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）：嗜血杆菌Ducreyi会导致冠状动脉，从而促进HIV传播。在人类的实验感染模型中，丘疹在24小时内发展，并消除或进化为脓疱。脓疱含有由PMN和巨噬细胞组成的脓肿，而T细胞，髓样树突状细胞（DC）和巨噬细胞在脓肿以下形成松散的肉芽肿。在失败的脓疱状态下，杜克里氏菌被吞噬细胞包围，这些吞噬细胞不会摄入生物体。尽管在某些受试者中形成了脓疱，但所有受试者的感染部位都在其他受试者中解析。当重新感染脓疱的形成器和解析器时，它们倾向于将其初始结果隔离，从而确认宿主效应。从两次形成脓疱的人的血液中分离出来的PMN和巨噬细胞两次或两次分析（RR组）在摄取H. ducreyi的能力上没有差异，这表明感染部位的环境调节了吞噬作用。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，证实其局部免疫反应不同。来自两组的髓样DC对H. ducreyi都有共同的转录本响应，但每个组都有独特的响应。被感染的PP DC上调的转录本是DC成熟的标记和半成熟或调节性DC的标志物以及已知的促进直流成熟或抗原加工的下调转录本已知。感染的RR直流仅上调直流成熟的转录本。我们的总体假设是，H. diucreyi与DC的相互作用以及感染DC与T细胞的相互作用是病变中有效的（RR）或无效（PP）吞噬响应的关键决定因素。来自PP组的DC可能会促进1型和TR反应失调，导致抗癌细胞细胞因子环境，而RR组的DC促进了导致促孢细胞环境的1型响应。为了检验这些假设，我们的具体目的包括：第三次感染RR和PP组后48小时收集的病变中转录本的比较； DC的基因表达和蛋白质组学特征的比较，来自PP的DC和暴露于Live H. ducreyi的RR组；测试DC与活螺旋杆菌脉冲并与RR组的T细胞共培养的DC是否会导致1型响应，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生物体的吞噬作用以及调节吞噬作用调节的机制。我们将通过对重新感染的PP和RR受试者获得的活检的观察结果来确认我们的体外结果。 摘要摘要：H。ducreyi是导致生殖溃疡的细菌。当我们用细菌感染手臂上的人类志愿者时，有些人会出现疾病，而另一些人则清除了感染。我们试图回答一个重要的问题：为什么有些感染细菌的人会生病，而另一些人则没有呢？