Effect of Microbial Metabolites on Growth of Cryptosporidium

微生物代谢产物对隐孢子虫生长的影响

• 批准号: 9927337
• 负责人: L. David Sibley
• 金额: $ 68.39万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-13 至 2023-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9927337
• 关键词: 2 year old; AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Adenocarcinoma Cell; Adult; Agriculture; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Antiviral Agents; Cells; Child; Chronic; Chronic diarrhea; Communities; Complex; Complication; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Effectiveness; Enteral; FDA approved; Feces; Food; Gene Expression; Growth; HIV; HIV diagnosis; Highly Active Antiretroviral Therapy; Host Defense; Human; Immunocompromised Host; Impairment; In Vitro; Individual; Indoles; Infection; Infection Control; Libraries; Life; Life Cycle Stages; Liquid substance; Mediating; Methods; Mus; Natural Immunity; Neonatal; Newborn Animals; Newborn Infant; Nuclear; Parasites; Pathway interactions; Patients; Pattern; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Production; Property; Receptor Signaling; Resistance; Resistance development; Resistance to infection; Role; Severities; Signal Pathway; Signal Transduction; Solid; Staphylococcus hominis; Testing; Time; Toxic effect; Zoonoses; analog; antimicrobial; bile salts; colonization resistance; design; diarrheal disease; effective therapy; enteric pathogen; hydroxyindole; immune function; improved; in vivo; in vivo Model; inhibitor/antagonist; innate immune pathways; juvenile animal; mature animal; microbial; microbial community; microbiome; microbiota; mouse model; nitazoxanide; novel therapeutic intervention; pathogen; patient population; pharmacokinetics and pharmacodynamics; receptor; small molecule; transcriptome; wasting

Summary Cryptosporidiosis is a common cause of severe, chronic diarrheal disease in immunocompromised patients such as those with HIV/AIDS. The only FDA approved drug for treatment of cryptosporidiosis, nitazoxanide, has limited effectiveness in immunocompromised patients. Despite the advent of HAART therapy, cryptosporidiosis still presents a major problem among patient populations where HIV diagnosis or anti-viral treatments are inadequate. As an enteric pathogen, Cryptosporidium interacts with the complex microbial community that constitutes the microbiome. Perturbations to the microbiota, such as through antibiotic treatment, are associated with increased susceptibility to infection in adult animals. Additionally, neonatal animals, which harbor an immature microbiota, are much more susceptible to Cryptosporidium infection than adults. One method by which the microbiota may influence susceptibility to Cryptosporidium infection is through the production of inhibitory small molecule metabolites. For example, high fecal indole levels were associated with lower susceptibility in a human challenge study of Cryptosporidium. Collectively, these findings raise the intriguing hypothesis that metabolites produced by the microbiota influence susceptibility to infection with Cryptosporidium. In preliminary studies, we have screened a library of bacterial metabolites that are abundant components of the normal adult microbiota for their ability to inhibit growth of C. parvum in vitro. We identified several classes of metabolites that are potent inhibitors of parasite growth at levels that are not toxic to host cells. The proposed studies will explore the mechanism(s) of inhibition by these microbial metabolites by determining which stage(s) of the parasite life cycle they target and whether they are static or cidal. We will also explore host cell signaling pathways that activate host defenses, as the potential mechanism by which these metabolites act. Finally, by employing animal models for cryptosporidiosis, we will test whether inhibitory metabolites can be used to treat infection in vivo. If successful, these studies may establish a new paradigm for treating persistent cryptosporidiosis in immunocompromised patients.

摘要 隐孢子虫病是免疫功能低下患者严重慢性腹泻的常见原因。 例如那些感染艾滋病毒/艾滋病的人。FDA批准的唯一治疗隐孢子虫病的药物--硝唑尼特， 对免疫功能低下的患者疗效有限。尽管HAART疗法的出现， 隐孢子虫病仍然是艾滋病毒诊断或抗病毒治疗患者群体中的一个主要问题 治疗是不够的。作为一种肠道病原体，隐孢子虫与复合微生物相互作用 组成微生物群的群落。对微生物区系的干扰，例如通过抗生素 治疗，与成年动物对感染的敏感性增加有关。此外，新生儿 拥有未成熟微生物区系的动物比其他动物更容易感染隐孢子虫 成年人。微生物群可能影响对隐孢子虫感染的敏感性的一种方法是 通过产生抑制性小分子代谢物。例如，较高的粪便吲哚水平 在人类对隐孢子虫的挑战研究中，与较低的敏感性有关。总而言之，这些发现 提出了一个耐人寻味的假设，即微生物区系产生的代谢物会影响感染的敏感性 隐孢子虫。在初步研究中，我们筛选了一个细菌代谢物库，这些代谢物是 在体外抑制微小隐孢子虫生长的正常成虫微生物区系中丰富的成分。我们 确定了几类有效抑制寄生虫生长的代谢物，其水平是无毒的 寄生细胞。拟议的研究将探索这些微生物代谢物的抑制机制(S) 通过确定它们针对寄生虫生命周期的哪个阶段(S)以及它们是静态的还是致死的。我们会 也探索激活宿主防御的宿主细胞信号通路，作为其潜在的机制 这些代谢物起作用。最后，通过使用隐孢子虫病的动物模型，我们将测试是否抑制 代谢产物可用于治疗体内感染。如果成功，这些研究可能会建立一个新的范式 治疗免疫功能低下患者的持续性隐孢子虫病。