HOST-PATHOGEN DETERMINANTS OF MOUSE TUBERCULOSIS LATENCY

与化疗引起的小鼠结核病潜伏期不同，免疫决定的结核病潜伏期要求细菌在感染灶停止繁殖，并在宿主免疫的影响下使感染趋于稳定。然而，我们假设人类不会存在与潜伏期相关的潜伏期状态，除非持续感染不能诱发进行性病理(疾病)。我们进一步假设，这种情况只存在于这样的小鼠身上，这些小鼠具有足够的遗传抵抗力，使得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。研究表明，在感染相对较低毒力的结核分枝杆菌R1Rv株的遗传抗性B6小鼠的所有器官中，都满足这些对结核病潜伏期的要求，但较强毒力的H37Rv株则不满足。我们预测，用更强的结核分枝杆菌毒株感染将在所有器官中稳定下来，这将导致除肺部以外的所有器官的疾病潜伏期。我们将确定潜伏疾病的稳定期R1Rv感染与进展性疾病的稳定期H37Rv感染在肺部促炎因子和其他细胞因子的产生方面是否有显著不同。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有一定的最低限度的杆菌数量，这取决于结核分枝杆菌菌株的毒力。潜伏期和获得性免疫表达之间的关系将通过跟踪R1Rv感染过程和感染诱导的病理发展来研究，这些小鼠不能产生参与保护性免疫的一个或另一个T细胞亚群。我们将确定已经潜伏的疾病是否在耗尽一个或多个这些T细胞亚群的小鼠中重新激活。将通过监测T细胞产生的Th1和其他细胞因子，以及潜伏期疾病器官中巨噬细胞的NOS2表达，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.