Over the past several years, using intraperitoneal infection of mice with Brugia malayi as our working model, we have sought to understand host-parasite interactions in this model system. One of the puzzles that we have been confronted with is the mechanism by which the mammalian body eliminates large, metazoan, extracellular, tissue dwelling parasites. Data that we have obtained over the last two or three years, strongly suggest that B lymphocytes play a critical role. Our findings, described in greater detail in section C, also suggest that the ultimate effectors of parasite killing are components of innate immunity. The ability to generate targeted mutations, both deletional (knockout mice) and insertional (transgenic mice), has made possible the evaluation of the functional importance of components of innate immunity in a manner hithertofore unimaginable. The goal of this proposal is to use these powerful tools, namely transgenic and knockout mutations in various genes affecting eosinophil function and number, to evaluate their role in host protection against Brugia malayi. The working hypothesis underlvinc this proposal that eosinophils. In the presence Qf the appropriate antibodies and complement components. Major role in the elimination Qf B. malayi from the murine peritoneal cavity. We will use IL-S transgenic and knockout mice, as well as antibodies against the chemokine receptor CCR3, to examine the role of eosinophils in host resistance to Brugia malayi infection. We will examine mechanism by which eosinophils accomplish their host protective function, using in vivo and in vitro models. We believe that the studies proposed herein will help us understand the mechanisms by which mammalian hosts combat infectious agents that are far larger than their own effector cells.
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