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Immunity to viral Infections. Introduction. Acute Vs chronic viral infections. Formation of immune complexes. Antiviral antibody and / or sensitized T cell may react with and injure virus- infected cells.
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Introduction • Acute Vs chronic viral infections. • Formation of immune complexes. • Antiviral antibody and / or sensitized T cell may react with and injure virus- infected cells. • During viral infections, viruses face sequential barriers or obstacles they have to overcome one after the other. • These obstacles represent host defense mechanisms that operate in a chronological order.
IMMUNE DEFENSES • The immune response to viral infection consists of: • Innate (nonspecific) defense: first line of immune defense, responds to any infection, recognizes characteristics common to microbial invaders, consists of interferons, complement, natural killer cells, and it dictates the adaptive response • Adaptive (specific) defense: antibody response and the lymphocyte-mediated response also called the humoral and cell-mediated responses
HOST DEFENSE AGAINST VIRAL INFECTION • Primary defenses: physical and chemical barriers - skin - mucous secretions - tears - acid pH - surface cleansing mechanisms (swallowing, blinking)
The innate immune response • Can be activated rapidly and functions within hours of a viral infection. • Continued activity is damaging to the host. • Considerable interplay occurs between the adaptive and innate immune defenses. • Important components are: - cytokines - complement - collectins - natural killer (NK) cells
Cytokines • Regulatory proteins that mediate intercellular communication during an antiviral defense. • Their presence is one of the first indicators that the host has been infected. • They act locally, near the cells that make them. • They control inflammation, induce and antiviral state in cells and regulate the adaptive immune response. • They exert their activities by binding to specific receptors and activating gene expression. • Three types of interferons are the most important cytokines in the innate response to viral infection.
Interferons • Proteins or glycoproteins • Cell- coded but induced by viruses and other agents. • Two types: - Type I ( IFNαand β) - Type II or immune ( IFNγ).
Type I Interferon Members of the IFN α / βsuperfamily represent the prototypical IFN molecules. All genes and proteins comprising this family are related to each other structurally. The genes form a cluster that is located on the short arm of chromosome 9. IFNα subfamily is composed of 15 closely related molecular species with 77 % - 100% homology.
IFNβ shows about 25-30% homology with members of the α subfamily at the amino acid level and about 45% homology in the coding sequence at the DNA level. Most IFNα proteins are not glycosylated whereas IFNβis glycosylated. In the human species, IFNβ is the predominant species produced by various nonhematipoietic cells after virus infection (epithelial cells & fibroblasts). In contrast, cells of hematopoietic origin tend to produce IFNα. All type I IFNs, compete for binding to the same receptor, and they exert similar biological activities.
Type II interferon (IFNγ) has no obvious structural homology to type I. It was given the name only because of its ability to induce a characteristic antiviral state ( functional symmetry). It utilizes a different receptor but signal transduction pathways by both receptors overlap. A single IFNγ gene has been localized to chromosome 12 and it contains 3 introns unlike type 1 genes which are intronless. It is glycosylated .
Induction IFNα and β synthesis can be induced in almost all cell types. Viral infection is the most common biological cause of IFN Induction. Other agents such as bacteria, mycoplasma, and protozoa as well as their constituents can also induce IFN synthesis. ds RNA is the most potent inducer of IFN. Organs of normal individuals contain small amounts of constitutively expressed IFN mRNA and protein.
Receptors IFNs bind to specific receptors on the cell surface and elicit the signals necessary for transcriptional induction of IFN- activatable genes. IFNα and β compete for the same receptor, whereas IFNγ signals via a different receptor. Receptor of type I IFN is present on all cell types and is coded for by a locus on chromosome 21. That of type II IFN on chromosomes 6 (α chain) and 21 (β chain).
IFNs induce gene expression at the transcriptional level after binding to specific cell surface receptors. • A cell that is bound to interferon and responds to it is in an antiviral state. • IFN induces expression of more that 100 genes, products of many of these genes possess broad spectrum antiviral activity. • They lead to cell death by apoptosis or programmed cells death, limiting cell to cell spread of virus.
IFNs have no direct effect on viruses. This antiviral state is the earliest (hours) in host defense, lasts for 2-3 days, and is limited to the immediate vicinity in time and space. Interferons have many diverse biologic effects. The lack of specificity means that it is difficult for viruses to evolve strategies to counteract their effects. They are also a cause of malaise, myalgia, chills and fever associated with viral infections.
