Avian influenza pathophysiology

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Pathophysiology

Data regarding the exact pathogenesis of avian influenza infection in hosts is limited.

Genetics

All reported cases of avian influenza are caused by influenza A. The genome of influenza A consists of 8 gene segments, which encode 11 proteins:

• Hemagglutinin (HA): Surface protein that acts as a receptor binding site. HA is targeted by host antibodies to neutralize the virus
• Neuraminidase (NA): Cleaves progeny virions from host cell receptors
• Polymerase proteins: PB1, PB2, PA, and PB1-F2. These proteins form the polymerase complex. Together with the NP protein, form the ribonucleoprotein (RNP) complex to induce replication and transcription. Additionally, PB1-F2 has a role in inducing apoptosis.
• NP: Together with the polymerase proteins, NP forms the RNP complex to induce replication and transcription.
• Non-structural proteins: NS1 and NS2. NS1 processes mRNA and helps the virus evade the host immune responses. NS2 controls the exporting process of RNP from the host nucleus.
• Matrix proteins: M1 and M2. M1 has a role in viral assembly. M2 controls pH during viral uncoating.

Viral Fusion with Host Cell

• The HA protein (receptor binding site) on the viral surface binds to host receptors that contain sialic acid.
• The precursor HA molecule undergoes proteolytic activation and cleaves to produce 2 molecules: HA1 and HA2.
• Following proteolytic activation, the virus fuses with the host cell.
• The number of residues at the cleavage site is directly associated with the virulence of the virus (Highly cleavable HA with more residues at the cleavage site is thought to be activated by intracellular proteases and result in systemic infections).

Viral Replication and Assembly

• Following fusion, viral replication typically takes place within 1 day in the upper and lower respiratory tracts, including the nasopharynx, trachea, and lungs. Less commonly, replication occurs in extrapulmonary organs, including the intestines, brain, heart, or placenta.
• Similar to human influenza, avian influenza replicates intracellularly via cytolytic or apoptotic mechanisms.
• The poylmerase proteins are the main constituents of the polymerase complex that is involved in viral replication. NP encapsulates the RNA gene segments, which allows these segments to be recognized by the polymerase complex.
• Durign replication, NS proteins play a major role in evading the host immune responses by deactivating immune reponses mediated by pro-inflammatory cytokines.
• Viral replication is inversely associated with outcomes among humans, where increased viral loads are associated with severe/fatal clinical disease.
• Following replication, the matrix proteins, which are present near the viral envelope, assemble the newly synthesized viruses.
• M2 provides the adequate pH in the Golgi apparatus for the viruses to replicate and assemble. Mutations in M2 protein have been associated with adaptive mechanisms of the virus to infect new hosts.

Pro-inflammatory Mechanisms

Following infection, the expression of cytokines and chemokines in the lungs significantly increases. The exaggerated up-regulation of these cytokines and chemokines may partly be responsible for the tissue injury associated with the influenza virus. The expression of the following proteins increases with avian influenza infection:

• Tumor necrosis factor-α

• Macrophage inflammatory protein 1-α

• Interferon-γ and interferon-β
• IL-6

It is thought that following infection, the TRAIL death receptor ligand is activated and is responsible for triggering apoptosis. The time onset of apoptosis induction may vary among influenza subtypes; this delay may, at least in part, account for the prolonged and severe infection associated with certain subtypes.

Reduced Host Immunogenicity

• It is thought that the hemagglutinin of influenza virus is responsible for the suppression of perforin protein in cytotoxic T-cells.
• As perforin expression is reduced, the cytotoxic capacity of the T-cells is also reduced, the the T-cells ultimately fail to clear the influenza.