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: 10527363
• 负责人: L. David Sibley
• 金额: $ 67.07万
• 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 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10527363
• 关键词: 2 year old; Acquired Immunodeficiency Syndrome; Adenocarcinoma Cell; Adult; Agriculture; Animal Model; Animals; Antibiotic Therapy; Antibiotics; Antibodies; Cells; Child; Chronic; Chronic diarrhea; Communities; Complex; Complication; Cryptosporidiosis; Cryptosporidium; Cryptosporidium parvum; Effectiveness; Enteral; FDA approved; Feces; Food; Gene Expression; Growth; HIV; HIV diagnosis; HIV/AIDS; 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; Newborn Animals; Newborn Infant; Nuclear; Parasites; Pathway interactions; Patients; Pattern; Persons; Pharmaceutical Preparations; Pharmacotherapy; Predisposition; Production; Property; Receptor Signaling; Resistance; Resistance development; Resistance to infection; Role; Severities; Signal Pathway; Signal Transduction; Solid; Testing; Time; Toxic effect; Viral; Zoonoses; analog; antimicrobial; bile salts; colonization resistance; design; diarrheal disease; effective therapy; enteric pathogen; hydroxyindole; immune function; improved; in vivo; in vivo Model; inhibitor; innate immune pathways; juvenile animal; mature animal; microbial; microbial community; microbiome; microbiota; mouse model; neonatal mice; nitazoxanide; novel therapeutic intervention; opportunistic pathogen; patient population; pharmacokinetics and pharmacodynamics; receptor; small molecule; transcriptome; transmission process; 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严重的慢性腹泻病的常见原因 例如患有艾滋病毒/艾滋病的人。 FDA唯一获得的用于治疗隐孢子虫病的药物，Nitazoxanide， 免疫功能低下的患者的有效性有限。尽管Haart疗法出现了 隐孢子虫病仍然提出了HIV诊断或抗病毒的患者人群中的一个主要问题 治疗不足。作为肠道病原体，隐孢子虫与复合物微生物相互作用 构成微生物组的社区。对微生物群的扰动，例如通过抗生素 治疗与成年动物感染的敏感性增加有关。另外，新生儿 具有未成熟微生物群的动物比隐孢子虫感染更容易 成年人。菌群可能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产物。例如，高粪吲哚水平为 与隐孢子虫的人类挑战研究中，与较低的易感性有关。总的来说，这些发现 提出了一个有趣的假设，即菌群产生的代谢产物会影响感染的敏感性 与隐孢子虫。在初步研究中，我们筛选了一个细菌代谢物的库 正常成年微生物群的大量成分具有抑制体外生长的生长的能力。我们 确定了几类代谢产物，它们是寄生虫生长的有效抑制剂，在没有毒性的水平上 宿主细胞。拟议的研究将探索这些微生物代谢物抑制的机制 通过确定它们靶向的寄生虫生命周期的哪个阶段以及它们是静态的还是CIDAL。我们将 还探索激活宿主防御的宿主细胞信号通路，作为潜在机制 这些代谢产物。最后，通过采用动物模型进行隐孢子虫病，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，这些研究可能会为 治疗免疫功能低下的患者中持续的隐孢子虫病。

项目成果

Multiple pathways for glucose phosphate transport and utilization support growth of Cryptosporidium parvum.

磷酸葡萄糖转运和利用的多种途径支持小隐孢子虫的生长。

• DOI: 10.1101/2023.06.27.546703
• 发表时间: 2023
• 期刊: bioRxiv : the preprint server for biology
• 作者: Xu,Rui;Beatty,WandyL;Greigert,Valentin;Witola,WilliamH;Sibley,LDavid
• 通讯作者: Sibley,LDavid

Insulinase-like Protease 1 Contributes to Macrogamont Formation in Cryptosporidium parvum.

• DOI: 10.1128/mbio.03405-20
• 发表时间: 2021-03-09
• 期刊: mBio
• 影响因子: 6.4
• 作者: Xu R;Feng Y;Xiao L;Sibley LD
• 通讯作者: Sibley LD

Cryptosporidium infection of human small intestinal epithelial cells induces type III interferon and impairs infectivity of Rotavirus.

• DOI: 10.1080/19490976.2023.2297897
• 发表时间: 2024-01
• 期刊: Gut microbes
• 影响因子: 12.2

Commensal Cryptosporidium colonization elicits a cDC1-dependent Th1 response that promotes intestinal homeostasis and limits other infections.

• DOI: 10.1016/j.immuni.2021.10.002
• 发表时间: 2021-11-09
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Russler-Germain EV;Jung J;Miller AT;Young S;Yi J;Wehmeier A;Fox LE;Monte KJ;Chai JN;Kulkarni DH;Funkhouser-Jones LJ;Wilke G;Durai V;Zinselmeyer BH;Czepielewski RS;Greco S;Murphy KM;Newberry RD;Sibley LD;Hsieh CS
• 通讯作者: Hsieh CS

Apical Secretory Glycoprotein Complex Contributes to Cell Attachment and Entry by Cryptosporidium parvum.

• DOI: 10.1128/mbio.03064-22
• 发表时间: 2023-02-28
• 期刊: mBio
• 影响因子: 6.4