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Review
. 2018 Oct-Nov;20(9-10):560-569.
doi: 10.1016/j.micinf.2018.03.005. Epub 2018 Apr 18.

Dissecting host cell death programs in the pathogenesis of influenza

Jeffrey Downey  1 , Erwan Pernet  1 , François Coulombe  1 , Maziar Divangahi  2
Affiliations
Review

Dissecting host cell death programs in the pathogenesis of influenza

Jeffrey Downey et al. Microbes Infect. 2018 Oct-Nov.

Abstract

Influenza A virus (IAV) is a pulmonary pathogen, responsible for significant yearly morbidity and mortality. Due to the absence of highly effective antiviral therapies and vaccine, as well as the constant threat of an emerging pandemic strain, there is considerable need to better understand the host-pathogen interactions and the factors that dictate a protective versus detrimental immune response to IAV. Even though evidence of IAV-induced cell death in human pulmonary epithelial and immune cells has been observed for almost a century, very little is known about the consequences of cell death on viral pathogenesis. Recent study indicates that both the type of cell death program and its kinetics have major implications on host defense and survival. In this review, we discuss advances in our understanding of cell death programs during influenza virus infection, in hopes of fostering new areas of investigation for targeted clinical intervention.

Keywords: Alveolar epithelial cells; Apoptosis; Cell death program; Influenza A virus; Necroptosis; Pulmonary macrophages.

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Figures

Fig. 1
Fig. 1
Activation of cell death pathways in IAV-infected epithelial cells. Following IAV infection, the viral protein NS1 inhibits apoptosis by activating the PI3K/Akt pro-survival pathway, therefore leading to increased viral replication. Later, viral proteins, predominantly NP, activate caspase signaling to facilitate viral protein packaging and virion production, leading to viral egress and consequentially apoptosis. Unknown viral factors induce necrosis through unelucidated mechanisms, causing enhanced inflammation. Finally, IAV-infected epithelial cells undergo necroptosis, a programmed form of necrosis involving the proteins RIPK3 and MLKL. By eliminating the natural replicative niche of the virus, necroptosis helps limit viral replication. Solid arrows indicate both direct viral and host effects, while dashed arrows indicate indirect by-products.
Fig. 2
Fig. 2
The impact of early versus late apoptosis of pulmonary macrophages on immunity to IAV infection. IAV induces early apoptosis in alveolar macrophages via the pro-apoptotic PB1-F2-IAV protein. We envision that the low levels of mitochondrial NLRX1 protein upon infection leads to early apoptosis and reduced production of type I IFN in alveolar macrophages. However, during the late phase of infection, high levels of mitochondrial NLRX1 protein disarm the pro-apoptotic function of PB1-F2 that leads to increased macrophage survival as well as IFN-I production. The increased levels of IFN-I in the alveolar space induce apoptosis in IAV-infected epithelial cells (Epith) and, thus, disrupt the niche for viral replication.
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References

    1. Hirsh A. New Sydenham Soc; London: 1883. Handbook of geographical and historical pathology.
    1. WHO . WHO; 2016. Influenza (seasonal) fact sheet.
    1. Taubenberger J.K., Morens D.M. 1918 influenza: the mother of all pandemics. Emerg Infect Dis. 2006;12:15–22. - PMC - PubMed
    1. Saunders-Hastings P.R., Krewski D. Reviewing the history of pandemic influenza: understanding patterns of emergence and transmission. Pathogens. 2016;5 - PMC - PubMed
    1. Chen H., Yuan H., Gao R., Zhang J., Wang D., Xiong Y. Clinical and epidemiological characteristics of a fatal case of avian influenza A H10N8 virus infection: a descriptive study. Lancet. 2014;383:714–721. - PubMed

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