Abstract
Within the last century, millions of lives have been lost to the four major Influenza pandemics. These influenza pandemics were all caused by Influenza Type A viruses (IAV) through their ability to undergo antigenic drifts and shifts. A greater understanding of IAV and host–pathogen interactions is required to develop effective therapeutics against future outbreaks. Annexin A1 (ANXA1) is a phospholipid binding, calcium-dependent protein known to play essential roles in multiple cellular functions including inflammation, proliferation, migration, and apoptosis. ANXA1 was previously shown to enhance apoptosis after IAV infection. The current study explores the role of ANXA1 in IAV infection of A549 lung epithelial cells further in the context of RIG-I-dependent signaling using A549 and Crispr/Cas9 ANXA1 deleted (A549∆ANXA1) cells. ANXA1 was found to enhance the expression of a cytoplasmic RNA sensor, RIG-I basally and post-infection. RIG-I activation by 5′ppp-RNA in A549 lung epithelial cell induces apoptotic cell death, which is inhibited when ANXA1 is deleted, and reversed when ANXA1 is re-expressed. RIG-I activation by 5′ppp-RNA stimulates the production of IFNβ from lung epithelial cells to the same extent as monocytic cells, albeit very late after infection at 48–72 h, through IRF3 and STAT1 activation. ANXA1 deletion delays the phosphorylation of IRF3 and STAT1, leading to lower expression of interferon-stimulated genes, such as IFIT1, and silencing IFIT1 inhibited RIG-I-induced cell death. In all, these results suggest that ANXA1 plays a regulatory role in RIG-I signaling and cell death in A549 lung epithelial cells.
Highlights
Introduction RigI like receptors (RLRs) are cytosolic RNA sensors that belong to a family of DExD/H box RNA helicases, and they have the capacity to hydrolyze ATP
As Annexin A1 (ANXA1) may play a role in regulating multiple different pathways in Influenza Type A viruses (IAV)-infected A549 lung epithelial cells, the focus of this study was on the cytoplasmic RNA sensor RIG-I
In the context of IAV-infection, TLR7 and RIG-I are known to be activated[20,21,22,23]. This was confirmed when IAV infection of A549 epithelial cells resulted in an increase in the levels of RIG-I, possibly as part of a positive feedback loop to trigger greater anti-viral responses
Summary
Introduction RigI like receptors (RLRs) are cytosolic RNA sensors that belong to a family of DExD/H box RNA helicases, and they have the capacity to hydrolyze ATP. There are three known RLRs which include RIG-I (retinoic acid-inducible gene I, known as RIG-I), melanoma differentiation-associated gene 5 (MDA5), and Laboratory. RLRs to their respective agonists, this triggers the activation of anti-viral responses in the cell. For RIG-I, the binding of the dsRNA with a 5′ppp-RNA motif results in a conformational change of RIG-I, a process dependent on ATP and allows oligomerization of RIG-I to form a tetramer[2]. The RIG-I tetramer forms a scaffold structure which allows for the binding to mitochondrial antiviralsignaling protein (MAVS), an adaptor protein present on the mitochondrial membrane[3]. RIG-I plays an essential role in IFN induction during RNA virus infections of non-pDC cell-types. Mice that are deficient in MDA5 and RIG-I are more susceptible to RNA viruses[4,5]
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