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• W1635544817 abstract "Influenza A virus infections in humans generally cause self-limited infections, but can result in severe disease, secondary bacterial pneumonias, and death. Influenza viruses can replicate in epithelial cells throughout the respiratory tree and can cause tracheitis, bronchitis, bronchiolitis, diffuse alveolar damage with pulmonary edema and hemorrhage, and interstitial and airspace inflammation. The mechanisms by which influenza infections result in enhanced disease, including development of pneumonia and acute respiratory distress, are multifactorial, involving host, viral, and bacterial factors. Host factors that enhance risk of severe influenza disease include underlying comorbidities, such as cardiac and respiratory disease, immunosuppression, and pregnancy. Viral parameters enhancing disease risk include polymerase mutations associated with host switch and adaptation, viral proteins that modulate immune and antiviral responses, and virulence factors that increase disease severity, which can be especially prominent in pandemic viruses and some zoonotic influenza viruses causing human infections. Influenza viral infections result in damage to the respiratory epithelium that facilitates secondary infection with common bacterial pneumopathogens and can lead to secondary bacterial pneumonias that greatly contribute to respiratory distress, enhanced morbidity, and death. Understanding the molecular mechanisms by which influenza and secondary bacterial infections, coupled with the role of host risk factors, contribute to enhanced morbidity and mortality is essential to develop better therapeutic strategies to treat severe influenza. Influenza A virus infections in humans generally cause self-limited infections, but can result in severe disease, secondary bacterial pneumonias, and death. Influenza viruses can replicate in epithelial cells throughout the respiratory tree and can cause tracheitis, bronchitis, bronchiolitis, diffuse alveolar damage with pulmonary edema and hemorrhage, and interstitial and airspace inflammation. The mechanisms by which influenza infections result in enhanced disease, including development of pneumonia and acute respiratory distress, are multifactorial, involving host, viral, and bacterial factors. Host factors that enhance risk of severe influenza disease include underlying comorbidities, such as cardiac and respiratory disease, immunosuppression, and pregnancy. Viral parameters enhancing disease risk include polymerase mutations associated with host switch and adaptation, viral proteins that modulate immune and antiviral responses, and virulence factors that increase disease severity, which can be especially prominent in pandemic viruses and some zoonotic influenza viruses causing human infections. Influenza viral infections result in damage to the respiratory epithelium that facilitates secondary infection with common bacterial pneumopathogens and can lead to secondary bacterial pneumonias that greatly contribute to respiratory distress, enhanced morbidity, and death. Understanding the molecular mechanisms by which influenza and secondary bacterial infections, coupled with the role of host risk factors, contribute to enhanced morbidity and mortality is essential to develop better therapeutic strategies to treat severe influenza. Influenza viruses are important pathogens from a public health perspective, because they are common causes of human respiratory illness. Significantly, influenza infections are associated with high morbidity and mortality, especially in elderly persons, infants, and those with chronic diseases.1Wright P.F. Neumann G. Kawaoka Y. Orthomyxoviruses.in: Knipe D.M. Howley P.M. Lippincott Williams & Wilkins, Philadelphia2007: 1691-1740Google Scholar Human influenza virus infections are associated with endemically circulating strains causing annual or seasonal epidemic outbreaks (usually in the winter months) and occasional and unpredictably emerging pandemic strains, as well as zoonotic infections from avian and mammalian animal