Immunity to Viruses and Parasites PDF

Immunity to pathogens Dr Felix N. Toka, DV, PhD, DSc., ACVM Objectives Understand infection and immune response Describe mechanisms of immune response to pathogens (bacteria, viruses, fungi and parasites) Understand injurious effects of immune response pathogens Describe immune...

Immunity to pathogens Dr Felix N. Toka, DV, PhD, DSc., ACVM Objectives Understand infection and immune response Describe mechanisms of immune response to pathogens (bacteria, viruses, fungi and parasites) Understand injurious effects of immune response pathogens Describe immune evasion by pathogens Development of an infectious disease Important events during infection are: entry of the microbe, invasion and colonization of host tissues, evasion of host immunity, tissue injury or functional impairment Microbes produce disease by: direct killing of the host cells they infect releasing toxins that can cause tissue damage and functional derangements stimulating innate and adaptive immune responses that injure and impair the function of normal tissues. The progression and outcome of infections Overview of Immune Responses to pathogens 1. Immunity against microbes is mediated by the effector mechanisms of innate and adaptive immunity. 2. The immune system responds in specialized and distinct ways to different types of microbes to combat these infectious agents most effectively. 3. The survival and pathogenicity of microbes in a host are critically influenced by the ability of the microbes to evade or resist the effector mechanisms of immunity. 4. Some microbes establish latent, or persistent, infections in which the immune response controls but does not eliminate the microbe. 5. Inherited and acquired defects in innate and adaptive immunity are important causes of susceptibility to infections. Immunity to Extracellular Bacteria What are extracellular bacteria? Bacteria that are capable of replicating outside host cells e.g., in blood, connective tissue, lumens of respiratory and GI tracts They induce inflammation which destroys tissue Disease They produce toxins which damage tissue Disease Innate Immunity to Extracellular Bacteria The main mechanism are : 1. Complement activation – peptidoglycans in G+ bacteria and LPS in G- bacteria will activate the alternative pathway Mannose expressing bacteria will activate the lectin pathway 2. Phagocytosis Phagocytes e.g., neutrophils and macrophages use mannose or scavenger receptors to recognize extracellular bacteria Fc receptors when Abs are present Complement receptors 3. Inflammatory response Phagocytes and dendritic cells secrete cytokines and other mediators of inflammation that induce leukocyte infiltration Innate lymphoid cells (ILCs) can be activated to secrete cytokines e.g., IL- 17, IL-22 which attract neutrophils. Adaptive Immunity to Extracellular Bacteria Humoral immunity is a major protective immune response against extracellular bacteria, and it functions to block infection, to eliminate the microbes, and to neutralize their toxin by high-affinity IgG, IgM, and IgA isotypes by the IgG1 and IgG3 subclasses of IgG by IgM, IgG1, and IgG3 The protein antigens of extracellular bacteria also activate: CD4+ helper T cells, which produce cytokines express cell surface molecules that induce local inflammation enhance the phagocytic and microbicidal activities of macrophages and neutrophils, stimulate antibody production  Injurious Effects of Immune Responses to Extracellular Bacteria The main injurious effects of host responses to extracellular bacteria are: 1. inflammation - causes tissue damage by local production of ROS and lysosomal enzymes – self limiting 2. sepsis – a pathologic consequence of severe infection by some G+ and G- bacteria cytokines secreted by MØ - TNF, IL-6 and IL-1 mediate sepsis - cause systemic disorders of tissue perfusion, coagulation, metabolism, and organ function may lead to septic shock the most severe and frequently fatal form of sepsis Polyclonal activation of T cells by bacterial superantigens e.g., staphylococcal enterotoxin B (SEB) as a superantigen Generation of disease-producing antibodies Can occur after streptococcal infections of the throat or skin long after clearance of infection Production of antibodies against bacterial cell wall antigens Some of these Abs cross react with: myocardial proteins - myocarditis glomerular antigens - glomerulonephritis Immune Evasion by Extracellular Bacteria Bacteria with polysaccharide-rich capsules resist phagocytosis Pathogenic G+ and G- bacteria contain sialic acid residues that inhibit complement activation by the alternative pathway A mechanism commonly used by bacteria to evade humoral immunity is variation of surface antigens Ability to alter antigens helps the bacteria to evade attack by antigen-specific antibodies Some bacteria also release surface antigens in membrane blebs, which may divert antibodies away from the microbes themselves. Immunity to Intracellular Bacteria Intracellular bacteria can survive and even replicate within phagocytes Inside the host cells they are inaccessible to circulating antibodies Their elimination requires the mechanisms of cell-mediated immunity  Innate Immunity to Intracellular Bacteria The innate immune response to intracellular bacteria is mediated mainly by phagocytes and natural killer (NK) cells TLRs and cytoplasmic proteins of the NOD- like receptor (NLR) family recognize bacteria and activate the phagocytes Phagocytes produce IL-12 and IL-15 which activates the NK cells Also, intracellular bacteria activate NK cells by inducing expression of NK cell–activating ligands on infected cells Adaptive Immunity to Intracellular Bacteria The major protective immune response against intracellular bacteria is cell-mediated immunity i.e., T cells and phagocytes CD4+ T cells activate phagocytes through the actions of CD40 ligand and IFN-γ, resulting in killing of microbes CD8+ cytotoxic T lymphocytes (CTLs) kill infected cells The macrophage activation that occurs in response to intracellular microbes can cause tissue injury  Immune Evasion by Intracellular Bacteria “Resistance to phagocyte-mediated elimination is also the reason that such bacteria tend to cause chronic infections that may last for years, often recur after apparent cure, and are difficult to eradicate”  Immunity