The Consequences of Reinfection with M. tuberculosis

 描述(申请人提供)：预防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无菌免疫。相比之下， 在文献中有许多关于先前患有结核病的人因再次感染结核分枝杆菌而引起的疾病的报告，事实上，先前的结核病通过复发或再感染增加了后续疾病的风险。此外，也有结核病患者混合感染的报告。然而，开创性的流行病学研究表明，临床上潜伏的结核分枝杆菌感染者可以预防因再次感染而发展成结核病。对文献的回顾表明，先前结核分枝杆菌感染对后续感染的影响研究很少，也不是很清楚。在本申请中，我们对再次感染结核分枝杆菌的后果进行了详细的研究。我们将尖端技术结合在一起，在建立的非人类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，以解决初级感染如何影响继发性感染。我们假设初次感染和随之而来的免疫反应将损害肉芽肿水平的继发感染的进展。我们将解剖原发灶和继发性皮损的免疫反应，以确定那些介导杀死皮损中细菌的因素。最后，我们将调查与临床相关的再感染情况： 挑战异源结核分枝杆菌血统，并在再次感染前治疗结核分枝杆菌感染。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.