hosts. Epidemic influenza infection results in up to 49,000 deaths and 200,000 hospitalizations each year in the United States alone.2Thompson M.G. Shay D.K. Zhou H. Bridges C.B. Cheng P.Y. Burns E. Bresee J.S. Cox N.J. Estimates of deaths associated with seasonal influenza: United States, 1976-2007.MMWR Morb Mortal Wkly Rep. 2010; 59: 1057-1062PubMed Google Scholar However, pandemic strains of influenza can cause even higher mortality. For example, the 1918 Spanish influenza pandemic resulted in approximately 675,000 deaths in the United States in a population approximately one-third the size of the current population and approximately 50 million deaths globally.3Johnson N.P. Mueller J. Updating the accounts: global mortality of the 1918-1920 “Spanish” influenza pandemic.Bull Hist Med. 2002; 76: 105-115Crossref PubMed Google Scholar, 4Taubenberger J.K. Morens D.M. 1918 Influenza: the mother of all pandemics.Emerg Infect Dis. 2006; 12: 15-22Crossref PubMed Scopus (23) Google Scholar Since 1997, there has been heightened concern that avian influenza viruses associated with zoonotic outbreaks, such as H5N1 and H7N9, could adapt to achieve efficient transmissibility in humans and cause a pandemic.5Peiris J.S.M. Avian influenza viruses in humans.Rev Sci Tech. 2009; 28: 161-173PubMed Google Scholar Influenza virus infections are generally acute, self-limited infections.6Taubenberger J.K. Morens D.M. The pathology of influenza virus infections.Annu Rev Pathol. 2008; 3: 499-522Crossref PubMed Scopus (759) Google Scholar Clinically, influenza manifests as an acute respiratory disease characterized by the sudden onset of high fever, coryza, cough, headache, prostration, malaise, and inflammation of the upper respiratory tree and trachea. Acute symptoms and fever often persist for 7 to 10 days, and in most cases, the infection is self-limited. Generally, pneumonic involvement is not clinically prominent, although weakness and fatigue may linger for weeks. People of all ages are afflicted, but the prevalence is greatest in school-aged children; disease severity is greatest in infants, elderly persons, and those with underlying illnesses. Influenza A viral replication peaks approximately 48 hours after infection of the nasopharynx and declines thereafter, with little virus shed after approximately 6 days. The virus replicates in both the upper and lower respiratory tract. The diagnosis of influenza can be established by viral culture, demonstration of viral antigens, demonstration of viral genetic material (in clinical specimens), or changes in specific antibody titers in serum or respiratory secretions.7Taubenberger J.K. Layne S.P. Diagnosis of influenza virus: coming to grips with the molecular era.Mol Diagn. 2001; 6: 291-305Crossref PubMed Google Scholar Influenza is the leading cause of respiratory viral disease in all hospitalized patients >16 years.8Gaunt E.R. Harvala H. McIntyre C. Templeton K.E. Simmonds P. Disease burden of the most commonly detected respiratory viruses in hospitalized patients calculated using the disability adjusted life year (DALY) model.J Clin Virol. 2011; 52: 215-221Abstract Full Text Full Text PDF PubMed Scopus (66) Google Scholar People with underlying comorbidities, including chronic pulmonary or cardiac disease, immunosuppression, or diabetes mellitus, are at high risk of developing severe complications from influenza A viruses (IAVs). These may include hemorrhagic bronchitis, laryngotracheitis in young children, pneumonia (primary viral or secondary bacterial), and death.6Taubenberger J.K. Morens D.M. The pathology of influenza virus infections.Annu Rev Pathol. 2008; 3: 499-522Crossref PubMed Scopus (759) Google Scholar, 9Kuiken T. Taubenberger J.K. The pathology of human influenza revisited.Vaccine. 2008; 26: D59-D66Crossref PubMed Scopus (263) Google Scholar Obesity has recently been identified as an independent risk factor, and pregnancy has long been associated with increased risk.10Karlsson E.A. Marcelin G. Webby R.J. Schultz-Cherry S. Review on the impact of pregnancy and obesity on influenza virus infection.Influenza Other Respir Viruses. 