Hantaviruses are the cause of 2 highly lethal human diseases: Hemorrhagic fever with renal syndrome (HFRS) and hantavirus pulmonary syndrome (HPS). However, mehanisms of hantavirus pathogenesis have not been defined and currently there is no animal model of hantavirus disease. We have recently determined that alphanubeta3 and alphaIIbbeta3 integrins are cellular receptors for pathogenic, but not non-pathogenic, hantaviruses and this finding directly relates hantavirus disease to the use of key adhesive integrins on platelet and endotheial cells. Further, human but not murine beta3 subunits render cells susceptible to infection by pathogenic hantaviruses. This permits us to define elements of beta3 integrins required for hantavirus interaction and to propose the development of human-beta3 transgenic mice for use as models of hantavirus infectivity and pathogenesis. beta3 integrin deficient knockout mice have recently been shown to mimic a human bleeding disorder, Glanzmanns thrombasthenia, and have marked vascular hemorrhage and defects in platelet aggregation. We have shown that cellular susceptibility to HPS- and HFRS-causing hantaviruses is confered by human beta3 integrins. Interestingly, human but not murine beta3 integrins permit hantavirus infection and this is consistent with the fact that laboratory mice (MUS musculis) are not hantavirus hosts. Although there is little known about beta3 integrins from their natural hosts, the findings demonstrate that beta3 subunits are sufficient to determine cellular susceptibility to pathogenic hantaviruses. The role of beta3 integrins in platelet and endothelial cell function, the nature of hantavirus disease and the use of beta3 integrins by only pathogenic hantaviruses, suggests that hantavirus-receptor interactions play a central role in hantavirus pathogenesis. We will investigate the interaction of pathogenic hantavirus with beta3 integrin receptors, and develop human beta3 integrin transgenic mice as potential models of hantavirus infectivity and pathogenesis. This proposal will define integrin specific requirements for hantavirus attachment and inhibitors of hantavirus infectivity with therapeutic and prophylactic uses. Development of an animal model of hantavirus pathogenesis within this proposal is broadly applicable to studies of hantavirus disease, therapeutics and protective immunity.
Specific Aims : 1) beta3 Integrin Requirements for Hantavirus Infectivity; 2) Blocking beta3 Integrin-Hantavirus Interactions; 3) Transgenic Model of Hantavirus Infection and Pathogenesis.
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