Viral Immunity and Pathogenesis: Host Defense Mechanisms and Infection Outcomes

Posted on Nov 21, 2025 in Biology

Host Defense Mechanisms Against Viruses

Innate, Intrinsic, and Adaptive Immunity

  • Innate Immunity: Non-specific, immediate response. Uses Pattern Recognition Receptors (PRRs) to detect Pathogen-Associated Molecular Patterns (PAMPs).
  • Intrinsic Immunity: Always present in cells (pre-existing defenses).
    • Examples: TRIM proteins, MxA, Tetherin, autophagy, apoptosis.
  • Adaptive Immunity: Specific, develops after infection.
    • Two arms: T cells (cell-mediated) and B cells (antibody-mediated/humoral).

Pathogen-Associated Molecular Patterns (PAMPs)

Viral signatures recognized by the host immune system include:

  • dsRNA (from ssRNA virus replication)
  • asRNA genomes (e.g., rotaviruses)
  • Unmethylated CpG DNA
  • Uncapped RNA 5′ ends

Intrinsic Immunity Components

  • TRIM Proteins: Large family, N-terminal tripartite motif (360 amino acids). Upregulated by Interferon (IFN), possess antiviral roles.
  • MxA: Binds nucleoprotein complexes, resisting Influenza A.
  • Tetherin: Prevents viral particle release (e.g., HIV, retroviruses).
  • Autophagy: Virus degraded in lysosomes.
  • Apoptosis: Programmed cell death, non-inflammatory.

Adaptive Immunity: Specific Responses

Activated after the innate response.

  • Two Arms:
    • Cell-mediated (T cells)
    • Humoral (B cells producing antibodies)
  • Systemic vs. Mucosal Immunity:
    • Systemic: Whole body response.
    • Mucosal: Localized at mucosal surfaces.

PRR Signaling Cascade: Initiating Antiviral Response

Steps detailing how Pattern Recognition Receptors (PRRs) signal infection:

  1. PAMP Detection: A Pathogen-Associated Molecular Pattern (PAMP) binds to a Pattern Recognition Receptor (PRR).
  2. Signal Initiation: PRR activation triggers intracellular signaling cascades.
  3. Kinase Activation: Kinases such as TBK1 and IKKε are activated.
  4. IRF3 Activation: Kinases phosphorylate and activate IRF3 (Interferon Regulatory Factor 3).
  5. Translocation to Nucleus: Activated IRF3 moves into the nucleus.
  6. IFN-β Transcription: IRF3 promotes transcription of the IFN-β gene.
  7. IFN-β Secretion: IFN-β is secreted from the cell to initiate an antiviral immune response.

RNA Interference (RNAi) Antiviral Mechanism

RNA interference (RNAi) is an intensive antiviral defense used by cells to silence viral gene expression by degrading viral RNA.

  1. Virus Introduces Long dsRNA: Viral replication produces double-stranded RNA (dsRNA), which is recognized as foreign by the host cell.
  2. Dicer Cleaves dsRNA: The Dicer enzyme cuts long dsRNA into short dsRNA fragments (~21–23 nucleotides). This cleavage interrupts viral replication.
  3. Argonaute Binds Short dsRNA: Short dsRNA associates with the Argonaute protein. The duplex is unwound, and one strand is selected as the guide strand.
  4. Guide Strand Loaded into RISC: The guide strand is incorporated into the RISC (RNA-induced silencing complex). RISC uses the guide strand to base-pair with complementary viral mRNA.
  5. RISC Cleaves Viral mRNA: Argonaute within RISC cleaves the viral mRNA. This inactivation stops translation, preventing the production of viral proteins.

Viral Evasion Strategies (Countermeasures)

Viruses employ various mechanisms to counteract host immunity:

  • Block PAMP recognition.
  • Inhibit Interferon-Stimulated Gene (ISG) effectors.

Examples of Viral Countermeasures:

  • Adenovirus VA RNA: Blocks PKR activation, allowing translation to continue.
  • Paramyxovirus V Proteins: Block IFN-β induction and ISG activation.

T Cell Subsets and Function

  • CD4+ T Helper (TH) Cells: Coordinate the immune response. Subtypes are defined by location, cytokines, and functions.
  • CD8+ Cytotoxic T Lymphocytes (TC Cells): Kill infected cells.

T Cell Receptor (TCR) Recognition:

  • The TCR recognizes peptide antigens bound to Major Histocompatibility Complex (MHC) proteins.
  • MHC Class I: Found on all nucleated cells; presents antigens to CD8+ Tc cells.
  • MHC Class II: Found on dendritic cells and B cells; presents antigens to CD4+ Th cells.

T Cell Activation Pathways

  1. Naïve CD4+ TH Cell Activation:
    1. Dendritic cell phagocytoses virus/proteins.
    2. Proteins are degraded, and peptides are loaded onto MHC II.
    3. CD4+ TH cell TCR recognizes the peptide–MHC II complex, leading to activation.
  2. Naïve CD8+ Tc Cell Activation:
    1. Infected cell presents viral peptides on MHC I.
    2. CD8+ Tc TCR recognizes the peptide–MHC I complex, leading to activation.
    3. The Cytotoxic T Lymphocyte (CTL) kills the infected cell.

Virus-Host Interactions and Infection Outcomes

The outcome of viral binding to a receptor on the host cell surface depends on both the virus and the cell type. The same virus can cause a cytopathic infection in one cell type and latency in another.

