The New World (NW) mammarenavirus group includes several zoonotic highly pathogenic viruses, such as Junin (JUNV) or Machupo (MACV). Contrary to Old World mammarenavirus, these viruses are not able to completely suppress the innate immune response, and trigger a robust interferon (IFN)-I response via retinoic acid-inducible gene I (RIG-I). Nevertheless, pathogenic NW mammarenaviruses trigger a weaker IFN response than their non-pathogenic relatives do. RIG-I activation leads to upregulation of a plethora of IFN-stimulated genes (ISGs), which exert a characteristic antiviral effect either as lone effectors, or resulting from the combination with other ISGs or cellular factors. The dsRNA sensor-protein kinase receptor (PKR) is an ISG that plays a pivotal role in the control of the mammarenavirus infection. In addition to its well-known protein synthesis inhibition, PKR further modulates the overall IFN-I response against different viruses, including mammarenaviruses. For this study, we employed Tacaribe virus (TCRV), the closest relative of the human pathogenic JUNV. Our findings indicate that PKR does not only increase IFN-I expression against TCRV infection, but also affects the kinetic expression and the extent of induction of Mx1 and ISG15 at both levels, mRNA and protein expression. Moreover, TCRV fails to prevent the effect of PKR on viral protein translation and its viral titer is inhibited when PKR is pre-stimulated via IFN-I. Here, we provide first evidence of the specific immunomodulatory role of PKR over selected ISGs, altering the dynamic of the innate immune response course against TCRV. IMPORTANCE: The mechanisms for innate immune evasion are key for emergence and adaptation of human pathogenic arenaviruses, and highly pathogenic mammarenaviruses such as JUNV or MACV trigger a weaker IFN response than non-pathogenic mammarenaviruses. Within the innate immune response context, PKR plays an important role in sensing and restricting the infection of TCRV virus. Although the mechanism of PKR for protein synthesis inhibition is well described, its immunomodulatory role is less understood. In this study, we found that TCRV protein expression and viral propagation are inhibited from early times after infection, and when externally activated, PKR inhibits TCRV viral progeny production. Our present findings further characterize the innate immune response in absence of PKR, unveiling the role of PKR in defining the ISG profile after viral infection.
Expression kinetics and innate immune response after electroporation and lipid nanoparticle mediated delivery of a self-amplifying mRNA in the skin of mice