Impacts of different expressions of PA-X protein on 2009 pandemic H1N1 virus replication, pathogenicity and host immune responses

Lee, Jinhwa; Yu, Hai; Li, Yonghai; Ma, Jingjiao; Lang, Yuekun; Duff, Michael; Henningson, Jamie; Liu, Qinfang; Li, Yuhao; Nagy, Abdou; Bawa, Bhupinder; Li, Zejun; Tong, Guangzhi; Richt, Jüergen A.; Ma, Wenjun

doi:10.1016/j.virol.2017.01.015

Cited by 36 publications

(69 citation statements)

References 31 publications

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“…4B). As expected, based on previous data (35,43), PA WT blocked the expression of both reporter genes ( Fig. 4A and B).…”

Section: Resultssupporting

confidence: 91%

“…4A and B). These results could be explained by differences in the efficiency of the frameshift between PA WT , PA PMUT , and PA MUT (16,35). According to these results, when PA protein expression levels were evaluated by Western blotting, PA WT and PA PMUT , which efficiently blocked GFP and Gluc expression, showed slightly lower PA protein levels than PA MUT (Fig.…”

Section: Resultsmentioning

confidence: 85%

“…3A). Several studies have reported that the PA-X protein is involved in the inhibition of host protein expression (15,16,18,20,35,42,43). In order to generate a PA-X-deficient construct, the frameshift sequence was changed to two different sequences to potentially inhibit PA-X expression (UCC UUC AGA or AGC UUC AGA) (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In order to generate a PA-X-deficient construct, the frameshift sequence was changed to two different sequences to potentially inhibit PA-X expression (UCC UUC AGA or AGC UUC AGA) (Fig. 3A) (15,16,18,20,35,42,43). Importantly, none of the approaches used for the abolition of the ribosomal frameshift motif changed the PA amino acid sequence.…”

Section: Resultsmentioning

confidence: 99%

“…To carry out this study, we have generated a ca, ts, and att A/California/4_NYICE_E3/2009 H1N1 strain (referred to here as pH1N1 LAIV virus) that provides three advantages: safety, sensitivity, and potential as a vaccine candidate. First, because a recombinant pH1N1 harboring inhibitory PA-X and NS1 proteins could lead to a more virulent virus (35)(36)(37)(38), we selected, for safety reasons, to use the ca, ts, and att pH1N1 LAIV virus. Second, we and others have previously shown that LAIVs provide a more sensitive approach to study mutations affecting overall viral replication and pathogenicity (5,7,(9)(10)(11)39).…”

mentioning

confidence: 99%

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Interplay of PA-X and NS1 Proteins in Replication and Pathogenesis of a Temperature-Sensitive 2009 Pandemic H1N1 Influenza A Virus

Nogales

Rodríguez

DeDiego

et al. 2017

J Virol

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Influenza A viruses (IAVs) cause seasonal epidemics and occasional pandemics, representing a serious public health concern. It has been described that one mechanism used by some IAV strains to escape the host innate immune responses and modulate virus pathogenicity involves the ability of the PA-X and NS1 proteins to inhibit the host protein synthesis in infected cells. It was reported that for the 2009 pandemic H1N1 IAV (pH1N1) only the PA-X protein had this inhibiting capability, while the NS1 protein did not. In this work, we have evaluated, for the first time, the combined effect of PA-X- and NS1-mediated inhibition of general gene expression on virus pathogenesis, using a temperature-sensitive, live-attenuated 2009 pandemic H1N1 IAV (pH1N1 LAIV). We found that viruses containing PA-X and NS1 proteins that simultaneously have (PA/NS1) or do not have (PA/NS1) the ability to block host gene expression showed reduced pathogenicity However, a virus where the ability to inhibit host protein expression was switched between PA-X and NS1 (PA/NS1) presented pathogenicity similar to that of a virus containing both wild-type proteins (PA/NS1). Our findings suggest that inhibition of host protein expression is subject to a strict balance, which can determine the successful progression of IAV infection. Importantly, knowledge obtained from our studies could be used for the development of new and more effective vaccine approaches against IAV. Influenza A viruses (IAVs) are one of the most common causes of respiratory infections in humans, resulting in thousands of deaths annually. Furthermore, IAVs can cause unpredictable pandemics of great consequence when viruses not previously circulating in humans are introduced into humans. The defense machinery provided by the host innate immune system limits IAV replication; however, to counteract host antiviral activities, IAVs have developed different inhibition mechanisms, including prevention of host gene expression mediated by the viral PA-X and NS1 proteins. Here, we provide evidence demonstrating that optimal control of host protein synthesis by IAV PA-X and/or NS1 proteins is required for efficient IAV replication in the host. Moreover, we demonstrate the feasibility of genetically controlling the ability of IAV PA-X and NS1 proteins to inhibit host immune responses, providing an approach to develop more effective vaccines to combat disease caused by this important respiratory pathogen.

