Mechanisms of Enteric Burkholderia psuedomallei infection

描述(申请人提供)：假鼻疽伯克霍尔德氏菌(BP)是一种革兰氏阴性细菌病原体，可导致人类从急性脓毒症到慢性脓肿的各种难以治疗的感染。虽然BP在东南亚和澳大利亚北部是地方病，但现在世界各地，包括中美洲和南美洲，被诊断出感染的频率越来越高。因此，BP感染很可能很快就会在美国被发现。尽管BP感染以前被认为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，在口服接种小鼠模型后，它很容易建立急性或持续性的胃肠道感染。然而，目前对BP肠道感染的发病机制基本上一无所知。因此，这里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的一个关键空白。首先，我们将使用BP感染的小鼠模型来确定大多数或所有BP菌株是否可以建立肠道感染，并鉴定强毒和无毒分离株。其次，我们将使用该模型来确定肠道作为BP感染的储存库的作用，并确定在慢性感染期间机体维持在胃肠道中的细胞。最后，我们将研究在慢性肠道感染期间BP是如何传播到其他器官的。这些研究中产生的信息将极大地改变我们对BP作为病原体的看法，并导致对口腔BP感染所构成的风险的重新评估。 与公共卫生相关：假性伯克霍尔德氏菌是一种重要而危险的细菌病原体，近年来似乎正在包括中美洲和南美洲在内的世界各地传播。这种微生物特别危险，因为它能够在土壤和水中存活数年，对大多数抗生素具有很强的抗药性，并能迅速引起人类的致命感染。以前人们认为这种细菌是通过吸入或皮肤损伤感染的，但我们的新数据表明，假鼻疽杆菌也具有很强的口腔传染性，并通过排泄物引起慢性肠道感染。因此，我们将使用小鼠感染模型来研究允许假鼻疽杆菌感染肠道的机制。

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.