Avian influenza pathophysiology: Difference between revisions
Jump to navigation
Jump to search
YazanDaaboul (talk | contribs) |
YazanDaaboul (talk | contribs) No edit summary |
||
| Line 9: | Line 9: | ||
===Genetics=== | ===Genetics=== | ||
All reported cases of avian influenza are caused by influenza A.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> The genome of influenza A consists of 8 gene segments, which encode 11 proteins<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref>: | All reported cases of avian influenza are caused by influenza A.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> The genome of influenza A consists of 8 gene segments, which encode 11 proteins<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref>: | ||
*'''Hemagglutinin (HA)''': Surface protein that acts as a receptor binding site. HA is targeted by host antibodies to neutralize the virus.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref><ref name="pmid16371632">{{cite journal| author=de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC et al.| title=Oseltamivir resistance during treatment of influenza A (H5N1) infection. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 25 | pages= 2667-72 | pmid=16371632 | doi=10.1056/NEJMoa054512 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16371632 }} </ref> | *'''Hemagglutinin (HA)''': Surface protein that acts as a receptor binding site. HA is targeted by host antibodies to neutralize the virus.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref><ref name="pmid16518756">{{cite journal| author=Zhou J, Law HK, Cheung CY, Ng IH, Peiris JS, Lau YL| title=Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian influenza virus-infected macrophages. | journal=J Infect Dis | year= 2006 | volume= 193 | issue= 7 | pages= 945-53 | pmid=16518756 | doi=10.1086/500954 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16518756 }} </ref><ref name="pmid16371632">{{cite journal| author=de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC et al.| title=Oseltamivir resistance during treatment of influenza A (H5N1) infection. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 25 | pages= 2667-72 | pmid=16371632 | doi=10.1056/NEJMoa054512 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16371632 }} </ref> | ||
*'''Neuraminidase (NA)''': Cleaves progeny virions from host cell receptors.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | *'''Neuraminidase (NA)''': Cleaves progeny virions from host cell receptors.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | ||
*'''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.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | *'''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.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref><ref name="pmid11546875">{{cite journal| author=Hatta M, Gao P, Halfmann P, Kawaoka Y| title=Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. | journal=Science | year= 2001 | volume= 293 | issue= 5536 | pages= 1840-2 | pmid=11546875 | doi=10.1126/science.1062882 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11546875 }} </ref> | ||
*'''NP''': Together with the polymerase proteins, NP forms the RNP complex to induce replication and transcription.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | *'''NP''': Together with the polymerase proteins, NP forms the RNP complex to induce replication and transcription.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | ||
*'''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.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | *'''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.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | ||
| Line 21: | Line 21: | ||
*Directly from birds or from avian virus-contaminated environments to humans. | *Directly from birds or from avian virus-contaminated environments to humans. | ||
*Through an intermediate host, such as a pig. | *Through an intermediate host, such as a pig. | ||
===Viral Fusion with Host Cell=== | ===Viral Fusion with Host Cell=== | ||
*The HA protein (receptor binding site) on the viral surface binds to host receptors that contain sialic acid. | *The HA protein (receptor binding site) on the viral surface binds to host receptors that contain sialic acid.<ref name="pmid16371632">{{cite journal| author=de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC et al.| title=Oseltamivir resistance during treatment of influenza A (H5N1) infection. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 25 | pages= 2667-72 | pmid=16371632 | doi=10.1056/NEJMoa054512 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16371632 }} </ref> | ||
*The precursor HA molecule undergoes proteolytic activation and cleaves to produce 2 molecules: HA1 and HA2. | *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. | *Following proteolytic activation, the virus fuses with the host cell. | ||
