Determinants of Paucibacillary Mtb Infection in Mice

结核病化疗可以消除疾病症状，但往往不能消毒分枝杆菌。 结核病(Mtb)使明显治愈的结核病患者面临疾病复发的风险。结核分枝杆菌是如何在后- 治疗持续性感染(PTPI)的定义不明确，我们对免疫决定因素缺乏充分的了解 可防止进展为活动性结核病(复发)。 我们开发了一种在人类体内模拟PTPI的少杆菌(低细菌数量)小鼠模型。我们发现 体内必需基因的沉默在一定程度上治愈了小鼠的结核分枝杆菌感染，以至于集落形成单位(CFU) 在琼脂平板上不再被检测到。然而，与人类一样，老鼠通常不会被绝育，而且 少杆菌感染导致复发性肺结核。我们的模型允许我们审问这两种机制， 使结核分枝杆菌能够持续存在，尽管宿主免疫和宿主因素是控制和消毒结核分枝杆菌所必需的 感染。我们将使用这个模型来(1)比较小鼠和人类的治疗后持续感染(PTPI) (2)确定特定的白细胞亚群对建立或控制少杆菌结核分枝杆菌的重要性 感染和(3)确定耐少杆菌所需的结核分枝杆菌基因。

Tuberculosis (TB) chemotherapy eliminates disease symptoms, but often fails to sterilize Mycobacterium tuberculosis (Mtb) leaving apparently cured TB patients at risk of disease relapse. How Mtb survives during post- treatment persistent infections (PTPI) is ill defined and we lack a full understanding of the immune determinants that prevent progression to active TB (relapse). We developed a paucibacillary (low bacterial numbers) mouse model that mimics PTPI in in humans. We found that silencing of in vivo essential genes cured Mtb infections in mice to the extent that colony forming units (CFU) were no longer detected on agar plates. However, as in humans, mice were often not sterilized, and paucibacillary infection resulted in relapse TB. Our model allows us to interrogate both, the mechanisms that enable Mtb to persist despite host immunity and the host factors that are required to control and sterilize Mtb infection. We will use this model to (1) compare post-treatment persistent infection (PTPI) in mice and humans (2) determine the importance of specific leukocyte subsets for the establishment or control of paucibacillary Mtb infection and (3) identify Mtb genes that are required for paucibacillary persistence.