HOST-PATHOGEN DETERMINANTS OF MOUSE TUBERCULOSIS LATENCY

免疫学确定的，而不是化疗诱导的，小鼠中的结核病潜伏期需要在感染灶处停止细菌繁殖，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，除非静止性感染不能诱导进行性病理（疾病）。 我们进一步假设，这种情况将只存在于遗传抗性足以使结核杆菌在生理上不能诱导宿主巨噬细胞在感染部位产生促炎细胞因子的小鼠中。 有人提出，结核病潜伏期的这些要求是满足所有器官的遗传抗性B6小鼠感染相对低毒力的结核分枝杆菌R1Rv株，但不是更毒力的H37Rv株。 我们预测，毒性更强的MTB菌株感染将在所有器官中变得稳定，这将导致除肺外的所有器官中的疾病潜伏期。 我们将确定是否静止R1Rv感染与潜伏性疾病是显着不同的静止H37Rv感染与进行性疾病，在肺部的促炎和其他细胞因子的生产。 我们将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中存在一定的最小数量的杆菌，这取决于MTB菌株的毒力。 潜伏期和获得性免疫表达之间的关系将通过在不能产生参与保护性免疫的一种或另一种T细胞亚群的小鼠中跟踪R1Rv感染的过程和感染诱导的病理学的发展来研究。 我们将确定是否已经潜伏的疾病是重新激活小鼠耗尽一个或多个这些T细胞亚群。将通过监测T细胞产生的Th1和其他细胞因子以及潜伏性疾病器官中巨噬细胞的NOS 2表达来研究持续表达免疫以维持潜伏期的需要。

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.