Effect of the gut microbiota on malaria

描述（由申请人提供）：疟原虫感染引起疟疾，几千年来一直是人类的祸害。不幸的是，我们仍然需要几年的时间才能为超过40%的世界人口提供有效的抗疟疾疫苗， 疟疾的风险。使疟疾的治疗和控制进一步复杂化的是，疟原虫和传播寄生虫的蚊子媒介都迅速对为治疗疟疾和控制蚊子种群而开发的新药产生耐药性。因此，迫切需要探索新的方法来控制疟疾。我们提出了一个探索性项目，以确定肠道微生物群对调节疟疾严重程度的影响，这有可能为治疗疟疾的新型和负担得起的方法提供见解。肠道微生物群已被证明会影响对肥胖、糖尿病的易感性，并调节宿主免疫的多个方面。这对于与胃肠道接触的免疫系统组分尤其如此。重要的是，肠道微生物群还增强了宿主对胃肠道外发生的细菌和病毒感染的免疫力。然而，没有关于肠道微生物群如何影响宿主对非胃肠道寄生虫感染（包括疟原虫）的免疫应答的报道。我们的初步数据表明，从不同供应商购买的C57 BL/6小鼠，已知其肠道微生物群发生变化，在感染约氏疟原虫17 XNL后表现出显著不同的寄生虫负荷水平。我们还证明，与对照处理的小鼠相比，用抗生素混合物处理的来自不同供应商的C57 BL/6小鼠在感染疟原虫后表现出动态反应。总的来说，我们的数据表明肠道微生物群调节疟疾的严重程度。我们假设特定的肠道细菌及其代谢副产物调节疟疾的易感性。我们将通过以下具体目标来解决这一假设：1）确定与对疟疾的不同易感性相关的肠道微生物群的差异，2）确定肠道微生物群将对疟疾的抗性或易感性转移到另一只小鼠的能力，以及3）确定驱动对疟疾的不同易感性的肠道代谢物。

DESCRIPTION (provided by applicant): Plasmodium infections, which cause malaria, have been a scourge to humanity for thousands of years. Unfortunately, we are still years away from an efficacious anti-malaria vaccine that is available to the >40% of the world's population that is at risk of malaria. Further complicating treatment and control of malaria is that both Plasmodium and the mosquito vector that transmits the parasite rapidly develop resistance to new drugs developed to treat malaria and control mosquito populations. Therefore, it is imperative novel approaches to control malaria are explored. We propose an exploratory project to determine the impact of the gut microbiota on regulating the severity of malaria, which has the potential to provide insights to novel and affordable approaches to treat malaria. The gut microbiota has been shown to shape susceptibility to obesity, diabetes, and regulate multiple aspects of host immunity. This is particularly true for components of the immune system that interface with the GI tract. Importantly, the gut microbiota also augments host immunity to bacterial and viral infections that occur outside of the GI tract. However, there are no reports as to how the gut microbiota influence host immune responses to non-GI tract parasitic infections, including Plasmodium. Our preliminary data demonstrate that C57BL/6 mice purchased from different vendors, which are known to have alterations in their gut microbiota, exhibit substantially different levels of parasite burden following infection with Plasmodium yoelii 17XNL. We have also demonstrated that C57BL/6 mice from different vendors treated with a cocktail of antibiotics exhibit dynamic responses following infection with Plasmodium compared to control treated mice. Collectively, our data suggest the gut microbiota regulates the severity of malaria. We hypothesize that specific gut bacteria and their metabolic by-products regulate susceptibility to malaria. We will address this hypothesis through the following specific aims: 1) Identify differences in gut microbiota populations that are associated with differential susceptibility to malaria, 2) Determine ability of the gut microbiota to transfer resistance or susceptibility to malaria to another mouse and 3) Identify gut metabolites that drive differential susceptibility to malaria.