Immunoregulation /immune Recognition In Filarial/Nonfilarial Parasitic Infection
丝虫/非丝虫寄生虫感染中的免疫调节/免疫识别
基本信息
- 批准号:7592120
- 负责人:
- 金额:$ 181.76万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:
- 资助国家:美国
- 起止时间:至
- 项目状态:未结题
- 来源:
- 关键词:AddressAntigen-Presenting CellsAntigensBloodCD8B1 geneCISH geneCell CommunicationCell physiologyChronicClinicalClinical TrialsDataDendritic CellsDiseaseDown-RegulationFilarial ElephantiasesFunctional disorderGene ExpressionGeneticGenus MycobacteriumGlobal ChangeGoalsHIVHelminthsHumanImmuneImmune responseImmunityImmunologicsIndigenousInduction of ApoptosisInfectionLegal patentLifeLigaseLoa loaLoiasisLymphangiogenesisLymphaticLymphatic Endothelial CellsMansonellaMolecular ProfilingNatural ImmunityNatural Killer CellsOnchocerciasisOutcomeParasite ControlParasitesParasitic infectionPathologyPathway interactionsPatientsPredispositionProteinsRegulationReverse Transcriptase Polymerase Chain ReactionRoleRole playing therapySignal PathwayT-Cell ActivationT-LymphocyteTNFSF10 geneTimeTubeVascular Endothelial CellWorkairborne allergencaspase-3immunoregulationin vitro Modelpreventresponse
项目摘要
The mechanisms underlying the profound modulation of parasite antigen-specific human T cell responses in lymphatic filariasis have been addressed by demonstrating the multiple pathways involved. By using live parasites and parasite antigen, we have demonstrated that antigen presenting cell (APC) function is profoundly altered in filarial infection both at the transcriptional and protein level. Moreover, this APC dysfunction extends to TLR-3 and -4 signaling pathways.
Beyond the APC dysfunction, T cells from patients with patent infection have induced pathways (SOCS genes, ubiquin ligases, regulatory networks) that in concert prevent Th1-type T cell activation. Moreover, the induction of apoptosis appears to be a common mechanism by which live filarial parasites influence the host response (in dendritic cells and NK cells at least) and does so in a TRAIL- and caspase 3-dependent fashion.
Because downregulatory mechanims are induced in chronic helminth infection, we have attempted to study the spillover effect of the this downregulation on responses and diseases that are non-parasitic. To this end, we have both clinical trials underway and in vitro models that have demonstrated the influence of pre-existing chronic helminth infection on susceptibility to mycobacteria, on modulating the response to aeroallergens, and potentially to HIV.
Because much of the pathology associated with filarial infections is related to lymphatic dysfunction, we have established a human in vitro model to examine parasite/lymphatic cell interaction. By purifying lymphatic endothelial cells (LEC) from blood vascular endothelial cells (BEC), we have been able to demonstrate the presence of filarial parasite molecules that induce lymphangiogenesis and abnormal vasculuar tube formation. In addition, the global changes in gene expression induced by filarial parasites in LEC have been characterized.
Filarial-induced CD4+ and CD8+ responses have been characterized fully (using microarray/quantitative RT-PCR) in both the generally more-responsive expatriate patients and the less responsive indigenous (with lifelong exposure) filarial-infected patients. These data provide clues to the pathways induced by infection and those systemic alterations seen in chronic helminth infection. Using a very similar approach, we have also been able to demonstrate expression signatures among patients infected with closely-related by phylogenetically distinct parasites (e.g., Loa loa and Mansonella perstans).