Acute and Cytopathic Infections

  • Cause cell death (lytic infections).
  • Can occur via lysis or apoptosis.
  • Easy to study in the lab due to visible cell killing.

Analyzing the Virus Growth Curve

A one-step growth curve shows:

  • Cell-associated infectivity.
  • Released infectivity in the medium.
  • Cytopathic effect (CPE) over time.

Mechanisms of Cell Death and Virus Release

  • Non-enveloped viruses: Released by lysis.
  • Enveloped viruses: Bud from membranes or vesicles without causing immediate lysis.
  • All membrane-bound viruses exit via budding.

Persistent Viral Infections

Continuous virus production occurs due to:

  1. Survival of infected cells.
  2. Limited spread, maintaining a balance between cell death and cell division.

Factors Influencing Persistent Infection Balance

Persistence is influenced by:

  • Virus-cell interaction alone.
  • Virus combined with host defenses (antibody, interferon).
  • Virus combined with defective-interfering (DI) particles.
  • A combination of these factors.

Role of Interferons in Persistence

A balance exists between virus replication and interferon suppression. Interferon reduces virus growth, but the virus rebounds when interferon levels drop, creating a cycle of persistence.

Defective Interfering (DI) Viruses and Persistence

Persistence occurs when a normal virus (which typically causes CPE) interacts with a Defective Interfering (DI) virus. The DI virus reduces replication, establishing a balance between infectious virus and DI virus over time.

Latent Viral Infections

Latent means the viral genome is present but no progeny virus is produced. The virus can reactivate later.

  • Examples:
    • Bacteriophages, AAV: Integrate a DNA copy into the host genome.
    • Herpesviruses: DNA remains episomal (not integrated).

Comparison of Infection Types

  • Acute: Rapid rise in virions, short duration (days).
  • Persistent: Continuous virus production (months/years).
  • Latent: Genome present, no virions produced, but capable of reactivation.

Transforming Infections and Cell Immortality

Viral infection can transform cells, leading to altered growth and properties. This is often preceded by the integration of the viral genome into host DNA.

One immortalized cell can dominate the population.

Key Features of Transformed Cells

  • Cytopathic Effect (CPE) is reduced or eliminated, allowing the cell to survive.
  • Viral replication is reduced or eliminated (no virions produced).
  • The cell continues dividing, becoming immortal.

Abortive and Null Infections

  • Abortive Infections: The cell has receptors, and the virus enters, but replication is inefficient, resulting in a low yield or defective progeny. Sometimes, no infectious particles are produced.
  • Null Infections: Cells lack receptors, so the virus cannot enter, resulting in no infection.

Case Study: HPV Cytopathology

Human Papillomavirus (HPV) infection causes characteristic cytopathic effects:

  • Koilocytes: The hallmark cytopathic effect.
  • Chromatin Margination: Viral particles accumulate in the nucleus.
  • Nuclear Moulding: Nuclei enlarge and crowd together.

Viral Mechanisms Disrupting Host Cell Function

Viruses employ diverse strategies to hijack cellular machinery:

  • Inhibit Host Transcription: Rhabdoviruses, Poliovirus
  • Compete Out Cellular mRNA: Semliki Forest virus
  • Block Translation Initiation: Poliovirus, Reovirus, Influenza, Adenovirus
  • Degrade Cellular mRNA: Influenza, Herpesvirus
  • Block mRNA Transport: Adenovirus, Influenza
  • Induce Apoptosis: Sindbis, Semliki Forest, Influenza A/B/C, HIV-1, Adenovirus, Measles
  • Alter Ion Balance: Semliki Forest, Rotavirus

SARS-CoV-2 Persistence and Immune Exhaustion

  1. Virus Replication: SARS-CoV-2 actively replicates inside host cells, producing viral RNA and antigens.
  2. Persistence of Viral Material: Even after acute infection resolves, persistent viral RNA or antigen may remain, keeping the immune system stimulated.
  3. Immune System Activation: The continuous presence of viral material leads to chronic immune stimulation.
  4. Immune Exhaustion: T cells express exhaustion markers (PD-1, TIM-3, NKG2A). NK cells also show NKG2A. Immune cells become “tired,” resulting in a reduced ability to clear the virus.
  5. Consequences: Viral cytopathic effects damage host cells. Persistent inflammation occurs due to constant immune activity. Cytotoxic molecules (granzyme, perforin) are released, contributing to tissue damage.
  6. Latent Virus Reactivation (Non-CoV-2): Other latent viruses (e.g., herpes) can reactivate if immune control fails. Reactivation can cause new infection episodes or contribute to persistence.

Patterns of Virus Production

Different infection types exhibit distinct patterns of virion production:

  1. Acute Infection (RNA Viruses): Rapid rise in virions, short duration (days).
  2. Latent Infection (Herpesviruses): Genome persists in the host. Periodic reactivation leads to bursts of virus production.
  3. Persistent Infection (HIV, HCV): Continuous virus production, long duration (months/years).

Mechanisms Suppressing Infectious Virions

The host and virus interact to limit the production of infectious particles:

  1. Host Mechanisms: Non-cytolytic clearance, prevention of virion maturation, suppression of RNA synthesis.
  2. Immune Factors: Antibody, IFN-γ, Tregs, IL-10, and IFN responses.
  3. Virus/Host Interactions: Mutations, Post-Translational Modifications (PTMs), immunosuppression (TGF-β), Defective Viral Genomes (DVGs), and RNA sensors triggering innate responses.
  4. Balance Achieved: The virus survives at low levels, and the host limits production to avoid cell death.