Genomic Signatures of Human versus Avian Influenza A Viruses

Chen, Guang-Wu; Chang, Shih-Cheng; Mok, Chee Keng; Lo, Yu-Luan; Kung, Yu-Nong; Huang, Ji-Hung; Shih, Yun-Han; Wang, Jiyi; Chiang, Chiayn; Chen, Chi-Jene; Shih, Shin‐Ru

doi:10.3201/eid1209.060276

Cited by 242 publications

(265 citation statements)

References 35 publications

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“…Analysis of phenotypic markers showed that 040078‐H3N2 is a well‐adapted human virus containing several markers associated with high transmissibility in humans 25. Seven glycosylation sites were predicted for the H3 HA protein at positions 24, 38, 79, 149, 181, 301, and 499.…”

Section: Resultsmentioning

confidence: 99%

Origin, distribution, and potential risk factors associated with influenza A virus in swine in two production systems in Guatemala

Gonzalez‐Reiche

Ramírez

Müller

et al. 2017

Influenza Resp Viruses

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BackgroundGuatemala is the country with the largest swine production in Central America; however, evidence of influenza A virus (IAV) in pigs has not been clearly delineated.ObjectivesIn this study, we analyzed the presence and spatial distribution of IAV in commercial and backyard swine populations.MethodsSamples from two nationwide surveys conducted in 2010 and 2011 were tested using virological (rRT‐PCR and virus isolation) and serological (ELISA and hemagglutination inhibition) assays to detect IAV.ResultsInfluenza A virus was detected in 15.7% of the sampled pigs (30.6% of herds) in 2010 and in 11.7% (24.2% of herds) in 2011. The percentage of seropositive pigs was 10.6% (16.1% of herds) and 1.4% (3.1% of herds) for each year, respectively. Three pandemic H1N1 and one seasonal human‐like H3N2 viruses were isolated. Antibodies against viruses from different genetic clusters were detected. No reassortant strains with swine viruses were detected. The H3N2 virus was closely related to human viruses that circulated in Central America in 2010, distinct to the most recent human seasonal vaccine lineages. Spatial clusters of rRT‐PCR positive herds were detected each year by scan statistics.ConclusionsOur results demonstrate circulation of IAV throughout Guatemala and identify commercial farms, animal health status, and age as potential risk factors associated with IAV infection and exposure. Detection of human‐origin viruses in pigs suggests a role for humans in the molecular epidemiology of IAV in swine in Guatemala and evidences gaps in local animal and human surveillance.

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Section: Resultsmentioning

confidence: 99%

Origin, distribution, and potential risk factors associated with influenza A virus in swine in two production systems in Guatemala

Gonzalez‐Reiche

Ramírez

Müller

et al. 2017

Influenza Resp Viruses

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“…As manual inspection of this volume of data is virtually impossible; it is necessary to use computational methods. Entropy (mutual-information)-based methods that use the amino acid frequency in each position are commonly used to this effect (27)(28)(29). These methods consider each position in the alignment separately, disregarding the possible relations between the sequence positions.…”

Section: Discussionmentioning

confidence: 99%

Putative amino acid determinants of the emergence of the 2009 influenza A (H1N1) virus in the human population