淋巴丝虫病中寄生虫抗原特异性人类T细胞应答的深刻调节的机制已经通过证明涉及的多个途径来解决。 通过使用活的寄生虫和寄生虫抗原,我们已经证明,抗原呈递细胞(APC)的功能深刻改变丝虫感染在转录和蛋白质水平。此外,这种APC功能障碍延伸到TLR-3和TLR-4信号通路。
除了APC功能障碍之外,患者感染的T细胞具有诱导的途径(SOCS基因,泛素连接酶,调节网络),这些途径共同阻止Th 1型T细胞活化。此外,细胞凋亡的诱导似乎是一种常见的机制,通过这种机制,活的丝虫寄生虫影响宿主反应(至少在树突状细胞和NK细胞中),并以TRAIL和半胱天冬酶3依赖的方式进行。
由于下调机制在慢性蠕虫感染中被诱导,我们试图研究这种下调对非寄生虫性反应和疾病的溢出效应。为此,我们正在进行临床试验和体外模型,证明了预先存在的慢性蠕虫感染对分枝杆菌易感性的影响,对调节对空气过敏原的反应,并可能对HIV产生影响。
由于许多与丝虫感染相关的病理学与淋巴功能障碍有关,我们建立了一个人体体外模型来研究寄生虫/淋巴细胞的相互作用。通过从血管内皮细胞(BEC)中纯化淋巴管内皮细胞(LEC),我们已经能够证明存在诱导淋巴管生成和异常脉管形成的丝虫寄生虫分子。此外,在LEC丝虫寄生虫诱导的基因表达的全球变化的特点。
丝虫诱导的CD 4+和CD 8+反应已被充分表征(使用微阵列/定量RT-PCR),在一般更敏感的外籍患者和反应较低的土著(终身暴露)丝虫感染患者。 这些数据为感染诱导的途径和慢性蠕虫感染中观察到的系统性改变提供了线索。 使用非常类似的方法,我们也能够证明感染了与遗传学上不同的寄生虫密切相关的患者中的表达特征(例如,Loa loa和Mansonella perstans)。
项目成果
期刊论文数量(0)
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Thomas B. Nutman其他文献
Strongyloidiasis as a Cause of Chronic Diarrhea, Identified Using Next-Generation Strongyloides stercoralis-Specific Immunoassays
- DOI:
10.1007/s40475-014-0026-7 - 发表时间:
2014-07-06 - 期刊:
- 影响因子:2.100
- 作者:
Alisa Thamwiwat;Rojelio Mejia;Thomas B. Nutman;Jeffrey T. Bates - 通讯作者:
Jeffrey T. Bates
NOD1 signaling regulates early tissue inflammation during helminth infection
NOD1 信号通路调节蠕虫感染期间的早期组织炎症
- DOI:
10.1016/j.mucimm.2024.12.004 - 发表时间:
2025-04-01 - 期刊:
- 影响因子:7.600
- 作者:
Camila de Almeida Lopes;Thais Leal-Silva;Flaviane Vieira-Santos;Jorge Lucas Nascimento Souza;Chiara Cassia Amorim Oliveira;Fabricio Marcus Silva Oliveira;Lucas Kraemer;Luisa Magalhaes;Pablo Bara-Garcia;Byunghyun Kang;Dario Zamboni;Remo Castro Russo;Ricardo Toshio Fujiwara;Thomas B. Nutman;Pedro Gazzinelli-Guimaraes;Lilian Lacerda Bueno - 通讯作者:
Lilian Lacerda Bueno
Two Patients With Angioedema and Persistent Lower Extremity Swelling
两名患有血管性水肿且下肢持续肿胀的患者
- DOI:
10.1016/j.jaip.2024.11.026 - 发表时间:
2025-02-01 - 期刊:
- 影响因子:6.600
- 作者:
Harris Richard Droghini;Thomas B. Nutman - 通讯作者:
Thomas B. Nutman
Correction to: No evidence of lymphatic filariasis transmission in Bamako urban setting after three mass drug administration rounds
- DOI:
10.1007/s00436-022-07718-x - 发表时间:
2022-11-10 - 期刊:
- 影响因子:2.000
- 作者:
Yaya Ibrahim Coulibaly;Moussa Sangare;Housseini Dolo;Lamine Soumaoro;Siaka Yamoussa Coulibaly;Ilo Dicko;Abdoul Fatao Diabaté;Lamine Diarra;Michel Emmanuel Coulibaly;Salif Seriba Doumbia;Abdallah Amadou Diallo;Massitan Dembele;Benjamin G. Koudou;Moses John Bockarie;Louise A. Kelly‑Hope;Amy D. Klion;Thomas B. Nutman - 通讯作者:
Thomas B. Nutman
Thomas B. Nutman的其他文献
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{{ truncateString('Thomas B. Nutman', 18)}}的其他基金
Immunoregulation /immune Recognition In Filarial/Nonfilarial Parasitic Infection
丝虫/非丝虫寄生虫感染中的免疫调节/免疫识别
- 批准号:
7732425 - 财政年份:
- 资助金额:
$ 181.76万 - 项目类别:
IMMUNOREGULATION /IMMUNE RECOGNITION IN FILARIAL/NONFILARIAL PARASITIC INFECTIONN
丝虫/非丝虫寄生虫感染的免疫调节/免疫识别
- 批准号:
6098886 - 财政年份:
- 资助金额:
$ 181.76万 - 项目类别:
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