Chronic infection and inflammation at mucosal surfaces

一层薄薄的粘液将呼吸道、消化道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受到感染和炎症。我的实验室，用大鼠前列腺作为模型系统，研究了细菌毒力因子的作用，这是细菌用来攻击宿主的武器，通过在这些表面形成生物膜来帮助细菌建立慢性感染。生物膜是附着在组织或植入的医疗设备上的黏液层中以相互作用菌落的形式生长的细菌，这些黏液层对宿主免疫系统和抗生素治疗不太敏感，从而使它们能够持续存在。我们已经开发了新的技术来测定生物膜的抗菌素敏感性，这导致了一个多因素模型来解释生物膜的耐药性。未来，我们将继续研究粘膜表面的感染和炎症以及生物膜的耐药机制。首先，我们将扩大前列腺作为粘膜炎症的更一般模型的使用，以研究囊性纤维化（CF）中所见的假单胞菌生物膜感染。由于正常肺部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肺部感染的模型。我们还将把该模型移植到小鼠身上，这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免疫系统对由生物膜形成引发的炎症性疾病过程的贡献。其次，我们将继续研究细菌在生物膜中的适应性，通过表征生物膜在挑战下产生的蛋白质来降低它们的抗菌素敏感性，以确定避免抗生素消除的机制。进一步，我们将研究酶在限制活性氧损伤中所起的作用，从而促进生物膜在抗菌素胁迫下的稳定性。我们预计这些研究将使我们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.