| Line 29: | Line 28: | ||
===Viral Replication and Assembly=== | ===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. | *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.<ref name="pmid16518756">{{cite journal| author=Zhou J, Law HK, Cheung CY, Ng IH, Peiris JS, Lau YL| title=Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian influenza virus-infected macrophages. | journal=J Infect Dis | year= 2006 | volume= 193 | issue= 7 | pages= 945-53 | pmid=16518756 | doi=10.1086/500954 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16518756 }} </ref><ref name="pmid16371632">{{cite journal| author=de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC et al.| title=Oseltamivir resistance during treatment of influenza A (H5N1) infection. | journal=N Engl J Med | year= 2005 | volume= 353 | issue= 25 | pages= 2667-72 | pmid=16371632 | doi=10.1056/NEJMoa054512 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16371632 }} </ref> | ||
*Similar to human influenza, avian influenza replicates intracellularly via cytolytic or apoptotic mechanisms. | *Similar to human influenza, avian influenza replicates intracellularly via cytolytic or apoptotic mechanisms.<ref name="pmid16518756">{{cite journal| author=Zhou J, Law HK, Cheung CY, Ng IH, Peiris JS, Lau YL| title=Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian influenza virus-infected macrophages. | journal=J Infect Dis | year= 2006 | volume= 193 | issue= 7 | pages= 945-53 | pmid=16518756 | doi=10.1086/500954 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16518756 }} </ref> | ||
*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. | *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.<ref name="pmid11546875">{{cite journal| author=Hatta M, Gao P, Halfmann P, Kawaoka Y| title=Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. | journal=Science | year= 2001 | volume= 293 | issue= 5536 | pages= 1840-2 | pmid=11546875 | doi=10.1126/science.1062882 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11546875 }} </ref> | ||
* | *During replication, NS proteins play a major role in evading the host immune responses by deactivating immune responses mediated by pro-inflammatory cytokines.<ref name="pmid11546875">{{cite journal| author=Hatta M, Gao P, Halfmann P, Kawaoka Y| title=Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses. | journal=Science | year= 2001 | volume= 293 | issue= 5536 | pages= 1840-2 | pmid=11546875 | doi=10.1126/science.1062882 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=11546875 }} </ref> | ||
*Viral replication is inversely associated with outcomes among humans, where increased viral loads are associated with severe/fatal clinical disease. | *Viral replication is inversely associated with outcomes among humans, where increased viral loads are associated with severe/fatal clinical disease.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | ||
*Following replication, the matrix proteins, which are present near the viral envelope, assemble the newly synthesized viruses. | *Following replication, the matrix proteins, which are present near the viral envelope, assemble the newly synthesized viruses.<ref name="pmid16713612">{{cite journal| author=Smith GJ, Naipospos TS, Nguyen TD, de Jong MD, Vijaykrishna D, Usman TB et al.| title=Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam. | journal=Virology | year= 2006 | volume= 350 | issue= 2 | pages= 258-68 | pmid=16713612 | doi=10.1016/j.virol.2006.03.048 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16713612 }} </ref> | ||
*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. | *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.<ref name="pmid16713612">{{cite journal| author=Smith GJ, Naipospos TS, Nguyen TD, de Jong MD, Vijaykrishna D, Usman TB et al.| title=Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam. | journal=Virology | year= 2006 | volume= 350 | issue= 2 | pages= 258-68 | pmid=16713612 | doi=10.1016/j.virol.2006.03.048 | pmc= | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=16713612 }} </ref> | ||
===Pro-inflammatory Mechanisms=== | ===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: | 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.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> The expression of the following proteins increases with avian influenza infection<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref>: | ||
*Tumor necrosis factor-α | *Tumor necrosis factor-α | ||
| Line 46: | Line 45: | ||
*IL-6 | *IL-6 | ||
<br> | <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. | It is thought that following infection, the TRAIL death receptor ligand is activated and is responsible for triggering apoptosis.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> 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.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | ||
