Mediators of Toxoplasma surviral during infection

描述（由申请人提供）：原生动物弓形虫可在免疫缺陷个体中引起严重的机会性疾病（弓形虫病），但多达三分之一的人口是良性感染。这个项目的长期目标是确定弓形虫是如何在宿主强大的先天免疫系统中有效地建立感染的。了解微生物病原体破坏宿主免疫防御的基本机制对于合理制定预防感染的新策略是必要的。

DESCRIPTION (provided by the applicant): The protozoan Toxoplasma gondii can cause severe opportunistic disease (toxoplasmosis) in immune-deficient individuals, yet up to one third of the human population is benignly infected. The long-term goal of this project is to determine how Toxoplasma efficiently establishes infection in the midst of the host's highly capable innate immune system. An understanding of the basic mechanisms used by microbial pathogens to subvert host immune defenses is necessary to rationally develop novel strategies for preventing infection. Our central hypothesis is that Toxoplasma uses natural serine proteases (serpins) to control innate immune defenses including inflammation and complement fixation via the alternative pathway. This is based on key roles for protease inhibitors in the regulation of inflammation and complement. Other studies have also established that several viruses and helminth parasites deploy serpins to subvert innate immunity. In line with the goals of the RO3 funding mechanism, this grant is designed to generate preliminary data in support of subsequent full scale testing of hypotheses. The specific aims are: (1) to create parasite strains deficient in expression of the serpins TgPI-1 and TgPI-2; (2) to test whether TgPl's possess anti-inflammatory activity; and (3) to test whether TgPl's block alternative complement fixation. The impact of this research will be a better understanding of the mechanisms permitting parasite survival during infection, with the added benefit of potentially leading to progressive approaches for boosting innate immunity and treating inflammatory diseases.