The arenavirus family consists of several highly pathogenic viruses, including the Old World (OW) arenavirus
Lassa fever virus (LASV) and the New World (NW) Junin virus (JUNV) and Machupo virus (MACV). Host response to
infection by these pathogenic arenaviruses is distinct in many aspects. JUNV and MACV
infections readily induce an
interferon (IFN) response in human cells, while LASV
infection usually triggers an undetectable or weak IFN response. JUNV induces an IFN response through RIG-I, suggesting that the host non-self
RNA sensor readily detects JUNV viral RNAs (vRNAs) during
infection and activates IFN response.
Double-stranded-RNA (dsRNA)-activated
protein kinase R (PKR) is another host non-self
RNA sensor classically known for its vRNA recognition activity. Here we report that
infection with NW arenaviruses JUNV and MACV, but not OW LASV, activated PKR, concomitant with elevated phosphorylation of the translation
initiation factor α subunit of
eukaryotic initiation factor 2 (eIF2α). Host
protein synthesis was substantially suppressed in MACV- and JUNV-infected cells but was only marginally reduced in LASV-infected cells. Despite the
antiviral activity known for PKR against many other viruses, the replication of JUNV and MACV was not impaired but was slightly augmented in wild-type (wt) cells compared to that in PKR-deficient cells, suggesting that PKR or PKR activation did not negatively affect JUNV and MACV
infection. Additionally, we found an enhanced IFN response in JUNV- or MACV-infected PKR-deficient cells, which was inversely correlated with virus replication.IMPORTANCE The detection of
viral RNA by host non-self
RNA sensors, including RIG-I and MDA5, is critical to the initiation of the innate immune response to
RNA virus infection. Among pathogenic arenaviruses, the OW LASV usually does not elicit an
interferon response. However, the NW arenaviruses JUNV and MACV readily trigger an IFN response in a RIG-I-dependent manner. Here, we demonstrate for the first time that pathogenic NW arenaviruses JUNV and MACV, but not the OW arenavirus LASV, activated the dsRNA-dependent PKR, another host non-self
RNA sensor, during
infection. Interestingly, the replication of JUNV and MACV was not restricted but was rather slightly augmented in the presence of PKR. Our data provide new evidence for a distinct interplay between host non-self
RNA sensors and pathogenic arenaviruses, which also provides insights into the pathogenesis of arenaviruses and may facilitate the design of
vaccines and treatments against arenavirus-caused diseases.