lec 13:Host Resistance to Viral Infections: Mechanisms and Immune Responses

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Host Resistance to Viral Infections

Overview of Host Resistance

Host resistance to viral infections refers to the ability of an organism to limit or prevent viral replication, spread, and disease. This resistance is achieved through a multi-layered defense system, including both innate (nonspecific) and adaptive (specific) immunity. The effectiveness of these defenses varies among individuals and species, influenced by genetic, immunological, and environmental factors.

Resistance: Reduces viral burden by eliminating or controlling the pathogen.
Tolerance: Minimizes tissue damage caused by infection, even if the virus is not cleared.

Mechanisms of Host Resistance

Innate Immunity: Nonspecific Host Defenses

Innate immunity provides the first line of defense against viral infections. It is non-specific, acting against a broad range of pathogens without immunological memory.

Physical and Chemical Barriers: The skin, mucus, and saliva prevent viral entry into the body.

Diagram of normal and disrupted skin barrier function, showing protection against viruses, bacteria, and toxins

Cellular and Molecular Responses:
- Interferons: Signaling proteins released by infected cells to alert neighboring cells and inhibit viral replication.
- Natural Killer (NK) Cells: Immune cells that identify and destroy infected cells.
- Antigen-Presenting Cells (APCs): Cells that present viral fragments to other immune cells, initiating adaptive responses.

Interferons and the Antiviral State

Interferons are key signaling proteins that establish an antiviral state in cells. They are released by infected and neighboring cells to warn the immune system and upregulate interferon-stimulated genes (ISGs), which encode proteins that disrupt various stages of the viral life cycle.

Diagram showing interferon signaling to neighboring cells to induce antiviral responses Diagram of interferon production and ISG induction in response to viral infection Diagram showing establishment and maintenance of the antiviral state in infected and uninfected cells

ISGs: Some degrade viral RNA, others inhibit viral protein synthesis.

Natural Killer (NK) Cells

NK cells are critical for early defense against viral infections. They kill infected cells directly and release cytokines to coordinate the immune response. NK cells can also mediate antibody-dependent cell-mediated cytotoxicity (ADCC).

Diagram showing activation of T helper cells and lysis by NK cells

Cytotoxic Killing: Release of perforin and granzymes induces lysis of infected cells.
ADCC: NK cells bind to antibody-coated infected cells and induce apoptosis.

Diagram of ADCC mechanism by NK cells

Cytokine Production: NK cells secrete cytokines to enhance antiviral immunity and regulate other immune cells.
Immunopathology: Excessive NK cell activity can cause tissue damage, highlighting the need for balance.

Antigen-Presenting Cells (APCs)

APCs, such as dendritic cells and macrophages, bridge innate and adaptive immunity. They ingest viruses, process them, and present viral peptides on MHC molecules to activate T cells in lymph nodes.

Diagram of dendritic cell presenting antigens to helper and cytotoxic T cells

Dendritic Cells: Located in tissues exposed to the environment, they present antigens to T helper cells via MHC II molecules.

Adaptive Immunity: Specific Host Defenses

Overview of Adaptive Immunity

Adaptive immunity is highly specific and develops more slowly than innate responses. It involves B cells (antibody production) and T cells (cell-mediated responses), as well as immunological memory for rapid response upon re-exposure.

B Cells: Produce antibodies that neutralize viruses.
T Cells: Include helper T cells (coordinate responses) and cytotoxic T cells (kill infected cells).
Immunological Memory: Memory B and T cells enable faster, stronger responses to subsequent infections.

Time Course of Immune Responses

Innate defenses act rapidly after infection, while adaptive responses take days to weeks to develop but are essential for viral clearance.

Graph showing time course of nonspecific and specific immune responses after viral infection

Humoral Response: Antibody Production

B cells are activated to produce antibodies that neutralize viruses, block attachment and entry, and mediate opsonization and ADCC.

Diagram of B cell activation and differentiation into plasma and memory cells

Neutralization: Antibodies bind to viral antigens, preventing entry into host cells.
Blocking Attachment: Antibodies block viral surface proteins from binding to host receptors.
Inhibiting Entry: Antibodies prevent fusion of viral and host membranes.

Opsonization and Phagocytosis

Antibodies coat viral particles (opsonization), marking them for destruction by phagocytic cells such as macrophages.

Diagram of opsonization and phagocytosis of antibody-coated viruses

Antibody-Dependent Cellular Cytotoxicity (ADCC)

Antibodies bind to viral antigens on infected cells, attracting NK cells that induce apoptosis via cytotoxic molecules.

Diagram of ADCC mechanism involving NK cells and antibody-coated target cells

Cell-Mediated Immunity: T Cells

T cells are essential for eliminating viruses that have already infected host cells. There are two main subtypes: cytotoxic T cells (CD8+) and helper T cells (CD4+).

Cytotoxic T Cells (CD8+): Recognize viral antigens presented on MHC I molecules and kill infected cells by releasing perforin and granzymes, inducing apoptosis.

Diagram of cytotoxic T cell recognizing infected cell via MHC I Diagram of cytotoxic T cell binding to infected cell Diagram of cytotoxic T cell targeting infected cell for destruction Diagram of apoptosis induction by cytotoxic T cell

Helper T Cells (CD4+): Recognize antigens presented by APCs on MHC II molecules, activate B cells to produce antibodies, enhance cytotoxic T cell responses, and boost innate immunity by secreting cytokines.

Factors Influencing Host Resistance

Genetic Factors: Genes, especially those in the major histocompatibility complex (MHC), influence immune responses.
Physiological Factors: Age, nutrition, stress, and health status affect resistance.
Co-evolution: Viruses evolve to evade host defenses, leading to an evolutionary arms race.

Distinction Between Resistance and Tolerance

Resistance: Reduces viral load by eliminating the pathogen.
Tolerance: Limits tissue damage without necessarily reducing viral load.
Example: The body may minimize tissue damage even if the virus persists.