Virology Ch.33

Host Cellular Defenses Against Virus Infection

  • Viral Spread:
    • Animal viruses spread through various routes:
    • Airborne: Respiratory viruses spread via aerosols or mucosal secretions; examples include rhinoviruses and influenza.
    • Oral-fecal: Ingestion of contaminated food or water; infections often start in the gut (e.g., reoviruses and poliovirus).
    • Blood-borne: Viremia established in the blood; transmitted by vectors or contaminated blood (e.g., flaviviruses, HIV, hepatitis B).
    • Sexual: Found in genital warts, semen, or vaginal secretions; affects genital mucosa (e.g., HPV, HSV-2, HIV).
    • Congenital: Infection occurs in utero or during passage through the birth canal (e.g., HIV, CMV).

Innate Immunity

  • Immediate Response (0-4 hours):

    • Recognition by preformed, non-specific effectors and removal of the infectious agent.

  • Early Induced Response (4-96 hours):

    • Recruitment of effector cells.
    • Recognition of Pathogen-Associated Molecular Patterns (PAMPs), activation of effector cells, and inflammation.

  • Adaptive Immune Response (> 96 hours):

    • Transport of antigen to lymphoid organs, recognition by naive B and T cells, followed by clonal expansion and differentiation.

Host Defense Mechanisms Against Pathogens

  • First Line of Defense:

    • Physical barriers (skin, mucous membranes) and chemical barriers (lysozymes, defensins).
    • Intrinsic Cellular Antiviral Factors: Recognize viral components, blocking infection immediately (e.g., siRNA, APOBEC3G).

  • Second Line of Defense:

    • Induced innate responses via Pattern Recognition Receptors (PRRs) (e.g., TLRs) leading to the production of cytokines and interferons.

  • Third Line of Defense:

    • Adaptive immune responses activated later.

RNA Interference (RNAi)

  • Small interfering RNAs (siRNA) combat viral infections in plants/invertebrates.
  • Initiated by Dicer (dsRNA-specific enzyme) that cleaves dsRNA into siRNA.
  • RISC (RNA-induced silencing complex) binds siRNA, which cleaves complementary RNA.
  • MicroRNAs (miRNAs) used in vertebrates control gene expression, targeting both viral and cellular RNAs.

Role of Interferons

  • Structure & Synthesis:

    • Types: Interferon-α, β, and γ.
    • Induced by virus infection or dsRNA; leads to transcriptional activation of antiviral genes and synthesis of antiviral proteins.
    • Jak-Stat Pathway: Interferons activate this pathway for signaling to induce ISGs (Interferon-Stimulated Genes).

  • Antiviral Activities:

    • Mx Proteins: Inhibit viral transcription.
    • 2',5'-Oligo(A) Synthetase: Activates RNase L to degrade mRNA.
    • PKR: Activated by dsRNA, inhibits protein synthesis.

Viral Defenses Against Interferon Responses

  • Viruses evolve mechanisms to evade detection and action from interferon responses (e.g., inhibiting PKR, interferon production).
    • Examples include HIV and Hepatitis C virus products that interfere with signaling pathways.

Cytokine Production

  • Cytokines:
    • Include pro-inflammatory (e.g., IL-1, TNF-α), recruitment (chemoattractants), and anti-inflammatory cytokines (e.g., IL-10, TGF-β).
    • Goal: stimulate protective reactions, activate immune cells, and recruit additional immune responses to sites of infection.

Apoptosis and Cell Death

  • Virus recognition can trigger apoptosis (cell death):
    • Extrinsic Pathway: Initiated by external signals (e.g., TNF-α).
    • Intrinsic Pathway: Activated by internal stress due to viral replication.

Conclusion of Fundamental Concepts

  • TLRs play a critical role in detecting viral infections.
  • Double-stranded RNA is a potent inducer of antiviral defense, activating multiple immune pathways leading to cytokine and interferon production.
  • Interferons exhibit diverse effects in immunity and are pivotal in modulating responses to infections, playing a crucial role in the defense against viral pathogens.