Immune Response to Infectious Diseases - Viruses PDF

Immune Response to Infectious Diseases - Viruses Learning Objectives On completion of this session you should be able to 1) Describe how the immune system recognises and responds to viral pathogens. 2) Identify various strategies employed by viral pathogens to evade detection and elimin...

Immune Response to Infectious Diseases - Viruses Learning Objectives On completion of this session you should be able to 1) Describe how the immune system recognises and responds to viral pathogens. 2) Identify various strategies employed by viral pathogens to evade detection and elimination by the immune system.  Viruses 1) Comprise DNA or RNA genome + protein shell (capsid) + outer lipid membrane (envelope) -> virion 2) Viruses are dependent on invading a host cell to replicate 3) Viruses invade a target cell by binding to specific receptors on the surface 4) They replicate within the host cell 5) New virions are released via budding or cell lysis 6) Viruses can infect neighbouring cells via intercellular junctions Outside of host cells, the viruses remain metabolically inert They exist as a protein coat or capsid, sometimes enclosed within a membrane The capsid encloses either DNA or RNA which codes for the virus elements Viruses – typical life cycle Viruses Structure & Function In contact with a cell, the virus, with help from surface molecules, will inject its genetic material into the cell Thus taking over the cell’s functions The infected cell produces more viral proteins and genetic material rather than it’s usual products In the cell, the virus has two phases: 1. The lysogenic phase 2. The lytic phase Immune Response The immune defence mechanisms against viruses involve: 1. Interferons – limit infection 2. Antibodies – virus in extracellular phase 3. Natural Killer cells – intracellular phase 4. Cytotoxic T cells – intracellular phase Response to Viral Infection 1. NK cells and IFN are important in the early response (innate) 2. Lymphocytes and Abs (adaptive) are important in the later stages and in forming memory Interferons 1) Interferons (-a and –b) are important in the early response to viral infections (innate immunity) 2) Interferon-g is produced by immune cells and functions are covered in relation to NK, Th1 and Tc cells. 3) IFN-g can be considered as effector molecule of innate (NK) and adaptive (Tc and Th1). Interferons in viral infection and antiviral immunity 1) Three types a, b, (produced by a range of cells) and g (produced by activated T cells and NK cells). 2) Subpopulation of DCs (Interferon Producing Cells - IPCs) produce large quantities of IFN-a and –b 3) IFN-a and –b induce transcription of genes whose products inhibit translation of viral mRNA 4) Interferons inhibit protein synthesis and hence viral replication, degrade viral RNA, promote MHC Class I expression and recruit lymphocytes Natural Killer (NK) Cells 1) Have preformed granules containing perforins and granzymes (similar to Tc cells) 2) Recognise targets through invariant receptors (considered innate cell mediated function) 3) Recognise and kill virus-infected and malignant cells 4) Activated by IL-12 and IFN-g to increase activity 20 – 100x 5) NK cells produce IFN-g and can contribute to Th1 production NK Cell Receptors 1. Activating Receptors – trigger NK cell killing of target cell Stimulate release of IFN-g by NK cell Recognise Fc regions of IgG (i.e. FcgRIII) 2. Inhibitory Receptors – bind MHC Class I proteins and Class 1b proteins Inhibit NK cell killing of target cell Whether an NK cell kills are target cell or not is determined by balance of ligand binding to Activating and Inhibitory receptors NK Cell Receptors 2 main families, each comprise both activating and inhibitory receptors 1. Killer cell Immunoglobulin-like Receptors (KIRs) For example, inhibitory KIRs bind classical HLA Class I molecules 2. Killer Lectin-like Receptors (KLRs) For example, inhibitory KLRs bind HLA-E and other Class Ib molecules Activating receptors bind molecules e.g. MICA, MICB induced by metabolic stress, infection, malignant transformation NK Cell Receptors 1) Recognition of IgG1 and IgG3 via FcgRIII on NK cells triggers release of granule contents 2) Process called antibody dependent cellular cytotoxicity (ADCC) Humoral Antibodies 1) Neutralise viruses and prevent infection (IgM, IgG in plasma/tissue fluids and IgA, IgM in secretions) 2) IgM and IgG can activate complement and cause lysis of virion 3) IgG can opsonise virions and mediate uptake and destruction by phagocytes 4) Antibodies bind virions in extracellular phase 5) Antibodies can recognise viral antigens on infected cell surfaces -> NK cell activation (ADCC) 6) IgE smooth muscle contraction, expelling the virus Cell-Mediated Antiviral Mechanisms Antibodies, although crucial in containing the spread of the virus, are not able to eliminate the virus once infection has occurred Once infection occurs, cell-mediated immune mechanisms become the most important 2 main components of cell-mediated antiviral defense 1. CD8+ Tc cells 2. CD4+ Th1 cells (CD4+ Tc cells) Tc Cells Adaptive response to virus infection Recognise cytosolic pathogens presented via MHC Class I Effector cells induce apoptosis in target cells via granzymes and perforins (as for NK cells) Cell-Mediated Antiviral Mechanisms Activated Th1 cells CTL activity produce several cytokines Arises within 3-4 days after IL-2 infections Acts indirectly by assisting Peaks by 7-10 days, and in the recruitment of CTL then declines precursors Have viral specificity Activates NK cells Eliminates specific virus- IFN-γ infected cells, thus getting Directly induces an rid of potential new sources antiviral state in cells of new virus Activates NK cells TNF Other Lymphocytes Evasion of Immune Detection 1. Modification of capsid proteins to avoid recognition by antibodies (antigenic drift). Occasionally sudden changes in surface proteins occurs producing highly virulent new strains which cause pandemics (antigenic shift) e.g. influenza virus 2. Viral envelopes derived from host cells during budding mask viral antigens 3. Viral latency e.g. Varicella-zoster virus (VZV) 4. Cause generalized or specific immunosuppression Influenza Virus Properties of the Influenza Virus Virions are roughly spherical or ovoid in shape with an average diameter of 90- 100nm Virions are surrounded by an outer envelope 2 proteins are inserted into this envelope 1. Hemagglutinin (HA) 2. Neuraminidase (NA) Inside the envelope: Matrix protein surrounds the nucleocapsid Consists of 8 different strands of ssRNA associated with protein and RNA polymerase Influenza Virus Influenza 3 major types– A, B, &C Distinguished by differences in their nucleoprotein and matrix proteins Distinguishing feature of influenza virus is its variability Two different mechanisms for variation in HA & NA 1. Antigenic Drift 2. Antigenic Shift Influenza Virus Influenza (Flu) Symptoms: Fever Muscle aches and pain Headache Fatigue Dry cough Sore throat Runny nose What makes this different from a cold? Influenza Virus Host Response to Influenza Infection Humoral Antibody specific for the HA molecule is produced during infection Serum antibodies important for resistance to reinfection by the same strain, but not required for recovery In addition, CTLs also play a role Summary 1. The immune system employs intricate mechanisms to recognise and respond to viral pathogens. 2. Viral pathogens have evolved various strategies to evade detection and elimination by the immune system.