The role of gut microbiota in human norovirus infections in transplant patients
肠道微生物群在移植患者诺如病毒感染中的作用
基本信息
- 批准号:10524718
- 负责人:
- 金额:$ 18.55万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-06-22 至 2027-05-31
- 项目状态:未结题
- 来源:
- 关键词:AcuteAdherent CultureAdultAntibioticsAntiviral AgentsB-LymphocytesBacteroidesBacteroides fragilisBindingBioinformaticsBlood Group AntigensCD8-Positive T-LymphocytesCellsCessation of lifeChildhoodChronicChronic diarrheaClinicalClinical TrialsComputerized Medical RecordDataDendritic cell activationEnteralEnterobacteriaceaeEtiologyExhibitsFamilyFlow CytometryFoundationsFutureGastroenteritisGoalsGrantHealth systemHematopoietic Stem Cell TransplantationHumanImmune responseImmunocompromised HostImmunologyImmunosuppressionIn VitroIncubatedIndividualInfectionInflammatoryInnate Immune ResponseIntegration Host FactorsInterferon Type IInterferon-alphaInterferonsInterleukin-10Interleukin-4Interleukin-5IntestinesKlebsiellaMalnutritionMediatingMetagenomicsModelingMolecularMusNatural HistoryNorovirusOrganPathogenesisPathogenicityPatientsPhysiciansPlayPolysaccharidesPre-Clinical ModelProbioticsProductionProteinsProteomicsRNAResolutionRoleSample SizeSamplingScientistSerumSeveritiesShotgun SequencingSolidSurfaceT cell responseTNF geneTaxonomyTherapeuticTrainingTransplant RecipientsUnited StatesViralViral PathogenesisVirusVirus ReplicationWasting Syndromeabstractingcohortcostcytokineenteric virus infectionexperimental studyfecal transplantationgut bacteriagut microbiomegut microbiotahuman microbiotainsightmembermicrobiome signaturemicrobiota profilesnext generation sequencingnovelpersistent symptomresponseskillsstool sampletool
项目摘要
PROJECT SUMMARY
Human norovirus (HuNoV) is the leading cause of acute gastroenteritis in the United States, resulting in $4.2
billion in direct health system costs annually. Due to underlying immunosuppression and the lack of effective
antiviral therapeutics, transplant patients may develop serious sequelae from HuNoV infections. Though
bacterial gut microbiota has been shown to enhance replication and pathogenesis of enteric viruses in preclinical
models, its role in HuNoV infection remains largely unknown. In this project, we aim to gain greater mechanistic
insights into how gut microbiota modulate HuNoV infection in transplant patients. Our central hypothesis is that
transplant patients with symptomatic HuNoV infection will have a gut microbiome signature showing an
enrichment of specific gut microbiota (Enterobacteriaceae) that facilitate infection of HIEs, and those who
develop chronic symptoms from HuNoV infection will have a concomitant depletion of specific gut microbiota
that modulate host innate immune responses (type 1 interferons). In Aim 1, we will further define both gut
microbiome and host factor differences in transplant patients ±HuNoV infections. First, we will establish a larger
cohort of adult and pediatric transplant patients and collect longitudinal stool specimens. Then, we will perform
comprehensive gut microbiome profiling (metagenomic shotgun sequencing and bacterial qPCR) to confirm our
preliminary results. We predict that HuNoV-infected transplant patients will have significantly different gut
microbiota signatures compared to uninfected counterparts, and that higher intensity of immunosuppression and
high antibiotic load will correspond with chronic diarrhea in HuNoV-infected transplant patients. In Aim 2, we will
determine if Enterobacteriaceae facilitate HuNoV infection using an in vitro HIE model. First, we will infect jejunal
HIEs with HuNoV and co-incubate HuNoV with various Enterobacteriaceae spp. Then, we will perform RNA
extractions and quantitative HuNoV RT-qPCR to evaluate the effect of co-incubating various Enterobacteriaceae
spp. on viral replication. We predict that Enterobacteriaceae promotes HuNoV infection of HIEs. If this is the
case, we will investigate if this is a phenomenon observed only in HBGA-expressing members of
Enterobacteriaceae. In Aim 3, we will determine if transplant patients with chronic symptomatic HuNoV infections
have different systemic cytokine signatures compared to uninfected counterparts. We will perform bulk cytokine
analysis on serum samples utilizing Isoplexis, a novel functional proteomic profiling platform. We predict that
transplant patients with chronic diarrhea from HuNoV infection will exhibit a paucity of genus Bacteroides,
resulting in depletion of type 1 interferons, which then leads to a decreased Th1 immune response, increased
Th2 immune response and increased expression of Th2-predominant cytokines (IL-4, IL-5, IL-10). The proposed
experiments, training and didactic coursework in this K23 will equip the candidate (Dr. Chong) with unique
skillsets that will enable her transition to independence as a physician scientist in gut microbiota-HuNoV
interactions in transplant patients.
