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.

概括 隐孢子虫病是免疫功能低下患者出现严重慢性腹泻的常见原因 例如艾滋病毒/艾滋病患者。 FDA 唯一批准用于治疗隐孢子虫病的药物硝唑尼特 对免疫功能低下的患者效果有限。尽管HAART疗法出现， 隐孢子虫病仍然是 HIV 诊断或抗病毒治疗患者群体中的一个主要问题 治疗措施不充分。作为一种肠道病原体，隐孢子虫与复杂的微生物相互作用 构成微生物组的群落。对微生物群的干扰，例如通过抗生素 治疗，与成年动物感染的易感性增加有关。此外，新生儿 含有不成熟微生物群的动物比动物更容易受到隐孢子虫感染 成年人。微生物群影响隐孢子虫感染易感性的一种方法是 通过产生抑制性小分子代谢物。例如，粪便中吲哚含量较高 在隐孢子虫的人类挑战研究中与较低的敏感性相关。总的来说，这些发现 提出了一个有趣的假设，即微生物群产生的代谢物会影响感染的易感性 与隐孢子虫。在初步研究中，我们筛选了一个细菌代谢物库， 正常成人微生物群的丰富成分，能够抑制体外微小念珠菌的生长。我们 确定了几类代谢物，它们是寄生虫生长的有效抑制剂，且水平无毒 到宿主细胞。拟议的研究将探索这些微生物代谢物的抑制机制 通过确定它们针对寄生虫生命周期的哪个阶段以及它们是静止的还是杀灭的。我们将 还探索激活宿主防御的宿主细胞信号传导途径，作为其潜在机制 这些代谢物起作用。最后，通过采用隐孢子虫病动物模型，我们将测试是否抑制 代谢物可用于治疗体内感染。如果成功的话，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。