Lymphatic filariasis caused by the nematode parasites Brugia malayi and Wuchereria bancrofti continues to cause considerable morbidity in human populations. An understanding of the pathogenesis of this disease is minimal. The long term goal of the proposed studies is to define the pathogenic mechanisms active in these infections using the Brugia pahangi-jird model system.
Four specific aims are proposed.
Specific Aim 1 is to identify the effect of protective immune responses on induction and modulation of lymphatic lesions. This will be accomplished by qualitatively and quantitatively assessing lesions and immune responses in vaccinated and subsequently challenged jirds.
Specific Aim 2 is to identify the parasite life cycle stages and factors responsible for the decreased inflammatory responses seen during chronic infections. The course of inflammatory reactions and immune responses of jirds with infections initiated by L-3, L4, adult male, adult female and microfilariae will be compared, and the relative inflammatory inducing and regulating potential of these individual life cycle stages assessed.
Specific Aim 3 is to characterize T-cell associated responses related to the induction and regulation of Brugia-induced granulomatous inflammatory responses. T-cell lines and clones and lymphocyte populations from jirds with acute and chronic infections will be characterized functionally and by the presence of cytokine specific m-RNAs.
Specific Aim 4 will identify Brugia proteins responsible for the induction of the granulomatous inflammatory response. Fractions of worm extracts or secretions will be tested in vivo for their ability to induce granulomas when coupled to sepharose beads and embolized into the lungs of jirds with acute and chronic infections. Purified proteins cloned from Brugia DNA, and indicated to have potential immunologic reactivity by our collaborators will similarly be assayed in this model system.
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