HOST-PATHOGEN DETERMINANTS OF TUBERCULOSIS LATENCY

与化疗诱导的结核潜伏期相反，由免疫决定的小鼠结核潜伏期要求细菌增殖在感染灶处停止，并且感染在宿主免疫的影响下变得静止。然而，我们假设与人类潜伏期相关的潜伏期状态将不存在，除非静止感染无法诱导进行性病理（疾病）。我们进一步假设，这种情况只存在于遗传抗性足够强的小鼠中，使结核杆菌在生理上无法诱导宿主巨噬细胞在感染部位产生促炎细胞因子。我们提出，感染了毒力相对较低的MTB R1Rv菌株的遗传耐药B6小鼠的所有器官都满足这些对结核潜伏期的要求，而感染了毒力较强的H37Rv菌株则不满足这些要求。我们预测，毒性更强的结核分枝杆菌菌株的感染将在所有器官中变得静止，这将导致除肺外所有器官的疾病潜伏期。我们将确定潜伏性疾病的静止性R1Rv感染与进展性疾病的静止性H37Rv感染在肺中促炎和其他细胞因子的产生方面是否有显著不同。我们将根据结核分枝杆菌菌株的毒力，确定免疫阻止由静止感染引起的疾病的能力是否取决于每个病变有一定的最小杆菌数。潜伏期和获得性免疫表达之间的关系将通过跟踪R1Rv感染的过程和感染诱导病理的发展来研究，使小鼠无法产生参与保护性免疫的一种或另一种T细胞亚群。我们将确定已经潜伏的疾病是否会在一个或多个这些T细胞亚群耗尽的小鼠中重新激活。我们将通过监测潜伏性疾病器官中T细胞产生的Th1和其他细胞因子，以及巨噬细胞表达的NOS2，来研究持续表达免疫以维持潜伏期的必要性。

Immunologically-determined, as opposed to chemotherapy-induced, tuberculosis latency in mice requires that bacterial multiplication cease at infectious foci, and that infection become stationary under the influence of host immunity. We hypothesize that a state of latency relevant to latency in humans will not exist, however, unless stationary infection is incapable of inducing progressive pathology (disease). We hypothesize further, that this situation will exist only in mice that are genetically resistant enough to render tubercle bacilli physiologically incapable of inducing host macrophages to produce proinflammatory cytokines at sites of infection. It is proposed that these requirements for TB latency are met in all organs of genetically resistant B6 mice infected with the relatively low virulence R1Rv strain of MTB, but not with the more virulent H37Rv strain. We predict that infection with more virulent MTB strains will become stationary in all organs, and that this will result in disease latency in all organs, except the lungs. We will determine whether stationary R1Rv infection with latent disease is strikingly different from stationary H37Rv infection with progressive disease, in terms of the production in the lungs of proinflammatory and other cytokines. We will determine whether the ability of immunity to arrest disease caused by stationary infection depends on there being a certain minimal number of bacilli per lesion, depending on the virulence of the MTB strain. The relationship between latency and the expression of acquired immunity will be investigated by following the course of R1Rv infection and the development of infection-induced pathology in mice made incapable of generating one or other of T cell subpopulations that participate in protective immunity. We will determine whether already latent disease is reactivated in mice depleted of one or more of these T cell sub-populations. The need for the continuous expression of immunity to maintain latency will be investigated by monitoring Th1 and other cytokine production by T cells, as well as NOS2 expression by macrophages in organs with latent disease.