Meroz

Yoon

Ducatez

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

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The emergence of the unique H1N1 influenza A virus in 2009 resulted in a pandemic that has spread to over 200 countries. The constellation of molecular factors leading to the emergence of this strain is still unclear. Using a computational approach, we identified molecular determinants that may discriminate the hemagglutinin protein of the 2009 human pandemic H1N1 (pH1N1) strain from that of other H1N1 strains. As expected, positions discriminating the pH1N1 from seasonal human strains were located in or near known H1N1 antigenic sites, thus camouflaging the pH1N1 strain from immune recognition. For example, the alteration S145K (an antigenic position) was found as a characteristic of the pH1N1 strain. We also detected positions in the hemagglutinin protein differentiating classical swine viruses from pH1N1. These positions were mostly located in and around the receptor-binding pocket, possibly influencing binding affinity to the human cell. Such alterations may be liable in part for the virus's efficient infection and adaptation to humans. For instance, 133 A and 149 were identified as discriminative positions. Significantly, we showed that the substitutions R133 A K and R149K, predicted to be pH1N1 characteristics, each altered virus binding to erythrocytes and conferred virulence to A/swine/NC/18161/02 in mice, reinforcing the computational findings. Our findings provide a structural explanation for the deficient immunity of humans to the pH1N1 strain. Moreover, our analysis points to unique molecular factors that may have facilitated the emergence of this swine variant in humans, in contrast to other swine variants that failed.A pandemic H1N1 (pH1N1) human influenza virus was identified in April 2009 (1) and has since spread to over 200 countries and caused over 18,000 deaths (2). Evolutionary analysis of the pH1N1 strain indicates that its HA belongs to the classical swine lineage. HAs in this lineage are more similar to those of historical human strains such as the 1918 H1N1 strain than to those of circulating H1N1 strains from recent years (3). Prior to the emergence of the pH1N1 strain, only sporadic cases of human infection by swine influenza viruses had been reported (4-8). The molecular basis enabling this recent strain to efficiently infect and be transmitted between humans remains obscure (9-12).Herein, we used a computational approach to uncover signature residues in the receptor-binding domain (RBD) of the pH1N1 HA protein. Using a machine-learning algorithm of alternating decision trees (ADTs) (13), we predicted positions that differentiated between HA protein sequences of the pH1N1 strain and HA sequences of other H1N1 strains. The algorithm combines moderately successful rules to produce highly accurate predictions (13). Here the rules represent correlations between the presence of specific amino acid type(s) in selected positions and the sequence annotation, e.g., pandemic versus seasonal strain. This is done by iteratively reweighting training examples (i.e., HA sequences), thus, concentratin...

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“…A single residue in the PB2 subunit of the influenza polymerase, amino acid 627, regulates polymerase activity in a species-specific fashion (5). PB2 derived from human viral isolates almost exclusively possesses a lysine at position 627 (K627), whereas glutamic acid (E627) at this position predominates in avian viruses (6). PB2 K627 correlates with enhanced polymerase activity, virus replication, transmission, and in certain cases, pathogenicity and mortality in mammals (5,(7)(8)(9)(10)(11)(12)(13)(14)(15)(16).…”

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confidence: 99%

Adaptive strategies of the influenza virus polymerase for replication in humans

Mehle¹,

Doudna

2009

Proc. Natl. Acad. Sci. U.S.A.

342

373

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Transmission of influenza viruses into the human population requires surmounting barriers to cross-species infection. Changes in the influenza polymerase overcome one such barrier. Viruses isolated from birds generally contain polymerases with the aviansignature glutamic acid at amino acid 627 in the PB2 subunit. These polymerases display restricted activity in human cells. An adaptive change in this residue from glutamic acid to the human-signature lysine confers high levels of polymerase activity in human cells. This mutation permits escape from a species-specific restriction factor that targets polymerases from avian viruses. A 2009 swineorigin H1N1 influenza A virus recently established a pandemic infection in humans, even though the virus encodes a PB2 with the restrictive glutamic acid at amino acid 627. We show here that the 2009 H1N1 virus has acquired second-site suppressor mutations in its PB2 polymerase subunit that convey enhanced polymerase activity in human cells. Introduction of this polymorphism into the PB2 subunit of a primary avian isolate also increased polymerase activity and viral replication in human and porcine cells. An alternate adaptive strategy has also been identified, whereby introduction of a human PA subunit into an avian polymerase overcomes restriction in human cells. These data reveal a strategy used by the 2009 H1N1 influenza A virus and identify other pathways by which avian and swine-origin viruses may evolve to enhance replication, and potentially pathogenesis, in humans.2009 A(H1N1) ͉ PB2 ͉ species barriers

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Genomic Signatures of Human versus Avian Influenza A Viruses

Abstract: Fifty-two species-associated amino acid residues were found between human and avian influenza viruses.

Cited by 242 publications

References 35 publications

Origin, distribution, and potential risk factors associated with influenza A virus in swine in two production systems in Guatemala

Origin, distribution, and potential risk factors associated with influenza A virus in swine in two production systems in Guatemala

Putative amino acid determinants of the emergence of the 2009 influenza A (H1N1) virus in the human population

Adaptive strategies of the influenza virus polymerase for replication in humans

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