Nature2014-06-26 6:57 PM

分枝杆菌分辨不同巨噬细胞的方式 Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids

论文摘要 

在其最初感染点上,结核病病原体感染巨噬细胞,后者将该细菌输送到更深的组织。该细菌在这些宿主细胞内是怎样生存的却不清楚。在这项研究中,Lalita Ramakrishnan及同事发现,结核分枝杆菌及其致病性近亲海洋分枝杆菌进化出了一个避开杀菌性巨噬细胞、同时招募那些允许它们生存的巨噬细胞的策略。这种偏向性的招募是通过两个步骤完成的:第一,该细菌通过生成“分枝杆菌结核菌醇双结核蜡酸酯”脂质来掩蔽被杀菌性巨噬细胞识别出的PAMPs (pathogen-associated molecular patterns,与病原体相关的分子模式);第二,它们产生“酚糖脂”,后者通过宿主的一个“趋化因子受体-2”介导的通道促进“宽容”的巨噬细胞的招募。

Abstract 

The evolutionary survival of Mycobacterium tuberculosis, the cause of human tuberculosis, depends on its ability to invade the host, replicate, and transmit infection. At its initial peripheral infection site in the distal lung airways, M. tuberculosis infects macrophages, which transport it to deeper tissues. How mycobacteria survive in these broadly microbicidal cells is an important question. Here we show in mice and zebrafish that M. tuberculosis, and its close pathogenic relative Mycobacterium marinum, preferentially recruit and infect permissive macrophages while evading microbicidal ones. This immune evasion is accomplished by using cell-surface-associated phthiocerol dimycoceroserate (PDIM) lipids to mask underlying pathogen-associated molecular patterns (PAMPs). In the absence of PDIM, these PAMPs signal a Toll-like receptor (TLR)-dependent recruitment of macrophages that produce microbicidal reactive nitrogen species. Concordantly, the related phenolic glycolipids (PGLs)2 promote the recruitment of permissive macrophages through a host chemokine receptor 2 (CCR2)-mediated pathway. Thus, we have identified coordinated roles for PDIM, known to be essential for mycobacterial virulence, and PGL, which (along with CCR2) is known to be associated with human tuberculosis. Our findings also suggest an explanation for the longstanding observation that M. tuberculosis initiates infection in the relatively sterile environment of the lower respiratory tract, rather than in the upper respiratory tract, where resident microflora and inhaled environmental microbes may continually recruit microbicidal macrophages through TLR-dependent signaling.

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