Avian influenza pathophysiology

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For more information about seasonal human influenza virus that is not associated with animal exposure, see Influenza

For more details about the structure and morphology of the influenza A virus, click here

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [3]; Associate Editor(s)-in-Chief: Yazan Daaboul, M.D.

Overview

All reported cases of avian influenza are caused by influenza A virus. The genome of influenza A consists of 8 RNA gene segments, which encode 11 proteins, including hemagglutinin, neuraminidase, non-structural proteins, matrix proteins, polymerase proteins, and nucleoprotein). Influenza virus is transmitted in aerosols of respiratory secretions. The HA protein on the viral surface functions as a receptor binding site and binds to host receptors that contain sialic acid to allow viral fusion to the host cell in the respiratory tract. Following fusion, viral replication typically takes place within 1 day, and polymerase proteins and nucleoproteins are involved in viral replication, whereas the matrix protein is responsible for viral assembly prior to viral release via cytolytic or apoptotic mechanisms. Viral proteins are, at least in part, responsible for down-regulation of cytotoxic T-cell activity, evasion of immune responses, and activation of cytokines and pro-inflammatory mechanisms that contribute to host tissue injury. Avian influenza undergoes antigenic drifts and shifts that ultimately result in genetic reassortment and capacity to reinfect the same host.

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 virus. 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.
• Nucleoprotein (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 in the Golgi body.

Transmission

• Influenza virus is transmitted in aerosols of respiratory secretions.
• Avian influenza A viruses may be transmitted from animals to humans in two main ways:
  1. Directly from birds or from avian virus-contaminated environments to humans.
  2. Through an intermediate host, such as a pig.

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.
• During replication, NS proteins play a major role in evading the host immune responses by deactivating immune responses 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.

Antigenic Drift and Antigenic Shift

Antigenic drift creates influenza viruses with slightly-modified antigens, while antigenic shift generates viruses with entirely novel antigens.

How antigenic shift, or reassortment, can result in novel and highly pathogenic strains of human influenza

Antigenic Drift

• These are small changes in the genes of influenza viruses that happen continually over time as the virus replicates.
• These small genetic changes usually produce viruses that are pretty closely related to one another, which can be illustrated by their location close together on a phylogenetic tree.
• Viruses that are closely related to each other usually share the same antigenic properties and an immune system exposed to an similar virus will usually recognize it and respond. (This is sometimes called cross-protection.)
• But these small genetic changes can accumulate over time and result in viruses that are antigenically different (further away on the phylogenetic tree).
• When this happens, the body’s immune system may not recognize those viruses.
• This process works as follows:

• A person infected with a particular flu virus develops antibody against that virus.
• As antigenic changes accumulate, the antibodies created against the older viruses no longer recognize the “newer” virus, and the person can get sick again.
• Genetic changes that result in a virus with different antigenic properties is the main reason why people can get the flu more than one time.

• This is also why the flu vaccine composition must be reviewed each year, and updated as needed to keep up with evolving viruses.

Antigenic Shift

Adapted from CDC

• Antigenic shift is an abrupt, major change in the influenza A viruses, resulting in new hemagglutinin and/or new hemagglutinin and neuraminidaseproteins in influenza viruses that infect humans.
• Shift results in a new influenza A subtype or a virus with a hemagglutinin or a hemagglutinin and neuraminidase combination that has emerged from an animal population that is so different from the same subtype in humans that most people do not have immunity to the new (e.g. novel) virus.
• Such a “shift” occurred in the spring of 2009, when an H1N1 virus with a new combination of genes emerged to infect people and quickly spread, causing a pandemic.
• When shift happens, most people have little or no protection against the new virus.
• While influenza viruses are changing by antigenic drift all the time, antigenic shift happens only occasionally.
• Influenza type A viruses undergo both kinds of changes
• Influenza type B viruses change only by the more gradual process of antigenic drift.

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  Antigenic Drift
  Click on the image to expand.
  Image courtesy of the National Institute of Allergy and Infectious Diseases (NIAID) [1]

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  Antigenic Shift
  Click on the image to expand.
  Image courtesy of the National Institute of Allergy and Infectious Diseases (NIAID) [2]