Presentation on Infection and Immunity

Infection and Immunity What does a pathogen have to do? • Infect (infest) a host • Reproduce (replicate) itself • Ensure that its progeny are transmitted to another host Mechanisms of Transmission • Aerosols - inhalation of droplets, e.g. Rhinoviruses, the 'Common Cold Virus' or Adenoviruses. • Faecal-Oral - e.g. Astroviruses, Caliciviruses; these viruses cause acute gastroenteritis. • Vector-borne - e.g. in Arthropods such as mosquitos, ticks, fleas: Arboviruses. • Close personal contact - especially exchange of bodily fluids: Sex; Blood, e.g. Herpesviruses Entry into the Host • Skin - dead cells, therefore cannot support virus replication. Most viruses which infect via the skin require a breach in the physical integrity of this effective barrier, e.g. cuts or abrasions. Many viruses employ vectors, e.g. ticks, mosquitos or vampire bats to breach the barrier. • Respiratory tract - In contrast to skin, the respiratory tract and all other mucosal surfaces possess sophisticated immune defence mechanisms, as well as non-specific inhibitory mechanisms (cilliated epithelium, mucus secretion, lower temperature) which viruses must overcome. • Entry into the Host • Gastrointestinal tract - a hostile environment; gastric acid, bile salts, etc • Genitourinary tract - relatively less hostile than the above, but less frequently exposed to extraneous viruses (?) • Conjunctiva - an exposed site and relatively unprotected Sites of virus entry Transmission patterns • Horizontal Transmission: Direct person-toperson spread. • Vertical Transmission: Relies on PERSISTENCE of the agent to transfer infection from parents to offspring. 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. Primary Replication • Having gained entry to a potential host, the virus must initiate an infection by entering a susceptible cell. This frequently determines whether the infection will remain localized at the site of entry or spread to become a systemic infection Localized Infections • Viruses Primary Replication • Rhinoviruses U.R.T. • Rotaviruses Intestinal epithelium • Papillomaviruses Epidermis Systemic Infections Virus Primary Replication Secondary Replication Enteroviruses Intestinal epithelium Lymphoid tissues, C.N.S. Lymphoid cells, C.N.S. Herpesviruses Oropharynx or G.U.tract Spread Throughout the Host • Apart from direct cell-cell contact, there are 2 main mechanisms for spread throughout the host: • via the bloodstream • via the nervous system via the bloodstream • Virus may get into the bloodstream by direct inoculation - e.g. Arthropod vectors, blood transfusion or I.V. drug abuse. The virus may travel free in the plasma (Togaviruses, Enteroviruses), or in association with red cells (Orbiviruses), platelets (HSV), lymphocytes (EBV, CMV) or monocytes (Lentiviruses). Primary viraemia usually proceeds and is necessary for spread to the blood stream, followed by more generalized, higher titre secondary viraemia as the virus reaches other target tissues or replicates directly in blood cells via the nervous system • spread to nervous system is preceded by primary viraemia. In some cases, spread occurs directly by contact with neurons at the primary site of infection, in other cases via the bloodstream. Once in peripheral nerves, the virus can spread to the CNS by axonal transport along neurons (classic - HSV). Viruses can cross synaptic junctions since these frequently contain virus receptors, allowing the virus to jump from one cell to another Cell/Tissue Tropism • Tropism - the ability of a virus to replicate in particular cells or tissues - is controlled partly by the route of infection but largely by the interaction of a virus attachment protein (V.A.P.) with a specific receptor molecule on the surface of a cell, and has considerable effect on pathogenesis. Many V.A.P.'s and virus receptors are now known. Secondary Replication • Occurs in systemic infections when a virus reaches other tissues in which it is capable of replication, e.g. Poliovirus (gut epithelium - neurons in brain & spinal cord) or Lentiviruses (macrophages - CNS + many other tissues). If a virus can be prevented from reaching tissues where secondary replication can occur, generally no disease results. : Localized Infections: Primary Replication: Virus: Rhinoviruses U.R.T. Rotaviruses Intestinal epithelium Papillomavirus Epidermis es Systemic Infections: Virus: Enteroviruses Herpesviruses Primary Replication: Intestinal epithelium Oropharynx or G.U.tract Secondary Replication: Lymphoid tissues, C.N.S. Lymphoid cells, C.N.S. Incubation periods of viral infections Influenza Common cold 1-2d 1-3d Chickenpox Mumps 13-17d 16-20d Bronchiolitis,croup Acute respiratory disease Dengue Herpes simplex Enteroviruses poliomyelitis Measles 3-5d 5-7d Rubella Mononucleosis Hepatitis A Hepatitis B Rabies Papilloma HIV 17-20d 30-50d 5-8d 5-8d 6-12d 5-20d 9-12d 15-40d 50-150d 30-100d 50-150d 1-10y Types of Infection • Inapparent infection( Subclinical infection) . • Apparent infection: • Acute infection • Persistent Infection Chronic infections Latent Infection Slow virus infections Chronic Infection • Virus can be continuously detected ; mild or no clinical symptoms may be evident. 