The Consequences of Reinfection with M. tuberculosis

 描述（由申请方提供）：针对许多传染病的疫苗是有效的，因为先前感染病原体也会诱导灭菌免疫。与此相反， 在文献中有许多关于在先前患有结核病的人中由结核分枝杆菌再感染引起的疾病的报道，事实上，先前的结核病通过复发或再感染增加了随后疾病的风险。此外，还报告了结核病患者的混合感染。然而，精液流行病学研究表明，临床潜伏M。结核病感染可防止结核病因再感染而发展。文献回顾表明，先验M。结核病感染对后续感染的影响研究甚少，也没有很好地了解。在本申请中，我们进行了详细的研究与M的再感染的后果。结核我们汇集了尖端技术，用于在已建立的非人灵长类结核病模型中分析单个肉芽肿中的细菌种群和免疫反应，以解决原发性感染如何影响继发性感染。我们假设原发感染和随后的免疫反应将损害肉芽肿水平继发感染的进展。我们将剖析原发性和继发性病变中的免疫反应，以确定介导病变中细菌杀灭的因素。最后，我们将研究临床相关的再感染情况： 用M的异源谱系攻击。结核病及M.结核病在再次感染之前。这些研究将揭示结核病生物学和免疫学的基本和新方面，并为疫苗开发和治疗人类潜伏感染的后果提供关键的翻译见解。

 DESCRIPTION (provided by applicant): Vaccines against many infectious diseases are effective because prior infection with the pathogen also induces sterilizing immunity. In contrast, there are numerous reports in the literature of disease caused by reinfection with Mycobacterium tuberculosis in those who have previously had tuberculosis, and in fact, prior tuberculosis increases the risk of subsequent disease, either through relapse or reinfection. In addition, mixed infections in tuberculosis patients have also been reported. However, seminal epidemiologic studies suggested that people with clinically latent M. tuberculosis infection can protect against development of tuberculosis due to reinfection. A review of the literature reveals that the effects of prior M. tuberculosis infection on subsequent infection are poorly studied and not well understood. In this application, we undertake a detailed study of the consequences of reinfection with M. tuberculosis. We bring together cutting edge technology for analysis of bacterial populations and immune responses in individual granulomas in an established non-human primate model of tuberculosis to address how a primary infection influences a secondary infection. We hypothesize that primary infection and the ensuing immune response will impair progression of the secondary infection at the granuloma level. We will dissect the immune responses in primary and secondary lesions to identify those factors that mediate killing of bacteria in the lesions. Finally, we will investigate clinically relevant scenarios of reinfection: challenge with a heterologous lineage of M. tuberculosis and treatment of M. tuberculosis infection prior to reinfection. The studies here will uncover basic and novel aspects of tuberculosis biology and immunology, as well as provide key translational insights into vaccine development and the consequences of treating latent infections in humans.