2012; 6: 449-460Crossref PubMed Scopus (46) Google Scholar, 11Memoli M.J. Harvey H. Morens D.M. Taubenberger J.K. Influenza in pregnancy.Influenza Other Respir Viruses. 2013; 7: 1033-1039Crossref PubMed Scopus (37) Google Scholar Complications of influenza, including hemorrhagic bronchitis, diffuse alveolar damage, and pneumonia, can develop within hours. Fulminant fatal influenza viral pneumonia occasionally occurs, but most pneumonias are caused by secondary bacterial infections.12Chertow D.S. Memoli M.J. Bacterial coinfection in influenza: a grand rounds review.JAMA. 2013; 309: 275-282Crossref PubMed Scopus (286) Google Scholar, 13Morens D.M. Taubenberger J.K. Fauci A.S. Predominant role of bacterial pneumonia as a cause of death in pandemic influenza: implications for pandemic influenza preparedness.J Infect Dis. 2008; 198: 962-970Crossref PubMed Scopus (1149) Google Scholar Development of pneumonia, dyspnea, cyanosis, hemoptysis, pulmonary edema leading to acute respiratory distress syndrome, and death may proceed in as little as 48 hours after the onset of symptoms. Progression to severe disease, including development of acute respiratory distress, pneumonia, and death, is likely a multifactorial process involving viral, host, and bacterial factors (Figure 1). In this review, we will examine each of these underlying factors to discuss their contribution to influenza pathogenesis. Influenza viruses (of the family Orthomyxoviridae) are enveloped, negative-sense, single-stranded RNA viruses with segmented genomes. There are five genera, including Influenzavirus A, Influenzavirus B, Influenzavirus C, Thogotovirus, and Isavirus (infectious salmon anemia virus).1Wright P.F. Neumann G. Kawaoka Y. Orthomyxoviruses.in: Knipe D.M. Howley P.M. Lippincott Williams & Wilkins, Philadelphia2007: 1691-1740Google Scholar, 14Palese P. Shaw M.L. Orthomyxoviridae: The Viruses and Their Replication.in: Knipe D.M. Howley P.M. Lippincott, Williams & Wilkins, Philadelphia2007: 1647-1690Google Scholar, 15Taubenberger J.K. Kash J.C. Influenza virus evolution, host adaptation, and pandemic formation.Cell Host Microbe. 2010; 7: 440-451Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar The Influenzavirus genera differ in host range and pathogenicity and diverged evolutionarily at least several thousand years ago.16Suzuki Y. Nei M. Origin and evolution of influenza virus hemagglutinin genes.Mol Biol Evol. 2002; 19: 501-509Crossref PubMed Scopus (86) Google Scholar Influenza A and B viruses have a similar structure, whereas influenza C is more divergent. Influenza A and B type viruses contain eight discrete single-stranded RNA gene segments, each encoding at least one protein. Influenza B and C viruses are predominantly human-adapted viruses, whereas IAVs naturally infect hundreds of warm-blooded animal hosts, including both avian and mammalian species. Wild aquatic birds are the major reservoir of IAV, where it causes predominantly asymptomatic gastrointestinal tract infections.17Webster R.G. Bean W.J. Gorman O.T. Chambers T.M. Kawaoka Y. Evolution and ecology of influenza A viruses.Microbiol Rev. 1992; 56: 152-179Crossref PubMed Google Scholar Mixed IAV infections and gene segment reassortment are common in wild aquatic birds. These data suggest that IAVs in wild birds form transient genome constellations without the strong selective pressure to be maintained as linked genomes, leading to the continual emergence of novel genotypes.18Dugan V.G. Chen R. Spiro D.J. Sengamalay N. Zaborsky J. Ghedin E. Nolting J. Swayne D.E. Runstadler J.A. Happ G.M. Senne D.A. Wang R. Slemons R.D. Holmes E.C. Taubenberger J.K. The evolutionary genetics and emergence of avian influenza viruses in wild birds.PLoS Pathog. 2008; 4: e1000076Crossref PubMed Scopus (315) Google Scholar This genetic and antigenic diversity of IAVs thus poses a significant risk of zoonotic infection, host switch events, and the generation of pandemic IAV strains. IAVs encode at least 13 proteins via alternative open reading frames, splicing, or ribosomal frame shifting.19Wise H.M. Hutchinson E.C. Jagger B.W. Stuart A.D. Kang Z.H. Robb N. Schwartzman L.M. Kash J.C. Fodor E. Firth A.E. Gog J.R. Taubenberger J.K. Digard P. Identification of a novel splice variant form of the influenza A virus M2 ion channel with an antigenically distinct ectodomain.PLoS Pathog. 