Complete-Proteome Mapping of Human Influenza A Adaptive Mutations: Implications for Human Transmissibility of Zoonotic Strains

Miotto, Olivo; Heiny, A. T.; Albrecht, Randy A.; Garcı́a-Sastre, Adolfo; Tan, Tin Wee; August, J. Thomas; Brusic, Vladimir

doi:10.1371/journal.pone.0009025

Cited by 79 publications

(113 citation statements)

References 69 publications

(63 reference statements)

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“…A number of viral determinants have been identified that contribute to the adaptation of avian influenza viruses to mammalian hosts , and several large-scale comparative analyses of proteins from avian and human viruses have been performed to cat-alog the amino acids that are conserved in each host species (29)(30)(31). The PB2, PB1, and PA subunits of the polymerase complex play a major role in virus pathogenicity and efficient viral growth in mammals.…”

mentioning

confidence: 99%

Identification of PB2 Mutations Responsible for the Efficient Replication of H5N1 Influenza Viruses in Human Lung Epithelial Cells

Yamaji

Yamada

et al. 2015

J Virol

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Highly pathogenic H5N1 avian influenza viruses have caused outbreaks among poultry worldwide, resulting in sporadic infections in humans with approximately 60% mortality. However, efficient transmission of H5N1 viruses among humans has yet to occur, suggesting that further adaptation of H5N1 viruses to humans is required for their efficient transmission among humans. The viral determinants for efficient replication in humans are currently poorly understood. Here, we report that the polymerase PB2 protein of an H5N1 influenza virus isolated from a human in Vietnam (A/Vietnam/UT36285/2010, virus 36285) increased the growth ability of an avian H5N1 virus (A/wild bird/Anhui/82/2005, virus Wb/AH82) in human lung epithelial A549 cells (however, the reassortant virus did not replicate more efficiently than human 36285 virus). Furthermore, we demonstrate that the amino acid residues at positions 249, 309, and 339 of the PB2 protein from this human isolate were responsible for its efficient replication in A549 cells. PB2 residues 249G and 339M, which are found in the human H5N1 virus, are rare in H5N1 viruses from both human and avian sources. Interestingly, PB2-249G is found in over 30% of human seasonal H3N2 viruses, which suggests that H5N1 viruses may replicate well in human cells when they acquire this mutation. Our data are of value to H5N1 virus surveillance. IMPORTANCEHighly pathogenic H5N1 avian influenza viruses must acquire mutations to overcome the species barrier between avian species and humans. When H5N1 viruses replicate in human respiratory cells, they can acquire amino acid mutations that allow them to adapt to humans through continuous selective pressure. Several amino acid mutations have been shown to be advantageous for virus adaptation to mammalian hosts. Here, we found that amino acid changes at positions 249, 309, and 339 of PB2 contribute to efficient replication of avian H5N1 viruses in human lung cells. These findings are beneficial for evaluating the pandemic risk of circulating avian viruses and for further functional analysis of PB2. Highly pathogenic H5N1 influenza A viruses continue to circulate among avian species. As a result, sporadic avian-tohuman transmission has occurred and the threat of a pandemic has persisted. The first human case caused by a highly pathogenic H5N1 influenza A virus was reported in Hong Kong in 1997 (1, 2). Although the mass culling ordered by the Hong Kong government temporarily ended the outbreak, a second outbreak of H5N1 viruses occurred in 2003. With the spread of H5N1 viruses among migrating birds and poultry, these viruses quickly spread beyond East Asia (3). This spread of H5N1 viruses has been accompanied by increasing reports of cases of avian-to-human transmission. As of January 2015, the total number of confirmed human cases of highly pathogenic H5N1 influenza A virus infection had reached 694, with 402 deaths (http://www.who.int/influenza/human _animal_interface/H5N1_cumulative_table_archives/en/) (4, 5). However, the human cases of H5N1 infe...

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confidence: 99%

Identification of PB2 Mutations Responsible for the Efficient Replication of H5N1 Influenza Viruses in Human Lung Epithelial Cells

Yamaji

Yamada

et al. 2015

J Virol

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“…Th is complex, unlike the surface antigens HA and NA, is highly conserved among all IAVs. However, the hostadaptation mutations were found in all subunits of viral RNA polymerase (Miotto et al, 2010). In general, they correlate with enhanced replication ability of avian viruses in mammals.…”

Section: Other Iav Proteins Infl Uencing the Virulencementioning

confidence: 98%

The role of fusion activity of influenza A viruses in their biological properties

