Regulation of host cell signaling molecules in response to arenavirus infection

Arenaviruses include important zoonotic pathogens that cause hemorrhagic fever (e.g. Junín virus; JUNV). However, other closely related viruses are often apathogenic in humans (e.g. Tacaribe virus; TCRV). While the basis for this difference remains unclear, we found that TCRV strongly induces apoptosis (i.e. caspase-mediated cell death) in infected cells, while JUNV does not - suggesting a role for this process in pathogenesis. Nonetheless, both viruses trigger similar upstream pro-apoptotic signaling events, including phosphorylation of p53. Further, the pro-apoptotic factor Bad is phosphorylated (leading to inactivation) in TCRV-infected cells. These phosphorylation events clearly implicate upstream kinases in regulating apoptosis. Consistent with this, we show activation of the stress-activated protein kinases p38 and JNK, both of which are known to phosphorylate p53. Further, we observe activation of Akt, which is known to phosphorylate Bad, but surprisingly only in JUNV-infected cells. Importantly, inhibition of these kinases dramatically reduces the growth of both viruses, although inhibition of apoptosis itself does not - indicating that kinase activation is crucial for virus infection, independent of its downstream role in apoptosis regulation. This role of kinase activation, and its relationship to apoptosis regulation as well as virus infection, needs to be further explored as it has the potential to shed further light on the determinants of arenavirus pathogenesis.


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