2012; 8: e1002998Crossref PubMed Scopus (164) Google Scholar IAVs express three surface proteins: hemagglutinin (HA), neuraminidase (NA), and matrix 2. IAVs are classified, or subtyped, by antigenic or genetic characterization of the HA and NA glycoproteins. Eighteen different HA and 11 different NA subtypes are known,18Dugan V.G. Chen R. Spiro D.J. Sengamalay N. Zaborsky J. Ghedin E. Nolting J. Swayne D.E. Runstadler J.A. Happ G.M. Senne D.A. Wang R. Slemons R.D. Holmes E.C. Taubenberger J.K. The evolutionary genetics and emergence of avian influenza viruses in wild birds.PLoS Pathog. 2008; 4: e1000076Crossref PubMed Scopus (315) Google Scholar, 20Wu Y. Tefsen B. Shi Y. Gao G.F. Bat-derived influenza-like viruses H17N10 and H18N11.Trends Microbiol. 2014; 22: 183-191Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar with 16 of the HAs and 9 of the NAs consistently found in avian hosts in various combinations (eg, H1N1 or H3N2).18Dugan V.G. Chen R. Spiro D.J. Sengamalay N. Zaborsky J. Ghedin E. Nolting J. Swayne D.E. Runstadler J.A. Happ G.M. Senne D.A. Wang R. Slemons R.D. Holmes E.C. Taubenberger J.K. The evolutionary genetics and emergence of avian influenza viruses in wild birds.PLoS Pathog. 2008; 4: e1000076Crossref PubMed Scopus (315) Google Scholar, 20Wu Y. Tefsen B. Shi Y. Gao G.F. Bat-derived influenza-like viruses H17N10 and H18N11.Trends Microbiol. 2014; 22: 183-191Abstract Full Text Full Text PDF PubMed Scopus (241) Google Scholar HA is a glycoprotein that functions both as the viral receptor-binding protein and as the fusion protein. HA binds to sialic acid (N-acetyl neuraminic acid) bound to underlying sugars on the tips of host cell glycoproteins. IAVs have HAs with varying specificities for the disaccharide consisting of sialic acids (SAs) and the penultimate sugar (galactose or N-acetylgalactosamine) with different glycosidic bonds. IAVs adapted to birds typically have HA receptor binding specificity for α2,3 SA, whereas HAs from IAVs adapted to humans have higher specificity for α2,6 SA.1Wright P.F. Neumann G. Kawaoka Y. Orthomyxoviruses.in: Knipe D.M. Howley P.M. Lippincott Williams & Wilkins, Philadelphia2007: 1691-1740Google Scholar, 14Palese P. Shaw M.L. Orthomyxoviridae: The Viruses and Their Replication.in: Knipe D.M. Howley P.M. Lippincott, Williams & Wilkins, Philadelphia2007: 1647-1690Google Scholar After receptor binding, the virus is internalized. The endosomal compartment's acidic pH leads to an HA conformational change, facilitating fusion of the viral and endosomal membranes, release of viral ribonucleoproteins (RNPs) into the cytoplasm, and their subsequent transport to the nucleus. Viral HA is a homotrimer, and each monomer undergoes proteolytic cleavage to generate HA1 and HA2 polypeptide chains before activation. IAV does not encode a protease and requires exogenous serine proteases (trypsin-like enzymes) for activation that recognize a conserved Q/E-X-R motif found at the HA cleavage site.21Chen J. Lee K.H. Steinhauer D.A. Stevens D.J. Skehel J.J. Wiley D.C. Structure of the hemagglutinin precursor cleavage site, a determinant of influenza pathogenicity and the origin of the labile conformation.Cell. 1998; 95: 409-417Abstract Full Text Full Text PDF PubMed Scopus (401) Google Scholar In humans and other mammals, Clara tryptase, produced by cells of the bronchiolar epithelium, likely serves this role. IAVs of H5 and H7 subtypes can acquire insertional mutations at the HA cleavage site, which change their protease recognition site to a furin-like recognition sequence R-X-R/K-R. This polybasic cleavage site broadens protease specificity, allowing for intracellular cleavage activation, and systemic replication of such viruses in poultry, resulting in the emergence of highly pathogenic avian influenza. NA is a glycoprotein with neuraminidase (sialidase) enzymatic activity required for cleavage of these host cell SAs, allowing newly produced virions to be released and to cleave SAs from viral glycoproteins to prevent aggregation of nascent viral particles. The surface glycoproteins HA and NA are the major antigenic targets of the humoral immune response to IAV, and NA is the target of the antiviral drugs oseltamivir and zanamivir. The matrix 1 protein is the most abundant structural protein. Localized beneath the viral membrane, it interacts with the cytoplasmic domains of the surface glycoproteins HA and NA and also with the viral RNP complexes. The small protein matrix 2 is a proton channel necessary for viral replication and is the target of the adamantane class of antiviral drugs.22Hayden F.G. Antivirals for influenza: historical perspectives and lessons learned.Antiviral Res. 2006; 71: 372-378Crossref PubMed Scopus (83) Google Scholar Matrix 2 functions as a low pH gated ion channel that lowers the pH of the virion after internalization and leads to membrane fusion with the lysogenic vacuole. The viral RNPs are released into the cytoplasm and are then translocated to the nucleus to initiate viral RNA synthesis. IAVs are segmented, negative-stranded viruses, and viral RNPs consist of each RNA gene segment, encapsidated by the single-stranded RNA binding protein nucleoprotein (NP) and associated with three viral polymerase proteins that comprise the RNA-dependent RNA polymerase-polymerase basic protein 2 (PB2), polymerase basic protein 1 (PB1), and polymerase acidic protein (PA). The polymerase proteins form a heterotrimer bound to short hairpin structures formed by the complementary terminal 5′ and 3′ untranslated regions of each RNA segment. PB1 is the RNA-dependent RNA polymerase, and PB2 functions in mRNA synthesis by binding host mRNA caps. Although PA is necessary for a functional polymerase complex, including endonucleolytic cleavage of host pre-mRNAs, its biological roles remain less well understood. NP plays important roles in transcription, and in the trafficking of RNPs between the cytoplasm and nucleus. IAV is dependent on the RNA processing machinery of the host cell, and transcription and replication occur in the host nucleus. Several non-structural proteins play important roles in the viral replicative cycle. The non-structural protein 1 has a variety of functions, including double-stranded RNA binding and antagonism of host cell type I interferon responses.14Palese P. Shaw M.L. Orthomyxoviridae: The Viruses and Their Replication.in: Knipe D.M. Howley P.M. Lippincott, Williams & Wilkins, Philadelphia2007: 1647-1690Google Scholar The NS2 (or NEP) protein enables nuclear export of viral RNP complexes. PB1-F2 targets the mitochondrial inner membrane and may play a role in apoptosis during IAV infection.23Conenello G.M. Palese P. Influenza A virus PB1-F2: a small protein with a big punch.Cell Host Microbe. 2007; 2: 207-209Abstract Full Text Full Text PDF PubMed Scopus (55) Google Scholar PAX is a newly discovered protein that functions to repress cellular gene expression and modulates IAV pathogenicity by an unknown mechanism.24Jagger B.W. Wise H.M. Kash J.C. Walters K.A. Wills N.M. Xiao Y.L. Dunfee R.L. Schwartzman L.M. Ozinsky A. Bell G.L. Dalton R.M. Lo A. Efstathiou S. Atkins J.F. Firth A.E. Taubenberger J.K. Digard P. An overlapping protein-coding region in influenza A virus segment 3 modulates the host response.Science. 2012; 337: 199-204Crossref PubMed Scopus (455) Google Scholar The viral RNA-dependent RNA polymerase lacks proofreading, and IAVs are thus evolutionarily dynamic viruses with high mutation rates that range from approximately 1 × 10−3 to 8 × 10−3 substitutions per site per year.25Chen R. Holmes E.C. Avian influenza virus exhibits rapid evolutionary dynamics.Mol Biol Evol. 2006; 23: 2336-2341Crossref PubMed Scopus (176) Google Scholar Mutations that alter amino acids in the antigenic portions of the surface glycoproteins HA and NA may allow IAVs to evade preexisting immunity. These mutations are especially important in human seasonal IAV strains, which are subjected to strong population immunological pressures. Anti-HA antibodies can prevent receptor binding, can neutralize infection, and are effective at preventing reinfection with the same strain. This selective mutation in the antigenic domains of HA and NA has been termed antigenic drift26Murphy B.R. Clements M.L. The systemic and mucosal immune response of humans to influenza A virus.Curr Top Microbiol Immunol. 