Mechanisms by which rickettsiae subvert autophagy pathway in macrophages
Mechanisms by which rickettsiae subvert autophagy pathway in macrophages
批准号:
10461972
负责人:
Rong Megan Fang
金额:
$20.0万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-08-04 至 2024-07-31
关键词:
5 year oldAchievementAddressAdultAnimal ModelAnti-Bacterial AgentsAntibioticsAutophagocytosisAutophagolysosomeAutophagosomeBacteriaC3H/HeN MouseCase Fatality RatesCase StudyCell modelCellsCessation of lifeChildCytosolDevelopmentDiseaseDisease ProgressionDoxycyclineEndosomesGoalsGuanosine Triphosphate PhosphohydrolasesHumanImmuneImmunityImmunotherapeutic agentImmunotherapyIn VitroIncidenceInfectionInfection ControlInflammasomeInterferonsInterleukin-1 betaInterruptionKnowledgeLifeLinkMAPK8 geneMediatingMusNutrientPathogenesisPathway interactionsPatientsPersonsPilot ProjectsPregnancyProductionProteinsPublic HealthReportingResearchRickettsiaRickettsia InfectionsRickettsia conoriiRoleTestingTherapeuticTherapeutic InterventionTick-Borne Diseasesbaseeffective therapyexperiencein vivoinhibition of autophagyinhibitorinnovationinsightmacrophagemouse modelnovelnovel therapeutic interventionpathogenrab GTP-Binding Proteinsresponsetick-borne
中文摘要
蜱传立克次体疾病继续在健康成人中造成严重疾病和死亡,
世界各地的儿童。立克次体病的发病率在过去六年中显著上升,
病死率高达10%。立克次体病患者对强力霉素反应良好,
要及早管理。然而,强力霉素不适合怀孕或5岁以下的患者
岁因此,迫切需要基于宿主机制的治疗干预。我们的长期
目的是研究专性胞内细菌立克次体进化以建立
它们在哺乳动物宿主细胞中的感染小生境。这些研究将为新型免疫治疗提供见解
干预措施。本研究的目的是揭示R.南方颠覆
自噬以促进巨噬细胞中的感染。在这个建议中要检验的假设是,R。
australis调节并利用Atg 5依赖的自噬通过抑制成熟来促进感染
自噬体和抵消宿主免疫控制的巨噬细胞。我们将评估
自噬抑制作为一种治疗策略,通过中断
参与R. australis诱导的Atg 5依赖性自噬体。本项目将对此进行研究
利用两个相互关联的特定目标的假设。目的1将确定R. australis
诱导和破坏Atg 5依赖性自噬体,以利于它们在巨噬细胞中的感染。的
将研究ULK 1在调节立克次氏体诱导的自噬体中的作用。我们会研究
MAVS/IRF 7/ISG 54和GTCRab 25参与抵消抗菌活性,
支持巨噬细胞感染。目的2将评估自噬抑制作为治疗的潜力
针对威胁生命立克次体感染的策略。我们将采用立克次体的体内小鼠模型
感染,以研究靶向Atg 5(+)自噬体作为免疫治疗的潜力
通过使用调节自噬体的关键分子的特异性抑制剂或刺激剂进行干预。是
相信完成这项提案的具体目标可能会为免疫学提供新的见解,
用于治疗致命性立克次体病的治疗策略。
英文摘要
Tick-borne rickettsial diseases continue to cause severe illness and death in otherwise healthy adults and
children worldwide. The incidence rate of rickettsial diseases significantly increased in the past six years with
case fatality rate as high as 10%. Patients with rickettsial diseases respond well to doxycycline if the antibiotics
are administered early. However, doxycycline is not appropriate for patients in pregnancy or under age of 5
years old. Therefore, host-mechanisms based therapeutic interventions are urgently needed. Our long term
goal is to study the key host molecules by which obligately intracellular bacteria, rickettsiae, evolve to establish
their infection niche in mammalian host cells. These studies will provide insights into novel immune therapeutic
interventions. The objectives of this proposal are to reveal the mechanisms by which R. australis subvert
autophagy to facilitate infection in macrophages. The hypothesis to be tested in this proposal is that R.
australis modulates and exploits Atg5-dependent autophagy to facilitate infection via inhibiting the maturation
of autophagosomes and counteracting host immune controls in macrophages. We will evaluate the potential of
autophagy inhibition as a therapeutic strategy against life-threatening rickettsial infection by interrupting the
pathways involved in R. australis-induced Atg5-dependent autophagosomes. This project will study this
hypothesis utilizing two linked specific aims. Aim 1 will determine the mechanisms by which R. australis
induces and subverts Atg5-dependent autophagosomes for the benefit of their infection in macrophages. The
role of ULK1 in regulating rickettsiae-induced autophagosomes will be investigated. We will study the
involvement of MAVS/IRF7/ISG54 and GTPase Rab 25 in counteracting the antibacterial activity and
supporting infection in macrophages. Aim 2 will evaluate the potential of autophagy inhibition as a therapeutic
strategy against life-threatening rickettsial infection. We will employ the in vivo mouse model of rickettsial
infection to investigate the potential of targeting Atg5 (+) autophagosomes as immune-therapeutic
interventions by using specific inhibitors or stimulators of key molecules regulating autophagosomes. It is
believed that completion of the specific aims of this proposal may provide novel insights into immuno-
therapeutic strategies for treating fatal rickettsioses.
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科研奖励(0)
会议论文
Rational development of a vaccine against tick-borne rickettsioses
-
批准号:10522492
-
项目类别:
-
资助金额:$81.8万
-
财政年份:2022
-
负责人:Rong Megan Fang
-
依托单位:
Rational development of a vaccine against tick-borne rickettsioses
-
批准号:10673846
-
项目类别:
-
资助金额:$78.34万
-
财政年份:2022
-
负责人:Rong Megan Fang
-
依托单位:
Mechanisms of Cytosolic Clearance of Rickettsiae
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批准号:8829741
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项目类别:
-
资助金额:$19.38万
-
财政年份:2014
-
负责人:Rong Megan Fang
-
依托单位:
Mechanisms of Cytosolic Clearance of Rickettsiae
-
批准号:8638611
-
项目类别:
-
资助金额:$23.22万
-
财政年份:2014
-
负责人:Rong Megan Fang
-
依托单位:
海外基金