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.

总结