Jakubcová¹,

Hollý²,

Varečková³

2016

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Summary. -Infl uenza A viruses (IAVs) cause acute respiratory infections of humans, which are repeated yearly. Human IAV infections are associated with signifi cant morbidity and mortality and therefore they represent a serious health problem. All human IAV strains are originally derived from avian IAVs, which, aft er their adaptation to humans, can spread in the human population and cause pandemics with more or less severe course of the disease. Presently, however, the potential of avian IAV to infect humans and to cause the disease cannot be predicted. Many studies are therefore focused on factors infl uencing the virulence and pathogenicity of IAV viruses in a given host. Th e virus-host interaction starts by virus attachment via the envelope glycoprotein hemagglutinin (HA) to the receptors on the cell surface. In addition to receptor binding, HA mediates also the fusion of viral and endosomal membranes, which follows the virus endocytosis. Th e fusion potential of HA trimer, primed by proteolytic cleavage, is activated by low pH in endosomes, resulting in HA refolding into the fusion-active form. Th e HA conformation change is predetermined by its 3-D structure, is pH-dependent, irreversible and strain-specifi c. Th e process of fusion activation of IAV hemagglutinin is crucial for virus entry into the cell and for the ability of the virus to replicate in the host. Here we discuss the known data about the characteristics of fusion activation of HA in relation to IAV virulence and pathogenicity.Keywords: infl uenza A viruses; pH optimum of fusion; IAV virulence and pathogenicity; HA conformation change; IAV interspecies transmission; adaptation changes * Corresponding author. E-mail: viruevar@savba.sk; phone: 421-2-59302427. Abbreviations: HA = hemagglutinin; HA0 = HA precursor; HA1 = heavy chain of HA; HA2 = light chain of HA; HPAI = highly pathogenic avian infl uenza; IAV(s) = infl uenza A virus(es); LPAI = low pathogenic avian infl uenza; M1 protein = matrix protein; mRNA = messenger RNA; NA = neuraminidase; NEP protein = nuclear export protein; NS1 protein = nonstructural protein 1; PA = polymerase acidic protein; PB1 = polymerase basic protein 1; PB2 = polymerase basic protein 2; RBS = receptor binding site; RNA = ribonucleic acid; RNP = ribonucleoprotein; SA = sialic acid; vRNA = viral RNA Content: 1. Introduction 2. Structure and function of hemagglutinin 2.1 Receptor binding activity and IAV host tropism 2.2 Fusion activity and structural rearrangements of HA during the membrane fusion 3. Th e HA cleavability by host proteases and HA fusion activation pH as factors of IAV virulence and pathogenicity 3.1 Cleavage activation of HA as a determinant of IAV pathogenicity 3.2 Fusion activation pH as a determinant of IAV virulence 4. Th e role of fusion activation pH and stability of HA in the adaptation of IAV to the new host 5. Other viral proteins infl uencing the IAV virulence 6. Conclusion

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“…Similarly, Figure 5 showed that the correlation of nuclear localization signals (NLS) of PB2 was the strongest in avian, human, and pandemic 2009 H1N1, and the correlation of the RNA cap binding domain of PB2 was the strongest in swine. To further quantify the correlation of these four proteins, the averaged counts of positions in the functional domains of the four proteins that had a positive MI value with other positions were calculated, based on the domain boundary information given in [21] (Figure 5). Comprehensive phylogenetic analysis suggested that the genes of 2009 pandemic H1N1 were derived from avian (PB2 and PA), human H3N2 (PB1), classical swine (HA, NP and NS), and …”

Section: Correlation Within Each Individual Protein and Between Proteinsmentioning

confidence: 99%

“…In a sense, the correlation information obtained from task two was pair dependent, i.e., it was about pairs. The third task was to mine the association of these four proteins with a pair independent approach, where the locations of pairs with positive MI values were counted according to each protein or to each functional domain in a protein as described in [21]. The strength of association was measured by the averaged counts of correlated pairs located within each protein or between proteins.…”

Section: Introductionmentioning

confidence: 99%

Correlated mutations in the four influenza proteins essential for viral RNA synthesis, host adaptation, and virulence: NP, PA, PB1, and PB2

Hu¹

2010

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The NP, PA, PB1, and PB2 proteins of influenza viruses together are responsible for the transcription and replication of viral RNA, and the latter three proteins comprise the viral polymerase. Two recent reports indicated that the mutation at site 627 of PB2 plays a key role in host range and increased virulence of influenza viruses, and could be compensated by multiple mutations at other sites of PB2, suggesting the association of this mutation with those at other sites. The objective of this study was to analyze the co-mutated sites within and between these important proteins of influenza. With mutual information, a set of statistically significant comutated position pairs (P value = 0) in NP, PA, PB1, and PB2 of avian, human, pandemic 2009 H1N1, and swine influenza were identified, based on which several highly connected networks of correlated sites in NP, PA, PB1, and PB2 were discovered. These correlation networks further illustrated the inner functional dependence of the four proteins that are critical for host adaptation and pathogenicity. Mutual information was also applied to quantify the correlation of sites within each individual protein and between proteins. In general, the inter protein correlation of the four proteins was stronger than the intra protein correlation. Finally, the correlation patterns of the four proteins of pandemic 2009 H1N1 were found to be closer to those of avian and human than to swine influenza, thus rendering a novel insight into the interaction of the four proteins of the pandemic 2009 H1N1 virus when compared to avian, human, and swine influenza and how the origin of these four proteins might affect the correlation patterns uncovered in this analysis.

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Complete-Proteome Mapping of Human Influenza A Adaptive Mutations: Implications for Human Transmissibility of Zoonotic Strains

Cited by 79 publications

References 69 publications

Identification of PB2 Mutations Responsible for the Efficient Replication of H5N1 Influenza Viruses in Human Lung Epithelial Cells

Identification of PB2 Mutations Responsible for the Efficient Replication of H5N1 Influenza Viruses in Human Lung Epithelial Cells

The role of fusion activity of influenza A viruses in their biological properties

Correlated mutations in the four influenza proteins essential for viral RNA synthesis, host adaptation, and virulence: NP, PA, PB1, and PB2

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