Acute hantavirus infection in humans triggers a rapid expansion and long-term persistence of NK cells.

Hantaviruses cause hemorrhagic fever with renal syndrome (HFRS) and hantavirus cardio-pulmonary syndrome (HCPS; also called hantavirus pulmonary syndrome (HPS)), both human diseases with high case-fatality rates. Endothelial cells are the main targets for hantaviruses. An intriguing observation in patients with HFRS and HCPS is that on one hand the virus infection leads to strong activation of CD8 T cells and NK cells, on the other hand no obvious destruction of infected endothelial cells is observed. Here, we provide an explanation for this dichotomy by showing that hantavirus-infected endothelial cells are protected from cytotoxic lymphocyte-mediated induction of apoptosis. When dissecting potential mechanisms behind this phenomenon, we discovered that the hantavirus nucleocapsid protein inhibits the enzymatic activity of both granzyme B and caspase 3. This provides a tentative explanation for the hantavirus-mediated block of cytotoxic granule-mediated apoptosis-induction, and hence the protection of infected cells from cytotoxic lymphocytes. These findings may explain why infected endothelial cells in hantavirus-infected patients are not destroyed by the strong cytotoxic lymphocyte response.

Hantaviruses, members of the Bunyaviridae family, are emerging pathogens that cause two zoonotic human diseases: hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia and hantavirus cardiopulmonary syndrome (HCPS) on the American continent, with mortality up to 40% depending on the specific hantavirus (33,41). Hantavirus infection per se is not cytopathogenic, and it has been suggested that HFRS and HCPS are caused rather by the immune responses raised during infection than by the virus itself (19,39).Type I interferons (IFNs) (consisting of IFN-␤ and of at least 13 different IFN-␣s in humans) and type II IFN (IFN-␥) have long been known to have antiviral effects against numerous viruses (16, 31), including hantaviruses (38). Recently, type III IFNs (IFN-1, -2, and -3, also called interleukin-29 , -28A, and -28B, respectively) were discovered and also shown to have antiviral capacities (23,34