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: 7195302
• 负责人: Stanley M. Spinola
• 金额: $ 38.74万
• 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 2011-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7195302
• 关键词: Abscess; All Sites; Biology; Biopsy; Blood; CD 200; CD44 gene; CD58 gene; CD80 gene; CSF2 gene; Cell Communication; Cell Maturation; Cells; Clinical; Coculture Techniques; Dendritic Cells; Disease; End Point; Environment; Event; Failure; Gender; Gene Expression; Genital system; Germ; Goals; Granulocyte-Macrophage Colony-Stimulating Factor; 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-10; Interleukin-16; Interleukin-18; Interleukin-7; Lead; Lesion; Life; Modeling; Myelogenous; Organism; Outcome; Phagocytes; Phagocytosis; Phenotype; Physiologic pulse; Predisposition; Proliferating; Proteomics; Pulse taking; Puncture wound; Rate; Research Personnel; Serum; Simulate; Site; Skin; Staging; T-Lymphocyte; TLR1 gene; TNFRSF5 gene; Testing; Time; Tissue Microarray; Tissues; Transcript; Transudate; Ulcer; Upper arm; Week; Woman; acquired immunity; antigen processing; bactericide; comparison group; cytokine; day; falls; immune function; in vitro Model; in vivo; interleukin-23; killings; macrophage; men; neutrophil; notch protein; pathogen; programs; response; size; transmission process

DESCRIPTION (provided by applicant): 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, confirming 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?

描述（由申请人提供）：杜克雷嗜血杆菌引起软下疳，促进HIV传播。在人类的实验感染模型中，丘疹在24小时内发展并消退或演变成脓疱。脓疱包含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。ducreyi被不摄取生物体的吞噬细胞包围。虽然在一些受试者中形成脓疱，但在其他受试者中所有感染部位均消退。当脓疱形成者和消退者再次感染时，它们倾向于向其初始结果分离，从而证实了宿主效应。从形成脓疱两次（PP组）或消退两次（RR组）的患者血液中分离的PMN和巨噬细胞摄取H的能力没有差异。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，各组之间的病变转录本不同，证实了它们的局部免疫反应不同。两组的髓样DC对H. ducreyi，但每个组都有独特的反应。感染的PP DC上调DC成熟标记物和半成熟或调节DC标记物的转录物，并且下调已知促进DC成熟或抗原加工的转录物。感染的RR DC仅上调DC成熟的转录本。我们的总体假设是H. ducreyi与DC的相互作用以及感染的DC与T细胞的相互作用是病变中有效（RR）或无效（PP）吞噬反应的关键决定因素。来自PP组的DC可能促进导致抗吞噬细胞因子环境的失调的1型和Tr应答，而来自RR组的DC促进导致促吞噬细胞环境的1型应答。为了验证这些假设，我们的具体目标包括：比较RR和PP组第三次感染后48小时收集的病变中的转录本;比较暴露于活H. ducreyi;测试DC是否与活H. ducreyi和与来自RR组的T细胞共培养导致1型应答，而来自PP组的共培养导致1型和Tr应答; ducreyi-DC- T细胞相互作用促进或抑制生物体的吞噬作用和调节吞噬作用的潜在机制。我们将通过对再次感染的PP和RR受试者的活检进行观察，确认我们的体外结果。 总结：H。ducreyi是一种导致生殖器溃疡的细菌。当我们用细菌感染人类志愿者的手臂时，有些人会患病，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，而另一些人则不会？