to Fungi Fungal infections are also called mycoses Many fungal infections are opportunistic - cause disease in immunocompromised animals Some may be found in extracellular tissue or within phagocytes Not much is known about antifungal immunity Innate and Adaptive Immunity to Fungi The main mediators of innate immunity against fungi are neutrophils, macrophages, and ILCs Macrophages and dendritic cells sense fungal organisms by TLRs and lectin-like receptors called dectins that recognize β- glucans on the surface of the fungi Macrophages and dendritic cells release cytokines that recruit and activate neutrophils directly or via the activation of tissue- resident ILCs Neutrophils phagocytose fungi for intracellular killing through ROS and lysosomal enzymes  Cell-mediated immunity is the major mechanism of adaptive immunity against intracellular fungal infections CD4+ T cells activate macrophages and neutrophils for intracellular killing CD8+ T cells may directly lyse fungal infected cells Extracellular fungi elicit a strong Th17 response for neutrophil recruitment Immunity to Viruses Viruses are obligatory intracellular pathogens They replicate by using the host protein synthesis mechanism Such replication interferes with normal cellular function This leads to cytopathic effects in the host cells  Both innate and adaptive mechanisms are involved in antiviral immune responses Kinetics of innate and adaptive immune responses to a virus infection  Innate Immunity to Viruses The principal mechanisms of innate immunity against viruses are inhibition of infection by type I interferons and NK cell– mediated killing of infected cells Virus infected cells and dendritic cells (plasmacytoid DCs) secrete type I IFNs (e.g., IFNα, IFNβ) Type I IFNs function to inhibit viral replication in both infected and uninfected cells Class I MHC expression is often shut off in virus-infected cells Viral infection may also stimulate expression of activating NK cell ligands on the infected cells NK cells can now kill virus-infected cells How type I interferons block virus replication  Adaptive Immunity to Viruses Adaptive immunity against viral infections is mediated by antibodies, which block virus binding and entry into host cells, and by CTLs, which eliminate the infection by killing infected cell Antibodies are effective against viruses only during the extracellular stage of the virus Antiviral antibodies bind to surface antigens of the virus and so neutralize virus Antibodies may opsonize viral particles and promote their clearance by phagocytes Complement activation – phagocytosis and possibly direct lysis  Elimination of viruses that are within cells is mediated by CTLs, which kill the infected cells APCs acquire viral antigens and present them to CD8+ T cells Activated CD8+ T cells (CTLs) recognize virus infected cells presenting the same antigens through MHC I and kill those cells In some viral infections, tissue injury may be caused by CTLs. Immune Evasion by Viruses FIV Antigenic variation Viruses can alter their antigens and are thus no longer targets of immune responses e.g., for influenza viruses, reassortment is the main mechanism of antigenic variation Point mutations can also lead to T cell epitope variation Inhibition of MHC molecules Some viruses inhibit class I MHC–associated presentation of cytosolic protein antigens different steps in antigen processing, transport, and presentation can be blocked some viruses produce proteins that act as NK cell inhibitory receptors and thus block NK cell activation  Inhibition of the immune response. Some viruses produce molecules that inhibit the immune response, e.g., Poxviruses encode soluble cytokine receptors for IFN-γ, TNF, IL-1, IL-18 Chronic viral infections are associated with failure of CTL responses, called exhaustion. persistent antigen stimulation leading to upregulation of T cell inhibitory receptors, such as PD-1 Viruses may infect and either kill or inactivate immunocompetent cells. obvious example is FIV, FeLV in cats which can infect CD4+ T cells Immunity to Parasites Parasites - single-celled protozoa, complex multicellular worms (helminths), and ectoparasites (e.g., ticks and mites) Complex life cycles, part in animals and other intermediate hosts Many parasitic infections are chronic due to: weak innate immunity, ability of parasites to evade or resist elimination by adaptive immune responses, not many effective antiparasitic drugs Innate Immunity to Parasites The principal innate immune response to protozoa is phagocytosis - but most are resistant phagocytosis! Protozoa such a Plasmodium spp., Toxoplasma gondii can be detected by TLR2 and TLR4 - phagocytosis Eosinophils contribute to the innate response to helminths – but thick tegument renders neutrophils and macrophages less effective http://www.dailymail.co.uk/sciencetech/article-2957265/When-white-blood-cells-ATTACK-Amazing-video- captures-moment-immune-takes-parasitic-worm.html Adaptive Immunity to Parasites parasites elicit distinct adaptive immune responses depending on the type of parasite  The principal defense mechanism against protozoa that survive within macrophages is cell-mediated immunity, particularly macrophage activation by Th1 cell–derived cytokines.  Protozoa that replicate inside various host cells and lyse these cells stimulate specific antibody and CTL responses The cytokine IFN-γ has been shown to be protective in many protozoal infections  Defense against many helminthic infections is mediated by the activation of Th2 cells, which results in production of IgE antibodies and activation of eosinophils. Th2 subset of effector cells, which secrete IL-4 and IL-5. IL-4 stimulates the production of IgE, which binds to the Fcε receptor of eosinophils and mast cells. IL-5 activates eosinophils. IgE coats the parasites, and eosinophils bind to the IgE and are activated to release their granule contents, which destroy the helminths Immune Evasion by Parasites  Challenges of parasitic antigens Two types of antigenic variation: Stage-specific change in antigen expression, e.g., the infective sporozoite stage of malaria parasites is antigenically distinct from the merozoites that reside in the host and are responsible for chronic infection Continuous variation of major surface antigens http://www.malariavaccine.org/malvac-lifecycle.php