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Systems-based candidate genes for human response to influenza infection.

ABSTRACT: Influenza A is a serious respiratory illness that can be debilitating and may cause complications leading to hospitalization and death. The outcome of infection with the influenza A virus is determined by a complex interplay of viral and host factors. With the ongoing threat of seasonal influenza and the potential emergence of new, more virulent strains of influenza viruses, we need to develop a better understanding of genetic variation in the human population and its association with severe outcomes from influenza infection. We propose a list of approximately 100 systems-based candidate genes for future study of the genetic basis of influenza disease and immunity in humans, based on evidence in the published literature for their potential role in the pathogenesis of this infection: binding of the virus to receptors on the host cell surface; cleavability of HA by host proteases; virus replication in host cells; destruction of host cells by apoptosis; state of immunocompetence of the individual host; and viral infections predisposing to bacterial infection.

SUBMITTER: Zhang L

PROVIDER: S-EPMC7106103 | biostudies-literature | 2009 Dec

REPOSITORIES: biostudies-literature

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Systems-based candidate genes for human response to influenza infection.

Zhang Lyna L Katz Jacqueline M JM Gwinn Marta M Dowling Nicole F NF Khoury Muin J MJ

Infection, genetics and evolution : journal of molecular epidemiology and evolutionary genetics in infectious diseases 20090730 6

Influenza A is a serious respiratory illness that can be debilitating and may cause complications leading to hospitalization and death. The outcome of infection with the influenza A virus is determined by a complex interplay of viral and host factors. With the ongoing threat of seasonal influenza and the potential emergence of new, more virulent strains of influenza viruses, we need to develop a better understanding of genetic variation in the human population and its association with severe out ...[more]

PMID: 19647099

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Project description:Influenza A viruses cause infections in the human respiratory tract and give rise to annual seasonal outbreaks, as well as more rarely dreaded pandemics. Influenza A viruses become quickly resistant to the virus-directed antiviral treatments, which are the current main treatment options. A promising alternative approach is to target host cell factors that are exploited by influenza viruses. To this end, we characterized the phosphoproteome of influenza A virus infected primary human macrophages to elucidate the intracellular signaling pathways and critical host factors activated upon influenza infection. We identified 1675 phosphoproteins, 4004 phosphopeptides and 4146 nonredundant phosphosites. The phosphorylation of 1113 proteins (66%) was regulated upon infection, highlighting the importance of such global phosphoproteomic profiling in primary cells. Notably, 285 of the identified phosphorylation sites have not been previously described in publicly available phosphorylation databases, despite many published large-scale phosphoproteome studies using human and mouse cell lines. Systematic bioinformatics analysis of the phosphoproteome data indicated that the phosphorylation of proteins involved in the ubiquitin/proteasome pathway (such as TRIM22 and TRIM25) and antiviral responses (such as MAVS) changed in infected macrophages. Proteins known to play roles in small GTPase-, mitogen-activated protein kinase-, and cyclin-dependent kinase- signaling were also regulated by phosphorylation upon infection. In particular, the influenza infection had a major influence on the phosphorylation profiles of a large number of cyclin-dependent kinase substrates. Functional studies using cyclin-dependent kinase inhibitors showed that the cyclin-dependent kinase activity is required for efficient viral replication and for activation of the host antiviral responses. In addition, we show that cyclin-dependent kinase inhibitors protect IAV-infected mice from death. In conclusion, we provide the first comprehensive phosphoproteome characterization of influenza A virus infection in primary human macrophages, and provide evidence that cyclin-dependent kinases represent potential therapeutic targets for more effective treatment of influenza infections.

Dataset Information

Systems-based candidate genes for human response to influenza infection.

Publications

Systems-based candidate genes for human response to influenza infection.

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