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 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 . Overall fate of the cell • The cell dies in cytocidal infections this may be acute (when infection is brief and selflimiting) or chronic (drawn out, only a few cells infected while the rest proliferate)-Cytocidal effect • The cell lives in persistent infections this may be productive or nonproductive (refers to whether or not virions are produced) or it may alternate between the two by way of latency and reactivation - Steady state infection Special cases • Transformation-Integrated infection (Viruses and Tumor) • Apoptosis Types of Viral infections at the cellular level Type Abortive Virus production Fate of cell No effect Cytolytic Persistent Productive Latent Transforming + Death + - Senescence No effect DNA viruses RNA viruses + Immortalization Immortalization Mechanisms of viral cytopathogenesis Inhibition of cellular protein synthesis Inhibition and degradation of cellular DNA Alteration of cell membrane structure Glycoprotein insertion Syncytia formation Disruption of cytoskeleton permeability Inclusion bodies Toxicity of Virion components Polioviruses, HSV, poxviruses, togaviruses herpesviruses All enveloped viruses HSV, VZ virus, HIV HSV, naked viruses Togaviruses, herpesviruses Rabies Adenovirus fibers 3. Viral Immunopathology Viral Immunopathogenesis • Influenza-like symptoms( IFN, lymphokins): • • • • • DTH and inflammation(Tcell, PMNs): Immune-complex disease(AB, complement): Hemorrhagic disease( T cell,AB, Complement): Postinfection cytolysis( T cells): enveloped viruses Immunosuppression: HIV; CMV; measlesvirus and influenza Persistence Long term persistence of virus results from two main mechanisms: • a) Regulation of lytic potential • b) Evasion of immune surveillance Persistence vs. Clearance Antiviral Immunity Overview of the Immune System Components of the Immune System Nonspecific Humoral complement, interferon, TNF etc. Specific Humoral Cellular T cells; other effectors cells Cellular macrophages, neutrophils NK cell antibodies Innate or Nonspecific Immunity Innate or Nonspecific Immunity • Anatomic and Physiologic Barriers: Intact skin / Mucus membrane Temperature /Acidity of gastric juices Protein factors • Phagocytic Barriers : 3 major types of phagocytic cells • Inflammatory Barriers and fever • Mucociliary clearance 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 • Anti-tumor and regulation of immunity 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 Properties of human interferons Property Principal cell source genes Introns in genes induction Glycosylation Stability at pH2 Function IFN-alpha Epithelium leukocytes >20 no Viruses dsRNA no stability Antiviral infection activation of NK cell IFN-beta Fibroblasts 1 no Viruses dsRNA yes stability IFN-gamma Lymphocytes 1 yes Immune activation yes labile immunity anti-tumor regulation of enhancement of CMI Activities of interferon Antiviral actions Interferons initiate an antiviral state in cells Interferons block viral protein synthesis Inferons inhibit cell growth Immunomodulatory actions Interferons-alpha and IFN-beta activate NK cells Interferons-alpha activates macrophages Interferons-gamma activate macrophages Interferons increase MHC antigen expression Interferons regulate the activities of T cells Other actions Interferons regulate inflammatory processes Interferons regulate tumor growth 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 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 Specific immunity Active/passive Overview of Specific immunity • specific recognition and selective elimination of foreign molecules. • Involves specificity, diversity, memory, and self/nonself recognition. The Role of MHC • The molecular basis of antigen recognition by T cells is well understood. The TcR recognizes short antigen-derived peptide sequences presented in association with self MHC class I or MHC class II molecules at the surface of an antigen presenting cell (APC). The Role of MHC • T cell recognition, therefore, involves direct cell-cell contact between the antigenspecific TcR on the T lymphocyte and an MHC compatible cell which presents the processed antigen in association with surface MHC molecules. The Role of MHC • The finding that self MHC molecules are involved in the recognition of antigen by T lymphocytes led to the concept of "MHC restriction" of T cell responses, and pointed to the important role that products of the major histocompatibility complex play in the cell mediated immune response. The major histocompatibility complex consists of a cluster of genes, most of which encode products with immunologically related functions. The Role of MHC • In humans, the MHC is located on the short arm of chromosome 6 and spans approximately 4 megabases of DNA. It can be divided into three regions termed class I, class II and class III: • The class III region contains genes which encode a number of complement components and the tumour necrosis factor cytokines, amongst other molecules. • MHC class I molecules consist of a polymorphic, MHCencoded, membrane-spanning heavy chain, and a monomorphic light chain, beta2-microglobulin. • MHC class II molecules consist of a heterodimer of two MHC-encoded, membrane-spanning proteins, the alpha and beta polypeptide chains of the MHC class II molecule. The Role of MHC MHC class I molecules present antigen to CD8+ T cells MHC class II molecules present antigen to CD4+ T cells T cells T cells are essential for controlling enveloped and noncytolytic viral infections T cells recognizes viral peptides presented by MHC molecules on cell surfaces Antigenic viral peptides can come from any viral protein TH1 CD4 responses are more important than TH2 responses CD8 cytotoxic T cells respond to viral peptide-class I MHC protein complexes on the cell surface TH2 CD4 responses are important for the maturation of antibody response TH2 CD4 responses may be detrimental if they prematurely limit the TH1 inflammatory and cytolytic responses 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 Humoral Immunity Antibody dependent cellular cytotoxicity or ADCC 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 • Neutralization antibody • Other antibody Passive Immunity • A high titer of antibody against a specific virus • A pooled sample from plasma donors that contains a heterogeneous mixture of antibodies with lower titer