Cell Migration in the Infected Brain

描述(由申请人提供)：了解控制中枢神经系统炎症的机制对于找到限制病原体或神经退行性疾病对大脑损害的治疗方法至关重要。然而，我们的知识主要局限于促进进入这个部位的黏附分子，而不是一旦进入大脑就影响炎症细胞的因素。感染原虫寄生虫弓形虫会导致中枢神经系统的慢性感染，大脑需要持续的炎症反应来维持潜伏期。缺乏适当的免疫反应会导致弓形虫脑炎(TE)的发展，因此是艾滋病相关死亡的常见原因。弓形虫是一种非常常见的人类感染，然而，在免疫能力强的宿主中，没有明显的与大脑持续炎症有关的病理。因此，弓形虫感染导致大脑中的免疫反应，足够强大，以提供对寄生虫的保护，但充分控制，以防止免疫病理。我们实验室正在检验的一个假设是，在慢性感染期间，细胞迁移可以通过趋化因子网络在大脑中引导，从而控制感染和限制组织损伤。我们最近的研究表明，弓形虫感染后，T细胞在脑实质内迁移的网状网络形成。此外，趋化因子CCL19和CCL21被与迁移T细胞相关的CCL21缆线显著上调。这些趋化因子以其在T细胞和树突状细胞在外周迁移中的作用而闻名，但在中枢神经系统内迁移的背景下还没有得到很好的研究。将进行实验来验证这一假设，即CCL19/CCL21在感染脑组织中的表达增加是引导脑实质内的白细胞控制感染的一种机制。了解外周细胞如何被引导到感染部位并仍然防止中枢神经系统的免疫病理变化，对于控制影响大脑的多种感染病原体直接相关。此外，它还可能导致新的机制来操纵中枢神经系统中的病理性或缺陷的免疫反应。

DESCRIPTION (provided by applicant): Understanding the mechanisms that control inflammation in the CNS is critical to finding therapies for limiting damage to the brain from pathogens or neurodegenerative disease. Yet our knowledge is primarily limited to the adhesion molecules that facilitate entry to this site and not the factors that influence inflammatory cells once within the brain. Infection with the protozoan parasite Toxoplasma gondii leads to a chronic infection in the CNS with a continuous inflammatory response required in the brain to maintain latency. The absence of an appropriate immune response leads to the development of Toxoplasmic encephalitis (TE) and is therefore a common cause of AIDS related fatalities. Toxoplasma is an extremely common human infection, yet, in the immune- competent host there is no apparent pathology related to continuous inflammation in the brain. Thus, T. gondii infection leads to an immune response in the brain robust enough to provide protection against the parasite but sufficiently controlled to prevent immunopathology. A hypothesis being examined in our lab is that during chronic infection, cell migration can be guided in the brain by chemokine networks thereby controlling infection and limiting tissue damage. Recent studies of ours have demonstrated that following Toxoplasma infection, the presence of a reticular network is formed on which T cells migrate within the parenchyma of the brain. In addition, the chemokines CCL19 and CCL21 are significantly upregulated with cables of CCL21 associated with migrating T cells. These chemokines, known for their role in T cell and dendritic cell migration in the periphery, have not been well studied in the context of migration within the CNS. Experiments will be conducted to test the hypothesis that increased expression of CCL19/CCL21 in the infected brain is a mechanism to guide leukocytes within the brain parenchyma to control infection. Understanding how peripheral cells are directed to the site of infection and still prevent immunopathology in the CNS has direct relevance to controlling the multiple infectious pathogens that affect the brain. In addition, it may also lead to novel mechanisms to manipulate a pathological or deficient immune response in the CNS.