Avian influenza pathophysiology: Difference between revisions

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Revision as of 14:42, 23 April 2015

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

Overview

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.

Transmission

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.

References

Template:WH Template:WS

@@ Line 1: / Line 1: @@
 __NOTOC__
 {{Avian influenza}}
-{{CMG}}
+{{CMG}}; {{AE}} {{YD}}
+==Overview==
 ==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.
 ===Transmission===
-{{H5N1}}
+===Viral Fusion with Host Cell===
-{{details more|H5N1|Transmission and infection of H5N1}}
+*The HA protein (receptor binding site) on the viral surface binds to host receptors that contain sialic acid.
-The highly [[pathogenic]] [[Influenza A virus]] subtype [[H5N1]] [[virus]] is an emerging avian [[influenza virus]] that has been causing global concern as a potential [[pandemic]] threat. It is often referred to simply as "bird flu" or "avian [[influenza]]" even though it is only one subtype of avian [[influenza]] causing [[virus]].
+*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.
-[[H5N1]] has killed millions of poultry in a growing number of countries throughout Asia, Europe and Africa. Health experts are concerned that the co-existence of human flu [[virus]]es and avian flu [[virus]]es (especially [[H5N1]]) will provide an opportunity for [[genetic]] material to be exchanged between [[species]]-specific [[virus]]es, possibly creating a new [[virulent]] [[influenza]] strain that is easily [[transmission|transmissible]] and lethal to humans.<ref name=FSRIO>Food Safety Research Information Office. [http://fsrio.nal.usda.gov/document_fsheet.php?product_id=207 "A Focus on Avian Influenza"]. Created May 2006, Updated November 2007.</ref>
+===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
-Since the first [[H5N1]] [[outbreak]] occurred in 1997, there has been an increasing number of HPAI [[H5N1]] bird-to-human [[transmission]]s leading to clinically severe and fatal human [[infection]]s. However, because there is a significant [[species]] barrier that exists between birds and humans, the [[virus]] does not easily cross over to humans, though some cases of [[infection]] are being researched to discern whether human to human [[transmission]] is occurring. More research is necessary to understand the [[pathogenesis]] and [[epidemiology]] of the [[H5N1]] [[virus]] in humans. Exposure routes and other disease [[transmission]] characteristics such as [[genetic]] and [[immunological]] factors, that may increase the likelihood of [[infection]], are not clearly understood<ref name=WHO>World Health Organization. (2006). [[http://www.who.int/mediacentre/factsheets/avian_influenza/en/%23humans http://www.who.int/mediacentre/factsheets/avian_influenza/en/#humans] Avian influenza (" bird flu") – The Disease in Humans.] Retrieved April 6, 2006.</ref>.
+*Macrophage inflammatory protein 1-α
-Although millions of birds have become [[infect]]ed with the [[virus]] since its discovery, 206 humans have died from the [[H5N1]] in twelve countries according to [[WHO]] data as of November 2007.
+*Interferon-γ and interferon-β
+*IL-6
+<br>
+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.
-The Avian Flu claimed at least 200 humans in Romania, Greece, Turkey and Russia. [[Epidemiologist]]s are afraid that the next time such a [[virus]] [[mutation|mutates]], it could pass from human to human. If this form of [[transmission]] occurs, another big [[pandemic]] could result. However, disease-control centers around the world are making avian flu their top priority.
+===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.
-''Bird flu'' may refer to:
-* [[Avian influenza]] - another name for bird flu or avian [[influenza]]
-* [[H5N1]] - the current type of bird flu [[virus]] that is the worst [[pandemic]] threat
-* [[Influenzavirus A|Influenza A virus]] - the species of [[virus]] that causes all bird flu.
-===Genetics===
-[[Genetic]] factors in distinguishing between "[[human flu]] viruses" and "avian flu [[virus]]es" include:
-*''PB2'': ([[RNA polymerase]]): [[Amino acid]] (or [[residue]]) position 627 in the PB2 [[protein]] encoded by the PB2 [[RNA]] [[gene]]. Until [[H5N1]], all known avian [[influenza virus]]es had a [[Glutamic acid|Glu]] at position 627, while all human [[influenza virus]]es had a [[lysine]].
-*''HA'': ([[hemagglutinin]]): Avian [[influenza]] HA bind alpha 2-3 [[sialic acid]] receptors while human [[influenza]] HA bind alpha 2-6 [[sialic acid]] [[receptor]]s. [[swine flu|Swine]] [[influenza]] [[virus]]es have the ability to bind both types of [[sialic acid]] [[receptor]]s.
 ==References==