Mechanisms of Enteric Burkholderia psuedomallei infection

描述（由申请方提供）：类鼻疽伯克霍尔德氏菌（Bp）是一种革兰氏阴性细菌病原体，可引起人类各种难以治疗的感染，从急性脓毒症到慢性脓毒症。虽然Bp在东南亚和澳大利亚北方是地方性的，但现在世界各地，包括中美洲和南美洲，越来越多地诊断出感染。尽管以前认为Bp感染是通过吸入或皮肤接种发生的，但我们的新研究表明，Bp实际上是一种主要的肠道病原体，在小鼠模型中口服接种后很容易建立急性或持续性胃肠道感染。然而，目前基本上没有什么是已知的肠道感染的发病机制与Bp。因此，本文提出的研究旨在填补我们对这种重要的新兴细菌病原体感染发病机制的理解中的关键空白。首先，我们将使用小鼠感染模型的Bp感染，以确定是否大多数或所有菌株的Bp可以建立肠道感染，并确定强毒和无毒力的菌株。其次，我们将使用该模型来定义肠道作为BP感染的储库的作用，并确定胃肠道中的细胞，在慢性感染期间维持生物体。最后，我们将探讨慢性肠道感染时，Bp是如何传播到其他器官的。这些研究中产生的信息将大大改变我们对Bp作为病原体的看法，并导致重新评估口腔Bp感染所带来的风险。 公共卫生相关性：类鼻疽伯克霍尔德氏菌是一种重要而危险的细菌病原体，近年来出现在世界各地，包括中美洲和南美洲。这种微生物特别危险，因为它能够在土壤和水中存活多年，对大多数抗生素具有很强的耐药性，并能迅速引起人类致命的感染。以前人们认为这种微生物只通过吸入或皮肤损伤而感染，但我们的新数据表明B。鼻疽假单胞菌也具有很强的口腔传染性，并引起伴随粪便脱落的慢性肠道感染。因此，我们将研究允许B的机制。使用小鼠感染模型，研究了类鼻疽假单胞菌感染肠道的情况。

DESCRIPTION (provided by applicant): Burkholderia pseudomallei (Bp) is a Gram-negative bacterial pathogen that can cause a variety of difficult-to-treat infections in humans ranging from acute sepsis to chronic abscesses. While Bp is endemic in Southeast Asia and northern Australia, infections are now being diagnosed with increasing frequency around the world, including in Central and South America. Therefore, it is likely that Bp infections will soon be identified in the U.S. Though infection with Bp was previously thought to occur by inhalation or skin inoculation, our new studies indicate that Bp is actually a primary enteric pathogen, which can readily establish acute or persistent GI tract infection following oral inoculation in mouse models. However, at present essentially nothing is known regarding the pathogenesis of enteric infection with Bp. Therefore, the studies proposed here are intended to fill a critical void in our understanding of pathogenesis of infection with this important and emerging bacterial pathogen. First, we will use the mouse infection model of Bp infection to determine whether most or all strains of Bp can establish enteric infection and to identify virulent and avirulent isolates. Second, we will use the model to define the role of the intestine as a reservoir for Bp infection and to identify cells in the GI tract where the organism is maintained during chronic infection. Last, we will investigate how Bp is disseminated to other organs during chronic enteric infection. The information generated in these studies will substantially alter our view of Bp as a pathogen and also lead to a reassessment of the risks posed by oral Bp infection. PUBLIC HEALTH RELEVANCE: Burkholderia pseudomallei is an important and dangerous bacterial pathogen that appears in recent years to be spreading around the world, including Central and South America. This organism is particularly dangerous because it is able to survive for years in soil and water, is very resistant to most antibiotics, and can cause rapidly fatal infections in humans. Previously it was assumed that the organism was contracted only by inhalation or skin injury, but our new data indicate that B. pseudomallei is also very infectious orally and causes chronic intestinal infection with fecal shedding. We will therefore study the mechanisms that allow B. pseudomallei to infect the intestinal tract, using mouse models of infection.