Heminth Modulation of Mtb

描述（由申请人提供）：由肺病原体结核分枝杆菌（Mtb）引起的死亡率和发病率仍然高得惊人。现已确定，对Mtb的保护性免疫应答依赖于宿主启动Th1细胞应答的能力。此外，我们还对Th1发育的机制和mtb反应性Thl反应启动的微环境动力学有了进一步的了解。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流行传染因子可能对人体内mtb特异性Th1免疫的发展产生的影响。世界上结核病高发地区也是寄生虫病的流行地区。蠕虫感染在宿主体内产生强烈的Th2反应。再加上Th2细胞因子对Th1反应有抑制作用，与蠕虫共感染很可能影响TB的发病机制。人们确实意识到，试图控制三大杀手——艾滋病、疟疾和结核病——需要考虑到慢性寄生虫感染使受害者更容易受到三大杀手的攻击。在这个应用程序中，我们汇集了Salgame和Gause实验室各自对分枝杆菌和蠕虫感染感兴趣的专业知识，以测试寄生虫感染改变宿主对Mtb的免疫力并调节结核病病程的假设，并确定负责这些影响的免疫机制。目的1将研究具有持续的巴西奈瑟菌（Nb）诱导的Th2反应的淋巴结中Th1反应的发展。目的2将在体内小鼠结核病模型中研究与蠕虫的共同感染是否会调节结核病。与公共卫生的相关性：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。在这个应用程序中，我们将测试寄生虫感染损害宿主抵抗结核病的能力的假设。从这些研究中获得的信息将对结核病疫苗的设计和治疗具有重要意义

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/