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Work package 5

Characterization of NK cell response in hantavirus-infected humans and mice

DSC_0529Hantaviruses (HTV), which are a part of the family Bunyaviridae, are emerging, enveloped RNA viruses, which cause hemorrhagic fever with renal syndrome (HFRS) in Europe and Asia with up to 20% mortality rate and hantavirus cardiopulmonary syndrome (HPS) in Americas with up to 40% mortality rate (Schmaljohn et al., Emerg Inf Dis, 1997). In Europe, two main HTV cause HFRS: Puumala (PUUV) and Dobrava (DOBV), but some low pathogenic HTV are detected as well (Markotic et al., Nat Med, 1996; Markotic et al., J Med Virol, 2002; Vapalahti et al., Lancet Infect Dis, 2003).

Reservoirs for HTV are small rodents with persistent infection and no manifest of the disease (LeDuc, Rev Infect Dis, 1989). There is still a significant lack of knowledge about the immune response to HTV in humans and rodents. The strong proinflammatory response during acute infection in humans is probably responsible for viral clearance but also for a potentially fatal proinflammatory-mediated disease. The mechanisms mediating the persistence of HTV and the absence of clinical symptoms in rodent reservoirs are still mostly unknown and the lack of an animal model additionally hinders HFRS research. So far, no effective antivirals, vaccines, or immunotherapeutics exist for HFRS.

NK cells are traditionally defined as cells of the innate immune response. However, evidence collected so far suggests that specific subsets of mouse NK cells can nevertheless develop long-lived and highly specific memory to a variety of antigens (Sun and Lanier, Nat Rev Immunol, 2011). Remarkably, in a recent report Bjorkstrom and colleagues described the expansion of a subset of CD94/NKG2C+ NK cells in patients infected with hantavirus. This NK cell subset was functional and its expansion was maintained at high levels for a prolonged period of time after infection. We expect to show that HTV induce NK cell memory in patients infected with PUUV, but also that a certain response could be provoked by heterologous DOBV. Also we suspect that such memory response could be time related. Our intention as well is to identify products involved in the specific recognition of HTV infected cells by activating KIRs. In addition, we expect to show that NK cell-mediated modulation of T cell responses is at least in part responsible for HTV persistence.