The collectins are collagenous lectins present in serum and lung secretions involved in innate immunity. Pulmonary surfactant proteins A and D (SP-A and SP-D), play important roles in defense against influenza A virus (IAV). Compared to controls, mice lacking SP-D due to gene-deletion (SP-D -/-) have markedly increased lung viral titers and inflammation after IAV infection. IAV infection of these mice will be characterized in more detail for this proposal. A better understanding of the mechanisms through which SP-D inhibits replication of IAV could elucidate why certain people are more susceptible to complications of IAV infection. This proposal will examine in vitro important functional aspects of SP-D relevant to its role in host defense against IAV, including its ability to bind to, aggregate and neutralize infectivity of IAV, and to modulate the interactions of phagocytic cells with IAV. In addition, the antiviral activities of recombinant preparations of polymorphic variants of SP-D will be tested. SP-D -/- have pulmonary lipidosis. Since phospholipid accumulation could play a role in the increased susceptibility SP-D -/- mice to IAV infection, relevant interactions of SP-D or IAV with surfactant phospholipids will also be examined. Another respiratory tract protein called gp340 binds to SP-D, and has cooperative antiviral effects when combined with SP-D. This proposal will examine further the antiviral activity of gp340 and the mechanisms through which it potentiates the antiviral effects of SP-D. Since SP-D binds to IAV, phagocytes, phospholipids and gp340, through its carbohydrate recognition domain (CRD), the contribution of specific parts of the CRD to these functional activities will be intensively examined. A series of recombinant constructs will be made in which parts of the SP-D CRD are replaced with analogous parts of serum collectins. Since several of the serum collectins have stronger ability to neutralize infectivity of IAV than SP-D, and probably differ from SP-D in terms of binding to phagocytes, phospholipids and gp340, this approach should identify more precisely which groups of amino acids on the CRD are critical for these functions. Based on prior experiments, it is likely that the modified forms of SP-D generated for this proposal will have greater ability to inhibit infectivity of IAV than wild type SP-D. This will be tested in vitro and in vivo by intranasal instillation or transgenic expression of some of these novel, recombinant SP-Ds in SP-D -/- mice. This proposal should not only increase our understanding of the complex mechanisms through which SP-D participates in host defense against IAV, but also provide evidence of the feasibility of restoring or enhancing collectin-mediated defense through use of recombinantly modified collectins.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Research Project (R01)
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Lung Biology and Pathology Study Section (LBPA)
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Denholm, Elizabeth M
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Boston Medical Center
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