Candida Pathogenesis in Surgery and Trauma

念珠菌是院内血流感染的第四大常见原因，在几乎所有研究中，白色念珠菌占念珠菌种类的50%至75%。尽管进行了适当的抗真菌治疗，死亡率仍为35%至75%。风险最高的患者包括免疫抑制患者、创伤患者和术后患者，很大一部分病例发生在重症监护病房。白色念珠菌经历可逆的形态转换，产生芽殖酵母和丝状形式，包括胚管、假菌丝和真菌丝。许多研究者认为丝状细胞是上皮浸润的原因。然而，最近来自小鼠肠外传播模型的数据表明，酵母细胞，而不是丝状形式，可能在白色念珠菌渗透肠上皮中更重要。我们的工作假设是酵母细胞在这种真菌与肠上皮的相互作用（粘附和渗透）中起关键作用。一般的方法是在体外（培养的肠细胞）和体内（小鼠模型）使用野生型和特征良好的白色念珠菌突变株（具有形态转换缺陷）来挑战这一假设。由于最近出现的光丝酵母菌是引起念珠菌病的第二大常见病原菌，而且在已知的80多种念珠菌中，光丝酵母菌是唯一一种不形成细丝且仅以酵母菌形式存在的菌种，因此实验也将重点放在光丝酵母菌上。体外实验旨在分别表征酵母和丝状形式与培养的肠细胞的相互作用（粘附、内化、细胞内存活），检测系统包括ELISA和使用钙粉和重要染料FUN-1的双荧光测定。小鼠模型包括抗生素诱导的肠道念珠菌定植，结扎的肠袢和Stamper-Woodruff试验。细菌细胞壁产物（脂多糖和肽聚糖）、地塞米松和缺氧对念珠菌肠外传播的影响也得到了澄清。如果我们的假设被证实（酵母细胞在肠外传播中起主要作用），那么设计更有效的体外敏感性试验以及更有效的预防和治疗方式的努力，可能更可靠地针对酵母而不是菌丝成分。这些知识应该能加快我们诊断、治疗和控制全身性念珠菌病的能力。

Candida species are the fourth most common cause of nosocomial blood stream infections, and C. albicans accounts for 50% to 75% of Candida species in essentially all studies. Despite appropriate antifungal therapy, mortality is 35% to 75%. Patients at highest risk include immunosuppressed patients, trauma patients, and postsurgical patients, and a large proportion of cases occur in intensive care units. C. albicans undergoes reversible morphologic switching, producing budding yeast and filamentous forms that include germ tubes, pseudohyphae and true hyphae. Many investigators have assumed that filamentous forms are responsible for epithelial invasion. However, recent data from mouse models of extraintestinal dissemination indicate that the yeast cell, rather than filamentous forms, might be more important in C. albicans penetration of intestinal epithelium. Our working hypothesis is that yeast cells play a key role in interactions (adherence and penetration) of this fungus with the intestinal epithelium. The general approach is to use wild type and well-characterized C. albicans mutant strains (with defects in morphologic switching) to challenge this hypothesis in vitro (cultured enterocytes) and in vivo (mouse models). Because C. glabrata has recently emerged as the second most frequent cause of candidiasis, and because C. glabrata is the only species (of the more than 80 recognized Candida species) that does not form filaments and exists only in the yeast form, experiments also focus on C. glabrata. In vitro experiments are designed to separately characterize the interactions (adherence, internalization, intracellular survival) of yeast and filamentous forms with cultured enterocytes, and assay systems include ELISA and a double fluorochrome assay using calcoflour and the vital dye FUN-1. Mouse models include antibiotic-induced intestinal Candida colonization, ligated intestinal loops, and the Stamper-Woodruff assay. The effect of bacterial cell wall products (lipopolysaccharide and peptidoglycan), dexamethasone, and hypoxia on extraintestinal dissemination of Candida is also clarified. If our hypothesis is validated (that the yeast cell is of primary importance in extraintestinal dissemination), then efforts to design more effective in vitro susceptibility assays, as well as more effective prophylactic and therapeutic modalities, might more reliably target yeast rather than hyphal elements. Such knowledge should accelerate our ability to diagnose, treat, and control systemic candidiasis.