Cerebral Malaria Associated Neurological Disorders in India

描述(申请人提供)：恶性疟原虫是最常见的感染中枢神经系统的寄生虫，也是导致幼儿弥漫性脑病的主要原因。这种脑病与10%-14%的死亡率有关，每年估计有100万-250万人死亡。恶性疟原虫是四种人类疟疾寄生虫(恶性疟原虫、间日疟原虫、恶性疟原虫、卵形疟原虫)中致死率最高的一种，估计每年感染3-5亿人。在所有恶性疟疾病例中，约有1%会导致脑型疟疾，从而影响至少300万人的中枢神经系统，尤其是幼儿。由于缺乏有效的疫苗来预防疟疾，加上全球抗疟疾药物耐药性的增加，疟疾正在重新成为热带和亚热带地区的一个主要公共卫生威胁。到目前为止，为了解疟疾对大脑和大脑功能的长期和短期影响而进行的大多数研究主要集中在疟疾引起的严重神经缺陷上，但关于这种疾病对学习、认知功能和神经心理的影响的数据很少。我们实验室以前使用西非人死后脑和血清样本进行的研究表明，RANTES及其相应的受体CCR1、CCR3和CCR5在可能导致神经损伤或功能障碍的脑免疫病理机制中发挥着非常重要的作用。我们假设脑型疟疾会导致神经损伤和认知功能下降。这一假设的一个推论是，这种神经损伤是由免疫病理机制介导的。我们提议由印度贾巴尔普尔的莫尔豪斯医学院、疾病控制中心和医学研究中心(ICMR)组成一个多学科的国际合作伙伴关系，以解决免疫致病机制在印度次大陆受疟疾影响最严重的人群中因恶性疟而导致的神经损害中的作用。第一个具体目标是进行初步的回顾性和前瞻性流行病学调查，以评估恶性疟疾S流行的印度中部地区恶性疟原虫引起的长期神经损害的程度。第二个具体目标将进行初步调查，以确定脑型疟疾康复后与神经损害相关的潜在免疫病理因素。该提案将在印度开展脑疟疾的流行病学和分子免疫学以及能力建设。这项拟议研究的数据将揭示脑疟疾导致神经和认知障碍的分子基础。

DESCRIPTION (provided by applicant): Plasmodium falciparum is the most common parasite to infect central nervous system and the leading cause of diffuse encephalopathy in young children. This encephalopathy is associated with 10-14% of mortality with an estimated annual death of 1-2.5 million annual deaths. P. falciparum is the most lethal species among the four human malaria parasites (P. falciparum, P. vivax, P. malariae, P. ovae) and it has been estimated that it infects 300-500 million people per year. About 1% of all cases of falciparum malaria results in cerebral malaria and thus affects central nervous system at least in 3 million people especially young children. In the absence of effective vaccine to protect against malaria coupled with the increasing anti-malaria drug resistance globally, malaria is re-emerging as a major public health threat in the tropics and subtropics. Most of the studies conducted to date to understand the long and short term effects of malaria on brain and brain function have focused largely on malaria-induced gross neurological defects but very little data is available on the impact of this disease on learning cognitive function and neuro-psychology. Previous studies in our laboratory using human post mortem brain and serum samples from West Africa indicated that RANTES and corresponding receptors CCR1, CCR3, and CCR5, play a very important role in brain immunopathogenesis that may result in neurological impairment or dysfunction. We hypothesize that cerebral malaria induces neurological impairment and reduces cognitive function. A corollary to this hypothesis is that this neurological impairment is mediated by immunopathogenesis. We propose a multidisciplinary international partnership involving Morehouse School of Medicine, Centers of Disease Control and the Medical Research Center (ICMR), Jabalpur, India to address the role of immunopathogenesis in malaria-induced neurological impairment following P. falciparum malaria in a population most affected by malaria in the sub-continent of India. The first specific aim will conduct preliminary retrospective and prospective epidemiological investigations to assess the extent of long-term neurological impairment associated with CM caused by P. falciparum in central India where falciparum malaria i s widespread. The second specific aim will conduct preliminary investigations to determine the potential immunopathological factors associated with neurological impairment after recovery from cerebral malaria. This proposal will pursue epidemiology and molecular immunology of cerebral malaria as well as capacity building in India. Data from the proposed research will reveal t he molecular basis of cerebral malaria induced neurological and cognitive impairment.