项目概要
人类诺如病毒 (HuNoV) 是美国急性胃肠炎的主要原因,造成 4.2 美元的损失
每年 10 亿美元的直接卫生系统费用。由于潜在的免疫抑制和缺乏有效的
如果接受抗病毒治疗,移植患者可能会因 HuNoV 感染而出现严重的后遗症。尽管
临床前研究表明,细菌肠道微生物群可增强肠道病毒的复制和发病机制
模型中,其在 HuNoV 感染中的作用仍然很大程度上未知。在这个项目中,我们的目标是获得更大的机械性
深入了解肠道微生物群如何调节移植患者的 HuNoV 感染。我们的中心假设是
患有 HuNoV 感染症状的移植患者的肠道微生物组特征显示
促进 HIE 感染的特定肠道微生物群(肠杆菌科)的富集,以及那些
HuNoV 感染出现慢性症状将伴随特定肠道微生物群的耗竭
调节宿主先天免疫反应(1 型干扰素)。在目标 1 中,我们将进一步定义肠道
移植患者的微生物组和宿主因素差异±HuNoV 感染。首先,我们将建立一个更大的
成人和儿童移植患者队列并收集纵向粪便标本。然后,我们将执行
全面的肠道微生物组分析(宏基因组鸟枪法测序和细菌 qPCR)以确认我们的研究
初步结果。我们预测 HuNoV 感染的移植患者的肠道会有显着不同
与未感染的对应物相比,微生物群特征,以及更高强度的免疫抑制和
高抗生素负荷将与 HuNoV 感染的移植患者的慢性腹泻相对应。在目标 2 中,我们将
使用体外 HIE 模型确定肠杆菌科是否促进 HuNoV 感染。首先,我们要感染空肠
HIE 与 HuNoV 以及 HuNoV 与各种肠杆菌科细菌共同培养。然后,我们将进行 RNA
提取和定量 HuNoV RT-qPCR 评估共培养各种肠杆菌科细菌的效果
种。关于病毒复制。我们预测肠杆菌科促进 HIE 的 HuNoV 感染。如果这是
情况下,我们将调查这是否是仅在 HBGA 表达成员中观察到的现象
肠杆菌科。在目标 3 中,我们将确定移植患者是否患有慢性症状性 HuNoV 感染
与未感染的对应物相比,具有不同的全身细胞因子特征。我们将进行批量细胞因子
利用 Isoplexis(一种新型功能蛋白质组分析平台)对血清样品进行分析。我们预测
因 HuNoV 感染而患有慢性腹泻的移植患者将表现出拟杆菌属的缺乏,
导致 1 型干扰素耗竭,进而导致 Th1 免疫反应降低、增加
Th2 免疫反应和 Th2 主要细胞因子(IL-4、IL-5、IL-10)表达增加。拟议的
K23 中的实验、培训和教学课程将为候选人(Chong 博士)提供独特的能力
将使她能够独立成为肠道菌群医学科学家的技能-HuNoV
移植患者之间的相互作用。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Pearlie Pao Ee Chong其他文献
Pearlie Pao Ee Chong的其他文献
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{{ truncateString('Pearlie Pao Ee Chong', 18)}}的其他基金
The role of gut microbiota in human norovirus infections in transplant patients
肠道微生物群在移植患者诺如病毒感染中的作用
- 批准号:
10651889 - 财政年份:2022
- 资助金额:
$ 18.55万 - 项目类别:
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