Highly Pathogenic New World and Old World Human Arenaviruses Induce Distinct Interferon Responses in Human Cells

The arenavirus family includes several important pathogens that cause severe and sometimes fatal diseases in humans. The highly pathogenic OldWorld (OW) arenavirus Lassa fever virus (LASV) is the causative agent of Lassa fever (LF) disease in hu-mans. LASV infections in severe cases are generally immunosuppressive without stimulating interferon (IFN) induction, a pro-inflammatory response, or T cell activation. However, the host innate immune responses to highly pathogenic NewWorld (NW) arenaviruses are not well understood.We have previously shown that the highly pathogenic NW arenavirus, Junin virus (JUNV), induced an IFN response in human A549 cells. Here, we report that Machupo virus (MACV), another highly pathogenic NW are-navirus, also induces an IFN response. Importantly, both pathogenic NW arenaviruses, in contrast to the OWhighly pathogenic arenavirus LASV, readily elicited an IFN response in human primary dendritic cells and A549 cells. Coinfection experiments revealed that LASV could potently inhibit MACV-activated IFN responses even at 6 h after MACV infection, while the replica-tion levels of MACV and LASV were not affected by virus coinfection. Our results clearly demonstrated that although all viruses studied herein are highly pathogenic to humans, the host IFN responses toward infections with the NW arenaviruses JUNV and MACV are quite different from responses to infections with the OW arenavirus LASV, a discovery that needs to be further inves-tigated in relevant animal models. This finding might help us better understand various interplays between the host immune system and highly pathogenic arenaviruses as well as distinct mechanisms underlying viral pathogenesis