Cyclic AMP secretion mechanisms in M. tuberculosis

摘要 控制目前的结核病流行需要更好地了解结核病的生物学特性， 结核分枝杆菌（Mtb）感知、响应和操纵宿主的机制 感染时的环境。环腺苷酸（cAMP）是一种通用的信号分子， 病原体和它们的哺乳动物宿主能够感知环境信号并作出反应。cAMP起着中枢作用， 在几种重要的细菌病原体中的毒力基因调控中起作用，并调节 哺乳动物宿主生物学，包括免疫反应。许多细菌，包括结核分枝杆菌，利用这一点， 通过升高宿主细胞中的cAMP水平作为致病策略来抑制常见的信号分子。水平 当细菌进入巨噬细胞时，Mtb细菌内的cAMP显著增加，其中一些cAMP增加了。 cAMP被分泌到宿主巨噬细胞中以改变感染过程。科学的前提是 提出的观点是cAMP从Mtb细菌输出到巨噬细胞有助于TB发病机制，但 cAMP分泌的机制及其在宿主细胞内的特异性活性尚不清楚。我们 假设细菌环AMP分泌受环境条件的调节， Mtb主动促进分泌的cAMP进入感染宿主的细胞质 巨噬细胞来操纵宿主对感染的反应。该提案的主要目标是确定 细菌因子，其i）控制来自Mtb细菌的cAMP分泌，和ii）影响这种cAMP的细胞质进入， 巨噬细胞感染时结核分枝杆菌分泌的cAMP。对这些因素的了解将提供一个关键的基础 了解cAMP输出过程的机制及其在Mtb中的具体作用 发病机制，具有鉴定新的结核病干预措施和/或 疾病进展。

Abstract Control of the current tuberculosis (TB) epidemic will require better understanding of the biological mechanisms used by Mycobacterium tuberculosis (Mtb) to sense, respond to and manipulate its host environment during infection. Cyclic AMP (cAMP) is a universal signal molecule used by both microbial pathogens and their mammalian hosts to sense and respond to environmental cues. cAMP plays a central role in virulence gene regulation in several important bacterial pathogens, and regulates many aspects of mammalian host biology, including the immune response. Many bacteria, including Mtb, exploit this common signaling molecule by elevating cAMP levels in their host cells as a pathogenic strategy. Levels of cAMP within Mtb bacteria increase dramatically upon bacterial entry into macrophages, and some of this cAMP is secreted into host macrophages to alter the course of infection. The scientific premise for this proposal is that the cAMP export from Mtb bacteria into macrophages contributes to TB pathogenesis, but the mechanisms underlying cAMP secretion and its specific activities within the host cell are not known. We hypothesize that cyclic AMP secretion from the bacterium is regulated in response to environmental conditions, and that Mtb actively facilitates access of secreted cAMP to the cytoplasm of infected host macrophages to manipulate the host response to infection. Major goals of this proposal are to identify bacterial factors that i) control secretion of cAMP from Mtb bacteria, and ii) affect cytoplasmic access of this Mtb-secreted cAMP during macrophage infection. Knowledge of these factors will provide a critical basis for understanding the mechanisms underlying both cAMP export processes and their specific roles in Mtb pathogenesis, with the long term potential for identification of new TB interventions and/or biomarkers of disease progression.