Pathogenesis of Haemophilus ducreyi Infections

超出规定的空间。杜氏嗜血杆菌引起软下疳，这是一种生殖器溃疡疾病，有利于艾滋病毒的传播。由于缺乏自然感染患者的标本，我们开发了人类受试者皮肤感染的实验模型，其临床过程和组织病理学都与自然疾病相似。在整个实验感染过程中，杜氏念珠菌与表皮和真皮上部的pmn和巨噬细胞以及真皮中的胶原蛋白和纤维蛋白共定位。尽管它与吞噬细胞有关，但在实验感染期间，杜氏分枝杆菌仍主要是细胞外的。这些发现与自然感染的相关性尚不清楚。我们在模型中测试了10对等基因突变/亲本对。许多这些突变体被评估，因为体外研究表明，感兴趣的基因编码一个毒力决定因素。然而，只有3个突变体的脓疱形成能力受损。因此，在体外具有功能的基因通常不会在体内形成脓疱。鉴定细菌基因在体内的排他性或差异性诱导导致了许多关于宿主-病原体相互作用的基本观察。我们最近放大了//。实验性病变活检的杜克雷伊转录本。随着H. ducreyi基因组序列的完成，我们希望解决在人类感染过程中细菌基因表达的假设，其中细菌暴露于相关组织（人体皮肤）和相关宿主反应。我们的第一个假设是，在疾病的溃疡期，H. ducreyi继续与pmn、巨噬细胞、胶原和纤维蛋白共定位，并在感染期间主要保持细胞外。我们的第二个假设是，特定的毒力决定因素在感染过程中被dureyi H.差异上调，并且这些上调基因中的等基因突变将在模型中减弱。为了验证这些假设，我们的目标包括：在自然发生的病变中定位细菌；细菌转录物在体内差异上调的捕获；选择差异上调基因的等基因突变体的构建模型中突变体的评估。网站性能 ======================================== 节结束 ===========================================

EXCEED THE SPACEPROVIDED. Haemophilus ducreyi causes chancroid, a genital ulcer disease that facilitates HIV transmission. Lacking specimens from naturally infected patients, we developed an experimental model of infection of the skin in human subjects, which resembles natural disease in both its clinical course and histopathology. Throughout the course of experimental infection, the H. ducreyi colocalizes with PMNs and macrophages in the epidermis and upper dermis, and with collagen and fibrin in the dermis. Despite its association with phagocytic cells, H. ducreyi remains predominantly extracellular during experimental infection. The relevance of these findings to natural infection is unknown. We have tested 10 isogenic mutant/parent pairs in the model. Many of these mutants were evaluated because in vitro studies suggested that the gene of interest encoded a virulence determinant. However, only 3 of the mutants were impaired in their ability to progress to pustule formation. Thus, genes that have functions in vitro frequently do not contribute to pustule formation in vivo. Identification of bacterial genes that are exclusively or differentially induced in vivo has led to many fundamental observations about host-pathogen interactions. We recently amplified //. ducreyi transcripts from biopsies of experimental lesions. With the completion of the H. ducreyi genome sequence, we wish to address hypotheses about expression of bacterial genes during human infection, where the bacteria are exposed to a relevant tissue (human skin) and a relevant host response. Our first hypothesis is that H. ducreyi continues to colocalize with PMNs, macrophages and collagen and fibrin during the ulcerative stage of disease and remains primarily extracellular throughout infection. Our second hypothesis is that specific virulence determinants are differentially upregulated by H. ducreyi during infection, and that isogenic mutants in these upregulated genes will be attenuated in the model. To test these hypotheses our aims include: localization of the bacteria in naturally occurring lesions; capture of bacterial transcripts differentially upregulated in vivo; construction of isogenic mutants in selected differentially upregulated genes; evaluation of the mutants in the model. PERFORMANCE SITE ========================================Section End===========================================