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“…4B). As expected, based on previous data (35,43), PA WT blocked the expression of both reporter genes ( Fig. 4A and B).…”

Section: Resultssupporting

confidence: 91%

Section: Resultsmentioning

confidence: 85%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

mentioning

confidence: 99%

See 3 more Smart Citations

Interplay of PA-X and NS1 Proteins in Replication and Pathogenesis of a Temperature-Sensitive 2009 Pandemic H1N1 Influenza A Virus

Nogales

Rodríguez

DeDiego

et al. 2017

J Virol

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PA-X: a key regulator of influenza A virus pathogenicity and host immune responses

Liu

2018

Med Microbiol Immunol

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PA-X, a fusion protein belonging to influenza A viruses (IAVs), integrating the N-terminal 191 amino acids of PA gene and the ribosomal frame-shifting product that lengthens out to 41 or 61 amino acids. Since its discovery in 2012, multiple functions have been attributed to this small protein, including a process, where wide-spread protein synthesis in infected host cells is shut down (called host shutoff), and viral replication, polymerase activity, viral-induced cell apoptosis, PA nuclear localization, and virulence are modulated. However, many of its proposed functions may be specific to strain, subtype, host, or cell line. In this review, we start by describing the well-defined global host-shutoff ability of PA-X and the potential mechanisms underlying it. We move on to the role played by PA-X in modulating innate and acquired immune responses in the host. We then systematically discuss the role played by PA-X in modulating the virulence of influenza viruses of different subtypes and host origins, and finish with a general overview of the research advances made in identifying the host cell partners that interact with PA-X. To uncover possible clues about the differential effects of PA-X in modulating viral virulence, we focus on systemically evaluating polymorphisms in PA-X from various viral subtypes and hosts, including avian and human H5N1, H5N6, H9N2, and H7N9 viruses. Finally, we conclude with a proposition regarding the possible future research directions for this important protein.

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Genetic characterization and diversity of circulating influenza A/H1N1pdm09 viruses isolated in Jeddah, Saudi Arabia between 2014 and 2015

et al. 2018

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The emerged influenza A/H1N1pdm09 viruses have replaced the previously circulating seasonal H1N1 viruses. The close antigenic properties of these viruses to the 1918 H1N1 pandemic viruses and their post-pandemic evolution pattern could further enhance their adaptation and pathogenicity in humans representing a major public health threat. Given that data on the dynamics and evolution of these viruses in Saudi Arabia is sparse we investigated the genetic diversity of circulating influenza A/H1N1pdm09 viruses from Jeddah, Saudi Arabia, by analyzing 39 full genomes from isolates obtained between 2014-2015, from patients with varying symptoms. Phylogenetic analysis of all gene segments and concatenated genomes showed similar topologies and co-circulation of clades 6b, 6b.1 and 6b.2, with clade 6b.1 being the most predominate since 2015. Most viruses were more closely related to the vaccine strain (Michigan/45/2015) recommended for the 2017/2018 season, than to the California/07/2009 strain. Low sequence variability was observed in the haemagglutinin protein compared to the neuraminidase protein. Resistance to neuraminidase inhibitors was limited as only one isolate had the H275Y substitution. Interestingly, two isolates had short PA-X proteins of 206 amino acids compared to the 232 amino acid protein found in most influenza A/H1N1pdm09 viruses. Together, the co-circulation of several clades and the predominance of clade 6b.1, despite its low circulation in Asia in 2015, suggests multiple introductions most probably during the mass gathering events of Hajj and Umrah. Jeddah represents the main port of entry to the holy cities of Makkah and Al-Madinah, emphasizing the need for vigilant surveillance in the kingdom.

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Impacts of different expressions of PA-X protein on 2009 pandemic H1N1 virus replication, pathogenicity and host immune responses

Cited by 36 publications

References 31 publications

Interplay of PA-X and NS1 Proteins in Replication and Pathogenesis of a Temperature-Sensitive 2009 Pandemic H1N1 Influenza A Virus

Interplay of PA-X and NS1 Proteins in Replication and Pathogenesis of a Temperature-Sensitive 2009 Pandemic H1N1 Influenza A Virus

PA-X: a key regulator of influenza A virus pathogenicity and host immune responses

Genetic characterization and diversity of circulating influenza A/H1N1pdm09 viruses isolated in Jeddah, Saudi Arabia between 2014 and 2015

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