1989; 146: 107-116PubMed Google Scholar and is the basis for the need to yearly update the annual influenza vaccine formulation.1Wright P.F. Neumann G. Kawaoka Y. Orthomyxoviruses.in: Knipe D.M. Howley P.M. Lippincott Williams & Wilkins, Philadelphia2007: 1691-1740Google Scholar The high mutation rate can also result in the rapid establishment of antiviral drug-resistant populations, including resistance to NA inhibitors and adamantanes. Clinical studies have shown that NA-resistant viruses can rapidly acquire mutations in NA after initiation of treatment,27Memoli M.J. Hrabal R.J. Hassantoufighi A. Eichelberger M.C. Taubenberger J.K. Rapid selection of oseltamivir- and peramivir-resistant pandemic H1N1 virus during therapy in 2 immunocompromised hosts.Clin Infect Dis. 2010; 50: 1252-1255Crossref PubMed Scopus (139) Google Scholar, 28Memoli M.J. Hrabal R.J. Hassantoufighi A. Jagger B.W. Sheng Z.M. Eichelberger M.C. Taubenberger J.K. Rapid selection of a transmissible multidrug-resistant influenza A/H3N2 virus in an immunocompromised host.J Infect Dis. 2010; 201: 1397-1403Crossref PubMed Scopus (40) Google Scholar without apparent loss of fitness. Global circulation of such human IAVs bearing antiviral resistance mutations has been observed for different strains of influenza viruses in the past decade.29Samson M. Pizzorno A. Abed Y. Boivin G. Influenza virus resistance to neuraminidase inhibitors.Antiviral Res. 2013; 98: 174-185Crossref PubMed Scopus (270) Google Scholar Because the IAV genome consists of eight RNA segments, coinfection of one host cell with two different IAVs can result in progeny viruses containing gene segments derived from both parental viruses. When the process of genetic reassortment involves the gene segments encoding the HA and/or NA genes, it is termed antigenic shift. Reassortment is an important feature in IAV evolution18Dugan V.G. Chen R. Spiro D.J. Sengamalay N. Zaborsky J. Ghedin E. Nolting J. Swayne D.E. Runstadler J.A. Happ G.M. Senne D.A. Wang R. Slemons R.D. Holmes E.C. Taubenberger J.K. The evolutionary genetics and emergence of avian influenza viruses in wild birds.PLoS Pathog. 2008; 4: e1000076Crossref PubMed Scopus (315) Google Scholar, 30Rambaut A. Pybus O.G. Nelson M.I. Viboud C. Taubenberger J.K. Holmes E.C. 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Influenza virus evolution, host adaptation, and pandemic formation.Cell Host Microbe. 2010; 7: 440-451Abstract Full Text Full Text PDF PubMed Scopus (551) Google Scholar Ultimately, influenza viruses must be able to infect target cells, replicate, and be transmitted efficiently to be adapted to a particular host. However, influenza pathogenesis does not require transmissibility, and zoonotic infections of nonadapted, or partially host-adapted, viruses can cause severe disease, such as observed in human infections with avian H5N1 and H7N9 viruses.5Peiris J.S.M. Avian influenza viruses in humans.Rev Sci Tech. 2009; 28: 161-173PubMed Google Scholar, 31Morens D.M. Taubenberger J.K. Fauci A.S. 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These pandemic HA-expressing viruses had an expanded cellular tropism to infect alveolar epithelial cells and macrophages, and this was correlated with an inability of these zoonotically derived HAs to be neutralized by lung surfactant protein D in v" @default.
• W1635544817 created "2016-06-24" @default.
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• W1635544817 date "2015-06-01" @default.
• W1635544817 modified "2023-10-17" @default.
• W1635544817 title "The Role of Viral, Host, and Secondary Bacterial Factors in Influenza Pathogenesis" @default.
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