===Reduced Host Immunogenicity=== | ===Reduced Host Immunogenicity=== | ||
*It is thought that the hemagglutinin of influenza virus is responsible for the suppression of perforin protein in cytotoxic T-cells. | *It is thought that the hemagglutinin of influenza virus is responsible for the suppression of perforin protein in cytotoxic T-cells.<ref name="pmid18403604">{{cite journal| author=Korteweg C, Gu J| title=Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans. | journal=Am J Pathol | year= 2008 | volume= 172 | issue= 5 | pages= 1155-70 | pmid=18403604 | doi=10.2353/ajpath.2008.070791 | pmc=PMC2329826 | url=http://www.ncbi.nlm.nih.gov/entrez/eutils/elink.fcgi?dbfrom=pubmed&tool=sumsearch.org/cite&retmode=ref&cmd=prlinks&id=18403604 }} </ref> | ||
*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. | *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. | ||
Revision as of 14:55, 23 April 2015
|
Avian influenza Microchapters |
|
Diagnosis |
|---|
|
Treatment |
|
Case Studies |
|
Avian influenza pathophysiology On the Web |
|
American Roentgen Ray Society Images of Avian influenza pathophysiology |
|
Risk calculators and risk factors for Avian influenza pathophysiology |
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.[1] The genome of influenza A consists of 8 gene segments, which encode 11 proteins[1]:
- Hemagglutinin (HA): Surface protein that acts as a receptor binding site. HA is targeted by host antibodies to neutralize the virus.[1][2][3]
- Neuraminidase (NA): Cleaves progeny virions from host cell receptors.[1]
- 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.[1][4]
- NP: Together with the polymerase proteins, NP forms the RNP complex to induce replication and transcription.[1]
- 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.[1]
- Matrix proteins: M1 and M2. M1 has a role in viral assembly. M2 controls pH in the Golgi body.[1]
Transmission
Avian influenza A viruses may be transmitted from animals to humans in two main ways:
- Directly from birds or from avian virus-contaminated environments to humans.
- 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.[3]
- 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.[2][3]
- Similar to human influenza, avian influenza replicates intracellularly via cytolytic or apoptotic mechanisms.[2]
- 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.[4]
- During replication, NS proteins play a major role in evading the host immune responses by deactivating immune responses mediated by pro-inflammatory cytokines.[4]
- Viral replication is inversely associated with outcomes among humans, where increased viral loads are associated with severe/fatal clinical disease.[1]
- Following replication, the matrix proteins, which are present near the viral envelope, assemble the newly synthesized viruses.[5]
- 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.[5]
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.[1] The expression of the following proteins increases with avian influenza infection[1]:
- 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.[1] 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.[1]
Reduced Host Immunogenicity
- It is thought that the hemagglutinin of influenza virus is responsible for the suppression of perforin protein in cytotoxic T-cells.[1]
- 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
- ↑ 1.00 1.01 1.02 1.03 1.04 1.05 1.06 1.07 1.08 1.09 1.10 1.11 1.12 1.13 Korteweg C, Gu J (2008). "Pathology, molecular biology, and pathogenesis of avian influenza A (H5N1) infection in humans". Am J Pathol. 172 (5): 1155–70. doi:10.2353/ajpath.2008.070791. PMC 2329826. PMID 18403604.
- ↑ 2.0 2.1 2.2 Zhou J, Law HK, Cheung CY, Ng IH, Peiris JS, Lau YL (2006). "Functional tumor necrosis factor-related apoptosis-inducing ligand production by avian influenza virus-infected macrophages". J Infect Dis. 193 (7): 945–53. doi:10.1086/500954. PMID 16518756.
- ↑ 3.0 3.1 3.2 de Jong MD, Tran TT, Truong HK, Vo MH, Smith GJ, Nguyen VC; et al. (2005). "Oseltamivir resistance during treatment of influenza A (H5N1) infection". N Engl J Med. 353 (25): 2667–72. doi:10.1056/NEJMoa054512. PMID 16371632.
- ↑ 4.0 4.1 4.2 Hatta M, Gao P, Halfmann P, Kawaoka Y (2001). "Molecular basis for high virulence of Hong Kong H5N1 influenza A viruses". Science. 293 (5536): 1840–2. doi:10.1126/science.1062882. PMID 11546875.
- ↑ 5.0 5.1 Smith GJ, Naipospos TS, Nguyen TD, de Jong MD, Vijaykrishna D, Usman TB; et al. (2006). "Evolution and adaptation of H5N1 influenza virus in avian and human hosts in Indonesia and Vietnam". Virology. 350 (2): 258–68. doi:10.1016/j.virol.2006.03.048. PMID 16713612.