Mediators of Toxoplasma surviral during infection

描述（由申请方提供）：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群被良性感染。该项目的长期目标是确定弓形虫如何有效地在宿主的高能力先天免疫系统中建立感染。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开发预防感染的新策略是必要的。 我们的中心假设是，弓形虫使用天然丝氨酸蛋白酶（丝氨酸蛋白酶抑制剂）来控制先天免疫防御，包括炎症和补体固定通过旁路途径。这是基于蛋白酶抑制剂在炎症和补体调节中的关键作用。其他研究也证实，几种病毒和蠕虫寄生虫利用丝氨酸蛋白酶抑制剂破坏先天免疫。 根据RO 3资助机制的目标，这笔赠款旨在生成初步数据，以支持随后的全面假设测试。具体目标是：（1）产生丝氨酸蛋白酶抑制剂TgPI-1和TgPI-2表达缺陷的寄生虫菌株;（2）测试TgPI是否具有抗炎活性;和（3）测试TgPI是否阻断替代补体结合。这项研究的影响将是更好地了解感染期间寄生虫存活的机制，并可能导致增强先天免疫和治疗炎症性疾病的渐进方法。

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.