Chronic infection and inflammation at mucosal surfaces

一层薄薄的粘液将呼吸道、消化和泌尿生殖道的管腔表面与外界隔开，使这些身体表面最容易感染和发炎。我的实验室以大鼠前列腺为模型系统，研究了细菌毒力因子在帮助细菌通过在这些表面形成生物膜来确定慢性感染方面的作用。细菌毒力因子是细菌用来攻击宿主的武器。生物膜是一种细菌，作为相互作用的菌落生长在附着在组织或植入的医疗设备上的粘液层中，这些粘液层不太容易受到宿主免疫系统和抗生素治疗的影响，从而使它们能够持续存在。我们开发了新的技术来检测生物被膜的抗菌药敏感性，这导致了一个解释生物被膜耐药性的多因素模型。在未来，我们将继续研究粘膜表面的感染和炎症以及生物被膜的抗菌素耐药机制。首先，我们将扩大使用前列腺作为更一般的粘膜炎症模型来研究囊性纤维化(CF)中的假单胞菌生物被膜感染。由于正常肺很容易清除假单胞菌感染，我们将使用前列腺，一个更容易形成生物膜的粘膜表面，作为CF肺这些感染的模型。我们还将把模型移植到小鼠身上，小鼠已经成为研究免疫反应的主要模型。这将使我们能够更好地确定宿主的免疫系统在生物膜形成引发的炎症性疾病过程中的作用。其次，我们将继续研究细菌在生物膜中的适应情况，通过表征生物膜在挑战下产生的蛋白质来降低细菌对抗生素的敏感性，以确定启动以阻止抗生素消除的机制。此外，我们还将探讨酶在限制抗菌素压力下生物膜稳定性方面所起的作用，以限制活性氧物种的损伤。我们预计，这些研究将使我们能够更好地了解和长期控制慢性粘膜感染。

A thin layer of mucous separates the luminal surface of the respiratory, digestive, and urogenital tracts from the outside world, making these surfaces of the body the most prone to infection and inflammation. My laboratory, using the rat prostate as a model system, has studied the role of bacterial virulence factors, which are weapons used by bacteria to attack the host, in helping bacteria to establishing chronic infections by forming biofilms at these surfaces. Biofilms are bacteria growing as interactive colonies within a slime layer attached to tissues or implanted medical devices that are less susceptible to the host immune system and to antibiotic treatment, thus allowing them to persist. We have developed new technologies for assaying antimicrobial susceptibility of biofilms, which has resulted in a multifactorial model to explain the resistance of biofilms. In future, we will continue to study infection and inflammation at mucosal surfaces and mechanisms of antimicrobial resistance of biofilms. First we will expand the use of the prostate as a more general model of mucosal inflammation to study Pseudomonas biofilm infections as seen in cystic fibrosis (CF). Since the normal lung clears Pseudomonas infections readily we will use the prostate, a mucosal surface more susceptible to biofilm formation, as a model of these infections of the CF lung. We will also move the model into the mouse, which has become the prime model to study the immune response. This will allow us to better ascertain the contribution of the host's immune system to the inflammatory disease process initiated by biofilm formation. Secondly, we will continue our study of the adaptations of bacteria in biofilms that result in their reduced antimicrobial susceptibility by characterizing the proteins made by biofilms under challenge in order to define the mechanisms initiated to stave off elimination by antibiotics. Further we will look at the role of enzymes involved in limiting damage from reactive oxygen species in contributing to the stability of biofilms under antimicrobial stress. We anticipate that these studies will allow us to better understand and in the long term control chronic mucosal infections.