Activity Interferons α and β act very early in viral infection and at very low concentrations ( 10-15/mol). Species- specific (more pronounced for type II). Two main enzymatic pathways are activated - 2- -5- (A) synthetase / RNase L Pathway. - ds RNA – dependent Protein kinase (PKR) ( pk 68 kinase, or elf –2 kinase) MX proteins
interferon-alpha, interferon-beta interferon receptor induction of 2’5’oligo A synthase induction of ribonuclease L induction of a protein kinase ds RNA ds RNA 2’5’oligo A activated 2’5’oligo A synthase activated ribonuclease L activated protein kinase ATP ATP phosphorylated initiation factor (eIF-2) 2’5’oligo A mRNA degraded inhibition of protein synthesis
Interferon induced antiviral responses • Both viral and cellular protein synthesis stops in IFN treated cells due to two cellular proteins, ds-RNA activated protein kinase (Pkr) and ribonuclease L (RNase L). • Pkr is a serine/ threonine kinase that has antiviral properties, as well as antiproliferative and antitumor functions. • Activated Pkr phosphorylates the alpha subunit of the translation initiation factor eIF2, inhibiting translation. • RNase L is a nuclease that can degrade cellular and viral RNA; its concentration increases after IFN treatment.
RNase L concentration increases 10-1,000 fold after IFN treatment, but is inactive unless 2’-5’-oligo(A) synthetase is produced. • 2’-5’-oligo(A) synthetase produces 2’, 5’ oligomers of adenylic acid, only when activated by dsRNA. • These poly(A) oligomers then activate RNase L, which degrades all host and viral mRNA in the cell. • RNase L participates not only in IFN-mediated antiviral defense, but also in apoptosis. • IFN is a broad spectrum, highly effective antiviral agent. However, viruses have developed numerous mechanisms for inhibiting interferon action.
NK Cells • First-line of defense against virus infection. • They are most active in the early stages of infection and their activity is stimulated by IFNγ. • Their target on the surface of infected cells is unknown but their action is inhibited by MHC class I antigens. • Cell killing is achieved by the release of perforin (cytolysin) • Activity peaks within 2 to 3 days and diminishes rapidly thereafter to disappear after 7 days.
The adaptive immune response • Differentiates self from nonself, tailored to the particular invader • Has ‘memory’; subsequent infection by the same agent is met with a robust and highly specific response that stops the infection • Consists of the: - antibody response - humoral response - lymphocyte mediated response- cell mediated response
The adaptive immune response • Humoral response - Consists of lymphocytes of the B-cell lineage - Interaction of a specific receptor on precursor B lymphocytes with antigens promotes differentiation into antibody secreting cells (plasma cells). • Cell-mediated response - Consists of lymphocytes of the T-cell lineage - Cytotoxic T cells (Tc cells) and T-helper cells (Th cells) are the key effectors of this response.
Cytolytic T cells (CTLs) • Peak activity at about 7 days post infection. • mechanisms of action: 1- Release of perforins and granzymes ( serine protease) 2- Apoptosis of target cells. 3- Lymphokine - mediated clonal proliferation of antigen- specific CTLS
Humoral Mechanisms • Antibodies are barely detectable in the acute (symptomatic) stage of infection. • In the case of some viruses (YF, measles) detectable level can linger for a life time. • Most important antibodies are of the IgG and IgA. • Neutralizing antibodies bind with high avidity to particular epitopes on a particular protein on capsid or envelope
Virus neutralization by antibodies result from a number of mechanisms: • Conformational changes in the virus capsid. • Blocking of the function of the virus target molecule. • Steric hindrance. • A secondary consequence of antibody binding is phagocytosis of antibody-coated target molecules by mononuclear cells.
Other antibodies are nonneutralizing and may impede access of neutralizing antibodies and may form damaging immune complexes. • Antibodies may act at steps other than attachment (uncoating, transcription). • Intact antibodies are not a prerequisite for antiviral effectiveness; Fab fragments specific for RSV F glycoprotein, when instilled into the lungs of infected mice, were effective.
Antibody vs. Cell mediated Immune Response • Historically: Monitoring antibody response was used to monitor virus infection. • Passive immunization based on transfer of antibody confers immune protection. BUT…. • IgG defective individuals are not very highly susceptible to virus infection THUS • Humoral immune response is necessary to control virus infection, but is not obligatory and insufficient.
Despite all of the above mechanisms, in overall terms, cell mediated immunity is probably more important than humoral immunity. This is demonstrated by the following observations:- *- Congenital defects in CMI predispose to viral infection more than bacterial. *- The functional defect in AIDS is a reduction in the ratio of CD4+ to CD8 + cells predisposing to many viral infections.
The inflammatory response • Essential in initiating immune defenses • Cell and tissue damage caused by infection induces the inflammatory response • Provides communication with the components of the immune system • Characterized by redness, heat, swelling and pain
Inflammation can be initiated in several ways: • By interferon released by immature dendritic cells • Locally produced cytokines, such as interleukin-1, tumor necrosis factor- a and interferon-g control the reactions that occur during inflammation • Inflammatory cytokines also activate B and T cells that are needed for the adaptive response
Viral response to host immune system Viruses may : block interferon binding inhibit function of interferon-induced proteins inhibit NK function interfere with MHC I or MHC II expression block complement activation inhibit apoptosis
