Heminth Modulation of Mtb

描述(由申请人提供)：由肺部病原体结核分枝杆菌(结核分枝杆菌)引起的死亡率和发病率仍然高得惊人。众所周知，对结核分枝杆菌的保护性免疫反应依赖于宿主启动Th1细胞反应的能力。此外，我们还对Th1的发育机制和启动结核分枝杆菌反应性Th1反应的微环境的动力学有了更多的了解。显然，这些研究为结核病的宿主保护机制提供了一些见解；然而，它们没有考虑到慢性共同地方性传染病对人类结核分枝杆菌特异性Th1免疫发展的影响。世界上结核病(TB)发病率高的地区也是蠕虫疾病的地方病。蠕虫感染会在宿主体内产生强烈的Th2反应。再加上Th2细胞因子对Th1反应具有抑制作用，合并蠕虫感染极有可能影响结核病的发病。人们确实意识到，试图控制艾滋病毒、疟疾和结核病这三大杀手的努力需要考虑到，慢性蠕虫感染使受害者更容易受到这三大杀手的影响。在这项应用中，我们汇集了萨尔加梅和高斯实验室在分枝杆菌和蠕虫感染方面各自感兴趣的专业知识，以检验寄生虫感染改变宿主对结核分枝杆菌的免疫并调节结核病病程的假设，并确定导致这些影响的免疫机制。目的1将研究在具有持续的巴西奈瑟氏菌(NB)诱导的Th2反应的淋巴结中Th1反应的发展。目的2将在活体小鼠结核病模型中检查与蠕虫混合感染是否调节结核病疾病。与公共卫生相关：越来越多的证据表明，感染寄生虫的人群更容易感染结核病。在这项应用中，我们将检验这样一种假设，即感染寄生虫会损害宿主抵抗结核病的能力。从这些研究中获得的信息将对结核病疫苗的设计和治疗非常重要。

DESCRIPTION (provided by applicant): Mortality and morbidity caused by the pulmonary pathogen Mycobacterium tuberculosis (Mtb) remains alarmingly high. It is well established that the protective immune response to Mtb is dependent on the host's ability to initiate Th1 cellular responses. In addition, we are also gaining an appreciation for the mechanics of Th1 development and the dynamics of the microenvironment where the Mtb-reactive Thl response is initiated. Clearly these studies are providing some insights into host protective mechanisms in tuberculosis; nevertheless they do not take into account the affect that chronic co-endemic infectious agents may have on the development of Mtb-specific Th1 immunity in humans. Regions of the world with high incidence of Tuberculosis (TB) are also endemic for helminthic diseases. Helminth infections generate a strong Th2 response in the host. Together with the fact that Th2 cytokines have suppressive effects on Th1 responses, it is highly likely that co-infections with helminths may impact on the pathogenesis of TB. There is indeed an enhanced awareness that attempts to control the Big three killers-HIV, Malaria and Tuberculosis- need to take into consideration that chronic helminth infections make their victims more vulnerable to the big three. In this application, we bring together the expertise of the Salgame and Gause laboratories with respective interests in mycobacterial and helminth infections, to test the hypothesis that parasitic infections alter host immunity to Mtb and modulate the course of tuberculosis disease, and to determine the immune mechanisms responsible for these effects. Aim 1 will examine the development of Th1 responses in lymph nodes that have an ongoing N. brasielinsis (Nb)-induced Th2 response. Aim 2 will examine in an in vivo murine model of TB whether co-infection with helminths modulates tuberculosis disease.Relevance to Public health: There is increasing evidence that suggests that populations infected with parasites are more susceptible to tuberculosis. In this application we will test the hypothesis that infection with parasites compromises the host's ability to resist tuberculosis disease. The information obtained from these studies will be important for vaccine design and treatment against tuberculosis/