Innate Immunity to Orthohantaviruses: Could Divergent Immune Interactions Explain Host-specific Disease Outcomes?

The genus Orthohantavirus (family Hantaviridae, order Bunyavirales) consists of numerous genetic and pathologically distinct viral species found within rodent and mammalian insectivore populations world-wide. Although reservoir hosts experience persistent asymptomatic infection, numerous rodent-borne orthohantaviruses cause severe disease when transmitted to humans, with case-fatality rates up to 40%. The first isolation of an orthohantavirus occurred in 1976 and, since then, the field has made significant progress in understanding the immune correlates of disease, viral interactions with the human innate immune response, and the immune kinetics of reservoir hosts. Much still remains elusive regarding the molecular mechanisms of orthohantavirus recognition by the innate immune response and viral antagonism within the reservoir host, however. This review provides a summary of the last 45 years of research into orthohantavirus interaction with the host innate immune response. This summary includes discussion of current knowledge involving human, non-reservoir rodent, and reservoir innate immune responses to viruses which cause hemorrhagic fever with renal syndrome and hantavirus cardio-pulmonary syndrome. Review of the literature concludes with a brief proposition for the development of novel tools needed to drive forward investigations into the molecular mechanisms of innate immune activation and consequences for disease outcomes in the various hosts for orthohantaviruses.