Dataset Information

Effects of the PA-X and PB1-F2 Proteins on the Virulence of the 2009 Pandemic H1N1 Influenza A Virus in Mice.

ABSTRACT: There have been several previous reports showing that PA-X and PB1-F2 proteins can regulate innate immune responses and may play roles in the adaptation of influenza viruses to new hosts. In this research, we investigated, for the first time, the combined effects of PA-X and PB1-F2 proteins on viral virulence in mice. Based on the 2009 pH1N1 A/Guangdong/1057/2010 virus backbone, four viruses encoding different combinations of full-length or truncated PA-X and PB1-F2 proteins were rescued by a reverse genetic engineering system. We analyzed viral replication, host-shutoff activity, in vitro viral pathogenicity and in vivo host immune response. We found that simultaneously expressing the full-length PA-X and PB1-F2 proteins enhanced viral replication in vitro through increasing the accumulation of the RNP complex protein and enhanced viral pathogenicity in mice during the early stage of infection. Furthermore, PA-X and PB1-F2 simultaneously regulated the host innate response, and different forms of PB1-F2 proteins may have impacts on the host shutoff activity induced by the PA-X protein. Our results provide a better understanding of the mechanisms of PA-X and PB1-F2 proteins during viral replication, pathogenicity and host immune response.

SUBMITTER: Ma J

PROVIDER: S-EPMC6734165 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Effects of the PA-X and PB1-F2 Proteins on the Virulence of the 2009 Pandemic H1N1 Influenza A Virus in Mice.

Ma Jun J Li Shun S Li Kangjian K Wang Xiangbin X Li Shoujun S

Frontiers in cellular and infection microbiology 20190903

There have been several previous reports showing that PA-X and PB1-F2 proteins can regulate innate immune responses and may play roles in the adaptation of influenza viruses to new hosts. In this research, we investigated, for the first time, the combined effects of PA-X and PB1-F2 proteins on viral virulence in mice. Based on the 2009 pH1N1 A/Guangdong/1057/2010 virus backbone, four viruses encoding different combinations of full-length or truncated PA-X and PB1-F2 proteins were rescued by a re ...[more]

PMID: 31552197

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Project description:In April 2009, a new pandemic strain of influenza infected thousands of persons in Mexico and the United States and spread rapidly worldwide. During the ensuing summer months, cases ebbed in the Northern Hemisphere while the Southern Hemisphere experienced a typical influenza season dominated by the novel strain. In the fall, a second wave of pandemic H1N1 swept through the United States, peaking in most parts of the country by mid October and returning to baseline levels by early December. The objective was to determine the seroprevalence of antibodies against the pandemic 2009 H1N1 influenza strain by decade of birth among Pittsburgh-area residents.Anonymous blood samples were obtained from clinical laboratories and categorized by decade of birth from 1920-2009. Using hemagglutination-inhibition assays, approximately 100 samples per decade (n = 846) were tested from blood samples drawn on hospital and clinic patients in mid-November and early December 2009. Age specific seroprevalences against pandemic H1N1 (A/California/7/2009) were measured and compared to seroprevalences against H1N1 strains that had previously circulated in the population in 2007, 1957, and 1918. (A/Brisbane/59/2007, A/Denver/1/1957, and A/South Carolina/1/1918). Stored serum samples from healthy, young adults from 2008 were used as a control group (n = 100). Seroprevalences against pandemic 2009 H1N1 influenza varied by age group, with children age 10-19 years having the highest seroprevalence (45%), and persons age 70-79 years having the lowest (5%). The baseline seroprevalence among control samples from 18-24 year-olds was 6%. Overall seroprevalence against pandemic H1N1 across all age groups was approximately 21%.After the peak of the second wave of 2009 H1N1, HAI seroprevalence results suggest that 21% of persons in the Pittsburgh area had become infected and developed immunity. Extrapolating to the entire US population, we estimate that at least 63 million persons became infected in 2009. As was observed among clinical cases, this sero-epidemiological study revealed highest infection rates among school-age children.

Project description:In 2009, a pandemic H1N1 influenza A virus (IAV) (pH1N1) emerged in the human population from swine causing a pandemic. Importantly, this virus is still circulating in humans seasonally. To analyze the evolution of pH1N1 in humans, we sequenced viral genes encoding proteins inhibiting general gene expression (nonstructural protein 1 [NS1] and PA-X) from circulating seasonal viruses and compared them to the viruses isolated at the origin of the pandemic. Recent pH1N1 viruses contain amino acid changes in the NS1 protein (E55K, L90I, I123V, E125D, K131E, and N205S), as previously described (A. M. Clark, A. Nogales, L. Martinez-Sobrido, D. J. Topham, and M. L. DeDiego, J Virol 91:e00721-17, 2017, https://doi.org/10.1128/JVI.00721-17), and amino acid changes in the PA-X protein (V100I, N204S, R221Q, and L229S). These amino acid differences between early and more recent pH1N1 isolates are responsible for increased NS1-mediated inhibition of host gene expression and decreased PA-X-mediated shutoff, including innate immune response genes. In addition, currently circulating pH1N1 viruses have acquired amino acid changes in the PA protein (V100I, P224S, N321K, I330V, and R362K). A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from currently circulating viruses is fitter in replication in cultured cells and in mice and is slightly more pathogenic than the original ancestor pH1N1 virus. These results demonstrate the need to monitor the evolution of pH1N1 in humans for mutations in the viral genome that could result in enhanced virulence. Importantly, these results further support our previous findings suggesting that inhibition of global gene expression mediated by NS1 and PA-X proteins is subject to a balance which can determine virus pathogenesis and fitness.IMPORTANCE IAVs emerge in humans from animal reservoirs, causing unpredictable pandemics. One of these pandemics was caused by an H1N1 virus in 2009, and this virus is still circulating seasonally. To analyze host-virus adaptations likely affecting influenza virus pathogenesis, protein amino acid sequences from viruses circulating at the beginning of the pandemic and those circulating currently were compared. Currently circulating viruses have incorporated amino acid changes in two viral proteins (NS1 and PA-X), affecting innate immune responses, and in the PA gene. These amino acid differences led to increased NS1-mediated and decreased PA-X-mediated inhibition of host gene expression. A recombinant pH1N1 virus containing PA, PA-X, and NS1 genes from recently circulating viruses is fitter in replication in tissue culture cells and in mice, and the virus is more pathogenic in vivo Importantly, these results suggest that a balance in the abilities of NS1 and PA-X to induce host shutoff is beneficial for IAVs.

Dataset Information

Effects of the PA-X and PB1-F2 Proteins on the Virulence of the 2009 Pandemic H1N1 Influenza A Virus in Mice.

Publications

Effects of the PA-X and PB1-F2 Proteins on the Virulence of the 2009 Pandemic H1N1 Influenza A Virus in Mice.

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