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?

嗜血杆菌Ducreyi会导致chancroid，从而促进HIV传播。在实验感染中 在人类中，丘疹在24小时内发展，并分解或进化为脓疱。脓疱包含 由PMN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。Ducreyi是 被吞噬的吞噬细胞包围，不会摄取生物体。虽然在某些主题中形成脓疱 感染的站点在其他受试者中解决。重新感染脓疱形的形成器和解析器时，它们倾向于 隔离他们的最初结果，确认宿主效应。与从 两次形成脓疱的人的血液（PP组）或两次分解（RR组）没有差异 能够摄取H. ducreyi的能力，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，两组之间的病变成绩单有所不同，与之相处 他们的局部免疫反应是不同的。两组的髓样DC都有共同的成绩单响应 对于H. ducreyi，但每个小组都有独特的反应。感染的PP DC上调的转录本 DC成熟的标记和半成熟或调节DC的标记和下调的转录本 已知可以促进直流成熟或抗原加工。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的相互作用，以及 用T细胞感染的DC是有效（RR）或无效（PP）吞噬反应的关键决定因素 病变。来自PP组的DC可能会促进失调的1型和TR响应，导致 抗炎细胞细胞因子环境，而RR组的DC促进了1型反应，导致 亲细胞环境。为了检验这些假设，我们的具体目的包括： RR和PP组第三次感染后48小时收集的病变中的转录本；基因的比较 DC的表达和蛋白质组学特征来自PP和暴露于Live H. ducreyi的RR基团； 测试DC是否用活于H. ducreyi脉冲并与RR组的T细胞共培养导致类型 1个反应，而源自PP组的共培养导致1型和TR响应；检查 H. ducreyi -dc- T细胞相互作用产生的细胞因子是否促进或抑制吞噬作用 吞噬作用调节的生物和机制。我们将确认我们的体外 对重新感染的PP和RR受试者获得的活检的观察结果。 摘要摘要：H。ducreyi是导致生殖溃疡的细菌。当我们感染人类志愿者 有胚芽的手臂，有些人患上疾病，而另一些人则清除了感染。我们试图回答 重要问题：为什么有些感染细菌的人会生病，而另一些人则没有？