Innate and adaptive immune responses against human Puumala virus infection: immunopathogenesis and suggestions for novel treatment strategies for severe hantavirus-associated syndromes

Two related hyperinflammatory syndromes are distinguished following infection of humans with hantaviruses: haemorrhagic fever with renal syndrome (HFRS) seen in Eurasia and hantavirus pulmonary syndrome (HPS) seen in the Americas. Fatality rates are high, up to 10% for HFRS and around 35%-40% for HPS. Puumala virus (PUUV) is the most common HFRS-causing hantavirus in Europe. Here, we describe recent insights into the generation of innate and adaptive cell-mediated immune responses following clinical infection with PUUV. First described are studies demonstrating a marked redistribution of peripheral blood mononuclear phagocytes (MNP) to the airways, a process that may underlie local immune activation at the site of primary infection. We then describe observations of an excessive natural killer (NK) cell activation and the persistence of highly elevated numbers of NK cells in peripheral blood following PUUV infection. A similar vigorous CD8 Tcell response is also described, though Tcell responses decline with viraemia. Like MNPs, many NK cells and CD8 T cells also localize to the lung upon acute PUUV infection. Following this, findings demonstrating the ability of hantaviruses, including PUUV, to cause apoptosis resistance in infected target cells, are described. These observations, and associated inflammatory cytokine responses, may provide new insights into HFRS and HPS disease pathogenesis. Based on similarities between inflammatory responses in severe hantavirus infections and other hyperinflammatory disease syndromes, we speculate whether some therapeutic interventions that have been successful in the latter conditions may also be applicable in severe hantavirus infections.