Hantaviruses employ multiple mechanisms to evade NK cell recognition (P6298)

Abstract

Abstract Rodent-borne hantaviruses, such as Andes virus (ANDV) and Hantaan virus (HTNV) cause hantavirus pulmonary syndrome (HPS) and hemorrhagic fever with renal syndrome (HFRS) respectively, two human diseases with high case-fatality rates and no specific treatment. Patients suffering from HPS or HFRS exhibit massive lymphocyte activation, including high numbers of responding CD8 T cells and NK cells, leading to hyperinflammation and vascular leakage. Interestingly, while endothelial cells are the main targets of hantaviruses, no direct cytopathic effects of the virus on the vascular endothelium have been found. Here, using an in vitro infection model with primary human endothelial cells, we show that hantavirus renders infected endothelial cells resistant to NK cell cytotoxicity by two mechanisms: first, by decreasing NK cell degranulation in an HLA class I-dependent manner and second, downstream of cytotoxic granule-release, by specifically inhibiting granzyme B and caspase 3 activity in infected endothelial cells. Although resistant to NK cell cytotoxicity, infected cells promote an highly activated NK cell phenotype and increased functional capacity. As clinical symptoms in HPS/HFRS most likely stem from the massive immune activation, a more complete understanding of how NK cell activation occurs and the role these activated cells may play in the pathogenesis of disease will be crucial to improve the clinical outcome of these, often fatal, infections.