Mycobacterium tuberculosis-manganese interactions and neurotoxicity

 描述(由申请人提供)：过量暴露于锰会导致帕金森症，即锰中毒，这显然与基底节损害有关，包括神经炎性异常，这是锰矿工的最佳特征。除了锰过量接触外，锰矿工的结核病患病率也最高，这表明同时接触锰和结核分枝杆菌的可能性很高。然而，到目前为止，在锰诱导的神经病理背景下，锰-Mtb相互作用的性质还没有被研究。我们更广泛的目标是在暴露情景和与人类高度相关的合并症，如结核病的背景下，研究和破译锰神经毒性的机制。因此，利用互补的小鼠模型和体外方法，结合创新的和职业相关的给药方法(气管内喷雾器)，并基于令人兴奋的初步数据，我们将从MN神经病理学的角度研究MN-Mtb的相互作用。我们假设，锰和结核分枝杆菌将在脑内和外周相互作用，因此联合暴露于锰/结核分枝杆菌将导致神经炎症增加，外周炎症增加，神经元对锰的影响增加。这一假设将通过以下两个具体的例子进行检验 目的：(1)确定Mtb和Mtb之间相互作用的性质，评价Mtb和Mtb共同作用于脑内(苍白球)或由气管内Mtb和Mtb直接感染所引起的神经毒性；(2)确定Mtb直接感染神经元是否调节Mn的神经毒性，这种调节是否具有神经细胞类型的特异性。总而言之，AIMS 1和AIMS 2中提出的工作将使我们能够确定结核病共病在与锰过量暴露相关的神经病理中的作用。这样的结果将产生变革性的积极影响，因为它们将是第一个报告高度流行病学相关的毒物(MN)和感染剂(MTB)相互作用的结果。拟议的研究还将对其他情况产生潜在的更广泛的影响，在这些情况下，面对金属过剩(或缺乏)的细菌感染是令人担忧的。

 DESCRIPTION (provided by applicant): Overexposure to manganese (Mn) results in a parkinsonian disorder, manganism, which is clearly associated with basal ganglia lesions that include aberrations of neuroinflammatory nature and is best characterized in Mn miners. Besides Mn overexposure, Mn miners also have the highest prevalence of tuberculosis (TB), suggesting high likelihood of co-exposure to Mn and Mycobacterium tuberculosis (Mtb). However, the nature of the Mn-Mtb interaction within the context of Mn-induced neuropathology has not been studied until now. Our broader objectives are to study and decipher the mechanisms of Mn neurotoxicity within the context of exposure scenarios and co-morbidities, such as TB, that are of high human relevance. Hence, using complementary mouse models and in vitro approaches, combined with innovative and occupationally-relevant delivery method (intratracheal sprayer), and based on exciting preliminary data we will investigate the Mn-Mtb interaction from a Mn neuropathology perspective. We hypothesize that Mn and Mtb will interact both within the brain and in the periphery, such that combined Mn/Mtb exposure will lead to increased neuroinflammation, increased peripheral inflammation, and increased neuronal susceptibility to the effects of Mn. This hypothesis will be tested with the following two specific aims: (1) to determine the nature of the interaction between Mn and Mtb and to evaluate the neurotoxicity caused by co-administration of Mn and Mtb directly into the brain (globus pallidus) or by intratracheal Mn and Mtb exposure and (2) to determine whether direct Mtb infection of neurons modulates the neurotoxicity of Mn and whether such modulation is neuronal cell-type specific. Collectively, the work proposed in aims 1 and 2 will enable us to determine the role of TB comorbidity in the neuropathology associated with Mn overexposure. Such results will have transformative positive impact because they will be the first to report on a highly epidemiologically-relevant toxicant (Mn) and infectious agent (Mtb) interaction. The proposed studies will also have potential broader consequences to other conditions where bacterial infections in the face of metal excess (or deficiency) are of concern.