Influenza A virus enhances its propagation through the modulation of Annexin-A1 dependent endosomal trafficking and apoptosis

Abstract

The influenza virus infects millions of people each year and can result in severe complications. Understanding virus recognition and host responses to influenza infection will enable future development of more effective anti-viral therapies. Previous research has revealed diverse yet important roles for the annexin family of proteins in modulating the course of influenza A virus (IAV) infection. However, the role of Annexin-A1 (ANXA1) in IAV infection has not been addressed. Here, we show that ANXA1 deficient mice exhibit a survival advantage, and lower viral titers after infection. This was accompanied with enhanced inflammatory cell infiltration during IAV infection. ANXA1 expression is increased during influenza infection clinically, in vivo and in vitro. The presence of ANXA1 enhances viral replication, influences virus binding, and enhances endosomal trafficking of the virus to the nucleus. ANXA1 colocalizes with early and late endosomes near the nucleus, and enhances nuclear accumulation of viral nucleoprotein. In addition, ANXA1 enhances IAV-mediated apoptosis. Overall, our study demonstrates that ANXA1 plays an important role in influenza virus replication and propagation through various mechanisms and that we predict that the regulation of ANXA1 expression during IAV infection may be a viral strategy to enhance its infectivity.

Dissecting host cell death programs in the pathogenesis of influenza

“…Furthermore, recent study has characterized H1N1 IAV nucleoprotein (NP) as a pro-apoptotic viral protein in human airway epithelial cells [61] that targets the host's anti-apoptotic protein AP15 [62]. In fact, host apoptotic machinery has been shown to be essential in promoting new virion production in epithelial cells in vitro [63e65], in a caspase-3-[66] and -9dependent manner [67], and in vivo by IAV-manipulation of annexin-A1 [68]. These findings outline IAV as an effective regulator of the host's apoptotic machinery in structural cells, capable of both inducing and blocking apoptosis to further its pathogenesis.…”

“…Efferocytosis is the phagocytosis of apoptotic bodies released from dying cells by neighboring M4 [139]. Recently, annexin A1, a key protein involved in efferocytosis [140,141,148], was shown to facilitate IAV replication and dissemination in vivo [68]. Interestingly, Tcherniuk et al showed that newly formed viral particles contained annexin A1 on their membranes, increasing their infectivity and viral replication through enhanced uptake [142].…”

Annexins – insights from knockout mice

“…-/-mice are partially protected against influenza A virus infection, involving reduced uptake and exit of internalized virus from late endosomes/MVBs (Arora et al, 2016). In contrast, AnxA1 deficiency interferes with cell fusion but not intracellular vesicle fusion, both needed for repair of myofiber sarcolemma, during repair and regeneration of injured skeletal myofiber (Leikina et al, 2015).…”

Multi-Omics Studies towards Novel Modulators of Influenza A Virus–Host Interaction

“…Interestingly, 41 of the 199 druggable cellular factors were shown to be implicated in IAV infection (Table S2) [10,20,21,22,23,24,25,26,27,28,29,30,31,32,33,34,35,36,37,38,39,40,41,42,43,44,45,46,47,48,49,50,51,52,53,54,55,56,57,58,59,60,61,62,63,64,65,66,67,68,69,70,71,72,73,74,75,76,77,78,79,80,81,82,83,84,85,86,...…”