentioned) o There are 4 potential outcomes of a viral infection – o Failed infection (abortive infection) o Cell death (lytic infection) o Replication without cell death (persistent infection) o Presence of virus without virus production but with potential for reactivation (latent-recurrent infection)

o Lytic infectionso Lytic infection results when virus replication kills the target cell. Some viruses damage the cell and prevent repair by inhibiting the synthesis of cellular macromolecules or by producing degradative enzymes and toxic proteins. o For example, HSV and other viruses produce proteins that inhibit the synthesis of cellular DNA and mRNA and synthesize other proteins that degrade host DNA to provide substrates for viral genome replication. Cellular protein synthesis may be actively blocked (e.g., poliovirus inhibits translation of 5 ′-capped cellular mRNA) or passively blocked (e.g., through production of much viral mRNA that successfully competes for ribosomes) o Viral infection or cytolytic immune responses may induce apoptosis in the infected cell. Apoptosis is a preset cascade of events that, when triggered, leads to cellular suicide. This process may facilitate release of the virus from the cell, but it also limits the amount of virus that is produced by destroying the viral “factory.” As a result, many viruses (e.g., herpesviruses, adenoviruses, hepatitis C virus) o Replication of the virus and accumulation of viral components and progeny within the cell can disrupt the structure and function of the cell or disrupt lysosomes, causing cell death. o Expression of viral antigens on the cell surface and disruption of the cytoskeleton can change cell-to-cell interactions and the cell’s appearance, making the cell a target for immune cytolysis. o Viral nucleic acids in the cytoplasm can activate pathogenassociated molecular pattern (PAMP) receptors to activate the inflammasome, cytokine, and interferon responses that can limit virus replication. o Persistent infection – o occurs in an infected cell that is not killed by the virus. Some viruses cause a persistent productive infection because the virus is released gently from the cell through exocytosis or through budding (many enveloped viruses) from the plasma membrane. o the longer the virus remains in the body and the more virus is produced to spread to other cells or individuals. o Latent infectiono may result from DNA virus infection of a cell that restricts or lacks the machinery for transcribing all the viral genes, or the virus may encode functions that suppress virus replication (e.g.,

cytomegalovirus) to extend its parasitism. The specific transcription factors required by such a virus may be expressed only in specific tissues, in growing but not resting cells, or after hormone or cytokine induction. o For example, HSV establishes a latent infection in neurons that do not express the nuclear factors required to transcribe the immediate early viral genes, but stress and other stimuli can activate the cells to allow viral replication....