Unravelling the Host Cell Response to Arenavirus infection

The arenaviruses are an important group of pathogens that includes both agents of severe human disease and many closely related family members that are often apathogenic. The basis for this difference remains poorly understood, however, the regulation of host cell responses to infection appear to be important. We have found that while both apathogenic (i.e. Tacaribe virus, TCRV) and highly pathogenic (i.e. Junín virus, JUNV) viruses induce the activation of stress-activated protein kinases (i.e. p38, JNK), associated with induction of p53 and resulting upregulation of proapoptotic factors (i.e. Puma, Noxa), JUNV but not TCRV can suppress cell death through caspase cleavage of its nucleoprotein (NP). Surprisingly, there seems to be little direct impact of apoptotic cell death on virus growth - rather, several factors involved in this process appear to contribute to virus infection through indirect mechanisms. Specifically, we found that caspase-induced PS-flipping supports the ability of TCRV, which cannot use the human form of the primary receptor, to efficiently infect macrophages. Further, we found that JUNV’s ability to use its NP as a caspase decoy generates NP isoforms that retain exonuclease activity and, due to their increased availability in the cytoplasm, are better positioned to combat dsRNA accumulation and subsequent RNA sensor activation. However, our recent work on dissecting the IFN inhibitory functions of NP suggest that its exonuclease function actually plays only a minor role in IFN antagonism, but may rather be important for control of other dsRNA responses, such as that through PKR – an observation that could provide a mechanistic basis for the lack of cytokine activation observed in response to JUNV infection in primary target cells such as macrophages, and thereby contribute to the successful establishment of infection.


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