Regulation of Cortisol by Mycobacterial Glycolipid TDM

描述(申请人提供)：在结核感染过程中观察到糖皮质激素调节已有多年，然而糖皮质激素免疫调节与对分枝杆菌抗原的破坏性病理和肉芽肿反应之间的关系仍知之甚少。事实上，系统和组织特异性皮质醇的相对数量可能在结核病的易感性中起关键作用，因此在随后的病理中起决定性作用。在急性实验性感染强毒结核分枝杆菌期间，C57BL/6小鼠表现出血清皮质醇水平在启动肉芽肿反应期间迅速下降。研究人员一直在积极寻找模拟与结核病相关的免疫病理学的药物。天然分枝杆菌糖脂海藻糖(TDM)就是其中之一，作为疾病期间生物事件和肉芽肿反应的介体，已被广泛研究。我们进一步确认分枝杆菌TDM能够影响全身血清皮质醇水平。这是首次观察到全身糖皮质激素对分枝杆菌糖脂的调节作用，值得进一步研究。 我们的初步发现表明，有必要探讨皮质醇对分枝杆菌糖脂TDM引起的免疫调节和免疫病理的初始事件的影响。因此，这项应用的目的是研究在肺肉芽肿反应的发展过程中，分枝杆菌糖脂诱导的免疫反应与血清和组织糖皮质激素(皮质醇)相关的并发失衡之间的关系。我们要求考虑这一建议，为R21提供资金，用于探索性研究植物神经免疫学的应用，以了解结核病感染期间免疫调节疾病的病理基础。

DESCRIPTION (provided by applicant): The observation of glucocorticoid modulation during tuberculosis infection has been known for many years, however the relationship between glucocorticoid immunomodulation and destructive pathological and granulomatous responses to mycobacterial antigens remains poorly understood. Indeed, relative amounts of both systemic and tissue specific cortisol may be crucial in susceptibility to tuberculosis, and therefore play a defining role in ensuing pathology. C57BL/6 mice demonstrate a rapid decrease in serum cortisol levels during initiation of granulomatous response during acute experimental infection with virulent Mycobacterium tuberculosis. Investigators have actively pursued agents that mimic immunopathology associated with tuberculosis. One such agent; the natural mycobacterial glycolipid trehalose 3,6'dimycolate (TDM) has been researched extensively as a mediator of biological events and granulomatous responses during disease. We have further identified mycobacterial TDM as able to influence systemic serum cortisol levels. This is the first observation of mediation of a systemic glucocorticoid to a mycobacterial glycolipid, and warrants further investigation. Our preliminary findings indicate a need to explore the influence of cortisol on initial events involved in the immunoregulation and immunopathology due to mycobacterial glycolipid TDM. The goal of this application is therefore to examine the relationship between immune- responses induced by mycobacterial glycolipid and associated concurrent imbalances in both serum and tissue glucocorticoids (cortisol) during development of the pulmonary granulomatous response. We request that this proposal be considered for R21 funding directed towards exploratory research into applications of physioneuroimmunology towards understanding the basis of immunoregulated disease pathology during tuberculosis infection.