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
基本信息
- 批准号:9927337
- 负责人:
- 金额:$ 68.39万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 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:
- 关键词:2 year oldAIDS/HIV problemAcquired Immunodeficiency SyndromeAdenocarcinoma CellAdultAgricultureAnimal ModelAnimalsAntibiotic TherapyAntibioticsAntibodiesAntiviral AgentsCellsChildChronicChronic diarrheaCommunitiesComplexComplicationCryptosporidiosisCryptosporidiumCryptosporidium parvumEffectivenessEnteralFDA approvedFecesFoodGene ExpressionGrowthHIVHIV diagnosisHighly Active Antiretroviral TherapyHost DefenseHumanImmunocompromised HostImpairmentIn VitroIndividualIndolesInfectionInfection ControlLibrariesLifeLife Cycle StagesLiquid substanceMediatingMethodsMusNatural ImmunityNeonatalNewborn AnimalsNewborn InfantNuclearParasitesPathway interactionsPatientsPatternPharmaceutical PreparationsPharmacotherapyPredispositionProductionPropertyReceptor SignalingResistanceResistance developmentResistance to infectionRoleSeveritiesSignal PathwaySignal TransductionSolidStaphylococcus hominisTestingTimeToxic effectZoonosesanalogantimicrobialbile saltscolonization resistancedesigndiarrheal diseaseeffective therapyenteric pathogenhydroxyindoleimmune functionimprovedin vivoin vivo Modelinhibitor/antagonistinnate immune pathwaysjuvenile animalmature animalmicrobialmicrobial communitymicrobiomemicrobiotamouse modelnitazoxanidenovel therapeutic interventionpathogenpatient populationpharmacokinetics and pharmacodynamicsreceptorsmall moleculetranscriptomewasting
项目摘要
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。
项目成果
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L. David Sibley其他文献
ワークショップ 本邦におけるトキソプラズマ分離株の分子タイピング
日本弓形虫分离株的分子分型研讨会
- DOI:
- 发表时间:
2013 - 期刊:
- 影响因子:0
- 作者:
永宗喜三郎;喜屋武向子;山本徳栄;山野安規徳;Asis Khan;L. David Sibley - 通讯作者:
L. David Sibley
Protozoan persister-like cells and drug treatment failure
原生动物类持久性细胞与药物治疗失败
- DOI:
10.1038/s41579-019-0238-x - 发表时间:
2019-08-23 - 期刊:
- 影响因子:103.300
- 作者:
Michael P. Barrett;Dennis E. Kyle;L. David Sibley;Joshua B. Radke;Rick L. Tarleton - 通讯作者:
Rick L. Tarleton
A combination of four emToxoplasma gondii/em nuclear-targeted effectors protects against interferon gamma-driven human host cell death
四种针对弓形虫核的效应蛋白的组合可防止干扰素γ驱动的人类宿主细胞死亡
- DOI:
10.1128/mbio.02124-24 - 发表时间:
2024-08-30 - 期刊:
- 影响因子:4.700
- 作者:
Brittany Henry;Aubrey J. Phillips;L. David Sibley;Alex Rosenberg - 通讯作者:
Alex Rosenberg
Cerebral Malaria Is Regulated by Host-Mediated Changes in emPlasmodium/em Gene Expression
脑型疟疾受宿主介导的疟原虫基因表达变化调节
- DOI:
10.1128/mbio.03391-22 - 发表时间:
2023-04-10 - 期刊:
- 影响因子:4.700
- 作者:
Clare K. Cimperman;Mirna Pena;Sohret M. Gokcek;Brandon P. Theall;Meha V. Patel;Anisha Sharma;ChenFeng Qi;Daniel Sturdevant;Louis H. Miller;Patrick L. Collins;Susan K. Pierce;Munir Akkaya;L. David Sibley - 通讯作者:
L. David Sibley
No more free lunch
天下没有免费的午餐
- DOI:
10.1038/415843a - 发表时间:
2002-02-21 - 期刊:
- 影响因子:48.500
- 作者:
L. David Sibley - 通讯作者:
L. David Sibley
L. David Sibley的其他文献
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{{ truncateString('L. David Sibley', 18)}}的其他基金
Regulation of host cell egress by Toxoplasma gondii
弓形虫对宿主细胞出口的调节
- 批准号:
10640220 - 财政年份:2022
- 资助金额:
$ 68.39万 - 项目类别:
Regulation of host cell egress by Toxoplasma gondii
弓形虫对宿主细胞出口的调节
- 批准号:
10441782 - 财政年份:2022
- 资助金额:
$ 68.39万 - 项目类别:
Interferon-mediated control mechanisms in human cells
人类细胞中干扰素介导的控制机制
- 批准号:
10041166 - 财政年份:2020
- 资助金额:
$ 68.39万 - 项目类别:
Interferon-mediated control mechanisms in human cells
人类细胞中干扰素介导的控制机制
- 批准号:
10194376 - 财政年份:2020
- 资助金额:
$ 68.39万 - 项目类别:
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:
10303025 - 财政年份:2019
- 资助金额:
$ 68.39万 - 项目类别:
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 - 财政年份:2019
- 资助金额:
$ 68.39万 - 项目类别:
INHIBITION OF STAT TRANSCRIPTION BY TOXOPLASMA
弓形虫对 STAT 转录的抑制
- 批准号:
9244190 - 财政年份:2016
- 资助金额:
$ 68.39万 - 项目类别: