Structure‐function analysis of the exoribonuclease domain of arenaviral nucleoproteins in mediating host immune evasion (LB138)

Several pathogenic arenaviruses, including Lassa virus, cause hemorrhagic fever (HF) infections that can result in significant morbidity and mortality in humans. A hallmark of severe HF is the high levels of viremia coupled with generalized immune suppression of the hosts, the mechanisms for which are unknown. Recent studies in our laboratory have revealed several potential mechanisms that arenaviruses use to cause virulent infection [McLay, et al., JVI 2013, Jiang, et al., JBC 2013; Kumar, et al., Virol 2012; Wang, et al., JVI 2012; Qi, et al., Nature 2010; Lan, et al., JVI 2009, Arch Virol 2008). A unique feature of lethal Lassa (LASV) arenaviral infection is that it is often associated with a generalized immune suppression of the infected hosts, the exact mechanism of which is unclear but is thought to involve the ability of the viral nucleoprotein (NP) to suppress the induction of type I interferons (IFN). We have recently determined the first crystal structure for LASV NP at 1.80 Angstrom resolution (Qi, et al., Nature 2010), which has unexpectedly revealed its unique mechanisms to suppress interferon‐beta production. Our structurally directed functional assays (using both biochemical and cell‐ and virus‐based assays) have demonstrated that the C‐terminal domain of LASV NP contains exoribonuclease enzymatic activity that is required for suppressing IFN‐beta induction by degrading immune stimulatory RNAs. We have also recently produced evidence to suggest that this is a common mechanism used by all known arenaviruses (Jiang, et al., JBC 2013). Novel insights learned from these studies can be exploited for the development of novel therapeutics and vaccines against deadly HF infections as recently reviewed by us (McLay, et al., Antiviral Research 2012, J Gen Virol 2014). Grant Funding Source : NIH R01 grants AI083409 to Y.L. and AI093580 to H.L.