Rohde Kyle, Yates Robin M, Purdy Georgiana E, Russell David G
Department of Microbiology and Immunology, College of Veterinary Medicine, Cornell University, Ithaca, NY 14853, USA.
Immunol Rev. 2007 Oct;219:37-54. doi: 10.1111/j.1600-065X.2007.00547.x.
Once across the barrier of the epithelium, macrophages constitute the primary defense against microbial invasion. For most microbes, the acidic, hydrolytically competent environment of the phagolysosome is sufficient to kill them. Despite our understanding of the trafficking events that regulate phagosome maturation, our appreciation of the lumenal environment within the phagosome is only now becoming elucidated through real-time functional assays. The assays quantify pH change, phagosome/lysosome fusion, proteolysis, lipolysis, and beta-galactosidase activity. This information is particularly important for understanding pathogens that successfully parasitize the endosomal/lysosomal continuum. Mycobacterium tuberculosis infects macrophages through arresting the normal maturation process of the phagosome, retaining its vacuole at pH 6.4 with many of the characteristics of an early endosome. Current studies are focusing on the transcriptional response of the bacterium to the changing environment in the macrophage phagosome. Manipulation of these environmental cues, such as preventing the pH drop to pH 6.4 with concanamycin A, abrogates the majority of the transcriptional response in the bacterium, showing that pH is the dominant signal that the bacterium senses and responds to. These approaches represent our ongoing attempts to unravel the discourse that takes place between the pathogen and its host cell.
一旦穿过上皮屏障，巨噬细胞就构成了抵御微生物入侵的主要防线。对于大多数微生物来说，吞噬溶酶体的酸性、具有水解能力的环境足以杀死它们。尽管我们了解调节吞噬体成熟的运输过程，但我们对吞噬体内腔环境的认识直到现在才通过实时功能分析得以阐明。这些分析可量化pH变化、吞噬体/溶酶体融合、蛋白水解、脂解和β-半乳糖苷酶活性。这些信息对于理解成功寄生在内体/溶酶体连续体中的病原体尤为重要。结核分枝杆菌通过阻止吞噬体的正常成熟过程来感染巨噬细胞，使其液泡保持在pH 6.4，具有许多早期内体的特征。目前的研究集中在细菌对巨噬细胞吞噬体内不断变化的环境的转录反应。操纵这些环境线索，如用 concanamycin A 阻止pH降至6.4，可消除细菌中的大部分转录反应，表明pH是细菌感知和响应的主要信号。这些方法代表了我们正在进行的解开病原体与其宿主细胞之间对话的尝试。
