Human Immune Response to Haemophilus Ducreyi Infection

人类对杜克雷嗜血杆菌感染的免疫反应

• 批准号: 8009845
• 负责人: Stanley M. Spinola
• 金额: $ 35.55万
• 依托单位: INDIANA UNIV-PURDUE UNIV AT INDIANAPOLIS
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-01-01 至 2013-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8009845
• 关键词: Abscess; Biology; Biopsy; Blood; CD 200; CD44 gene; CD58 gene; CD80 gene; Cell Communication; Cell Maturation; Cells; Clinical; Coculture Techniques; Dendritic Cells; Disease; Environment; Event; Failure; Gender; Gene Expression; Genital system; Germ; Goals; Granuloma; HIV; HIV-1; Hemophilus ducreyi; Histopathology; Homologous Gene; Human; Human Genome; Human Volunteers; IRF1 gene; Immune; Immune response; Immunologics; In Vitro; Infection; Intercellular adhesion molecule 1; Interleukin-1; Interleukin-10; Interleukin-16; Interleukin-18; Interleukin-7; Lead; Lesion; Life; Modeling; Myelogenous; Organism; Outcome; Phagocytes; Phagocytosis; Phenotype; Physiologic pulse; Predisposition; Proliferating; Proteomics; Puncture wound; Research Personnel; Serum; Simulate; Site; Skin; Staging; T-Lymphocyte; TLR1 gene; TNFRSF5 gene; Testing; Time; Tissue Microarray; Tissues; Transcript; Transudate; Ulcer; Upper arm; Woman; acquired immunity; antigen processing; arm; bactericide; cytokine; immune function; in vitro Model; in vivo; interleukin-23; killings; macrophage; men; neutrophil; notch protein; pathogen; programs; response; transmission process

Haemophilus ducreyi causes chancroid, which facilitates HIV transmission. In an experimental infection model in humans, papules develop within 24 h and either resolve or evolve into pustules. Pustules contain an abscess composed of PMNs and macrophages, while T cells, myeloid dendritic cells (DC) and macrophages form a loose granuloma below the abscess. In the failed pustular state, H. ducreyi is surrounded by phagocytes that do not ingest the organism. Although pustules form in some subjects, all infected sites resolve in other subjects. When pustule formers and resolvers are re-infected, they tend to segregate towards their initial outcome, confirming a host effect. PMNs and macrophages isolated from the blood of those who formed pustules twice (PP group) or resolved twice (RR group) did not differ in their ability to ingest H. ducreyi, suggesting that the environment at the site of infection modulates phagocytosis. In PP and RR subjects infected a third time, lesional transcripts differed between the groups, confriming that their local immune responses are different. Myeloid DC from both groups had a common transcript response to H. ducreyi, but each group had unique responses. Infected PP DC upregulated transcripts that were markers of DC maturation and markers of semi-mature or regulatory DC and downregulated transcripts known to promote DC maturation or antigen processing. Infected RR DC only upregulated transcripts of DC maturation. Our overall hypothesis is that the interaction of H. ducreyi with DC, and the interaction of infected DC with T cells are key determinants of effective (RR) or ineffective (PP) phagocytic responses in lesions. DC from the PP group likely promote a dysregulated Type 1 and Tr response that leads to an antiphagocytic cytokine environment, while DC from the RR group promote a Type 1 response that leads to a pro-phagocytic environment. To test these hypotheses, our specific aims include: comparison of transcripts in lesions collected 48 h after a third infection of the RR and PP groups; comparison of the gene expression and proteomic profiles of DC derived from the PP and the RR groups exposed to live H. ducreyi; testing whether DC pulsed with live H. ducreyi and co-cultured with T cells from the RR group result in Type 1 responses while co-cultures derived from the PP group lead to Type 1 and Tr responses; examination of whether the cytokines generated by H. ducreyi - DC - T cell interaction promotes or inhibits phagocytosis of the organism and of the mechanisms underlying the modulation of phagocytosis. We will confirm our in vitro results with observations made on biopsies obtained from PP and RR subjects who are re-infected. Lay summary: H. ducreyi is a germ that causes genital ulcers. When we infect human volunteers on the arm with the germ, some people develop disease while others clear the infection. We seek to answer an important question: Why do some people who become infected with a germ get sick, while others do not?

杜克雷嗜血杆菌引起软下疳，这有助于艾滋病毒的传播。在一次实验性感染中 在人类模型中，丘疹在24小时内发展，并且消退或演变成脓疱。脓疱含有 由中性粒细胞和巨噬细胞组成的脓肿，而T细胞、髓样树突状细胞（DC）和 巨噬细胞在脓肿下方形成松散的肉芽肿。在失败的脓疱状态下，H。杜克雷伊群岛 被吞噬细胞包围，而这些吞噬细胞并不吞噬生物体。虽然脓疱形成在一些科目，所有 感染部位在其他受试者中消退。当脓疱形成者和消退者再次感染时， 分离到最初的结果，证实了宿主效应。分离的PMN和巨噬细胞 两次形成脓疱（PP组）或两次消退（RR组）的患者的血液中， 能消化H。ducreyi，表明感染部位的环境调节吞噬作用。 在第三次感染的PP和RR受试者中，两组之间的病变转录本不同，这证实了 它们的局部免疫反应是不同的。两组的骨髓DC具有共同的转录反应 到H. ducreyi，但每个组都有独特的反应。感染的PP DC上调转录本， DC成熟的标志物和半成熟或调节性DC的标志物以及下调的转录物 已知促进DC成熟或抗原加工。感染的RR DC仅上调DC的转录本 成熟我们的总体假设是H. ducreyi与DC，以及 用T细胞感染的DC是有效（RR）或无效（PP）吞噬应答的关键决定因素， 病变来自PP组的DC可能促进失调的1型和Tr反应，导致 抗吞噬细胞因子环境，而RR组的DC促进1型反应，导致 一个有利于吞噬的环境为了验证这些假设，我们的具体目标包括： RR组和PP组第三次感染后48小时收集的病变中的转录物; 来自暴露于活H的PP和RR组的DC的表达和蛋白质组学谱。ducreyi; 测试直流是否有带电H脉冲。ducreyi并与来自RR组的T细胞共培养导致 1反应，而来自PP组的共培养物导致1型和Tr反应; H. ducreyi-DC- T细胞相互作用促进或抑制 生物体和调节吞噬作用的机制。我们将确认我们的体外 结果与对从再次感染的PP和RR受试者获得的活组织检查进行的观察。 总结：H。ducreyi是一种导致生殖器溃疡的细菌。当我们感染志愿者时， 由于细菌的存在，有些人会发病，而另一些人则会清除感染。我们试图回答一个 重要的问题：为什么有些人感染了细菌会生病，而另一些人不会？