Mycobacteria manipulate macrophage recruitment through coordinated use of membrane lipids

Nature (Impact Factor: 41.46). 12/2013; 505(7482). DOI: 10.1038/nature12799
Source: PubMed


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) 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 signalling.

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    • "Recently, another chemokine receptor, Ccr2, has also been shown to mediate macrophage recruitment following hindbrain infection of M. marinum in zebrafish embryos (Cambier et al., 2014). This Ccr2- mediated pathway is dependent on the presence of phenolic glycolipids on the mycobacterial cell surface and it recruits a population of macrophages that are permissive for mycobacterial growth, because activation of the host immune response is largely avoided owing to the presence of other cell surface lipids in virulent mycobacteria (phthiocerol dimycoceroserate lipids), which physically mask the underlying PAMPs. "
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    ABSTRACT: The recruitment of leukocytes to infectious foci depends strongly on the local release of chemoattractant mediators. The human CXC chemokine receptor 3 (CXCR3) is an important node in the chemokine signaling network and is expressed by multiple leukocyte lineages, including T-cells and macrophages. The ligands of this receptor originate from an ancestral CXCL11 gene in early vertebrates. Here we used the optically accessible zebrafish embryo model to explore the function of the CXCR3/CXCL11 axis in macrophage recruitment and show that disruption of this axis increases the resistance to mycobacterial infection. In a mutant of the zebrafish ortholog of CXCR3 (cxcr3.2), macrophage chemotaxis to bacterial infections was attenuated, while migration to infection-independent stimuli was unaffected. Additionally, attenuation of macrophage recruitment to infection could be mimicked by treatment with NBI74330, a high affinity antagonist of CXCR3. We identified two infection inducible CXCL11-like chemokines as the functional ligands of Cxcr3.2, showing that the recombinant proteins exerted a Cxcr3.2-dependent chemoattraction when locally administrated in vivo. During infection of zebrafish embryos with Mycobacterium marinum, a well-established model for tuberculosis, we found that Cxcr3.2 deficiency limited the macrophage-mediated dissemination of mycobacteria. Furthermore, the loss of Cxcr3.2 function attenuated the formation of granulomatous lesions, the typical histopathological features of tuberculosis, and led to a reduction in the total bacterial burden. Prevention of mycobacterial dissemination by targeting the CXCR3 pathway, therefore, might represent a host-directed therapeutic strategy for treatment of tuberculosis. The demonstration of a conserved CXCR3/CXCL11 signaling axis in zebrafish extends the translational applicability of this model for studying diseases involving the innate immune system.
    Full-text · Article · Jan 2015 · Disease Models and Mechanisms
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    • "This occurs either through an initial mobilization of innate immune mechanisms or, failing that, through adaptive immunity. In this Review, we have tried to point out how the outcome of each step of the host-pathogen interaction can represent ''success'' for the host—infection can be suppressed or cleared at the first site of infection, in the innate granuloma , or later, when the granuloma is further re-enforced by adaptive immunity (Cambier et al., 2014; Lin et al., 2014; Adams et al., 2011; Rengarajan et al., 2005; Szumowski et al., 2013). Suppression of infection can result in a clinical latency during which the bacteria persist indefinitely in the host and can produce active disease even decades later—a scenario that is emphasized in the literature (Chao and Rubin, 2010; Cosma et al., 2003; Rittershaus et al., 2013). "
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    ABSTRACT: Tuberculosis, an ancient disease of mankind, remains one of the major infectious causes of human death. We examine newly discovered facets of tuberculosis pathogenesis and explore the evolution of its causative organism Mycobacterium tuberculosis from soil dweller to human pathogen. M. tuberculosis has coevolved with the human host to evade and exploit host macrophages and other immune cells in multiple ways. Though the host can often clear infection, the organism can cause transmissible disease in enough individuals to sustain itself. Tuberculosis is a near-perfect paradigm of a host-pathogen relationship, and that may be the challenge to the development of new therapies for its eradication. Copyright © 2014 Elsevier Inc. All rights reserved.
    Full-text · Article · Dec 2014 · Cell
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    • "the functional capacity of antigen-presenting cells in its favor, a recent study in zebrafish shows that its close pathogenic relative, Mycobacterium marinum, is able to avoid immune recognition by using cell surface– associated phthiocerol dymycoceroserate (PDIM) lipids, and at the same time, to promote the recruitment of permissive macrophages to site of infection via phenolic glycolipids (PGLs) (Cambier et al. 2013). Although the description of this study does not include the modulation of monocytes or dendritic cells by M. marinum, it can be inferred that PGLs may also be responsible for the induction of anti-inflammatory factors that modulate the recruitment of monocytes that differentiate poorly into effective antigen-presenting dendritic cells, as shown recently for M. tuberculosis and M. leprae (Goulart et al. 2000; Hashimoto et al. 2002). "
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    ABSTRACT: Over the past 20 years, there has been an emerging appreciation about the role of the mononuclear phagocyte system (MPS) to control and eradicate pathogens. Likewise, there have been significant advances in dissecting the mechanisms involved in the microbial subversion of MPS cells, mainly affecting their differentiation and effector functions. Mycobacterium tuberculosis is a chronic bacterial pathogen that represents an enigma to the field because of its remarkable ability to thrive in humans. One reason is that M. tuberculosis renders a defective MPS compartment, which is perhaps the most ingenious strategy for survival in the host given the prominence of these cells to modulate microenvironments, their function as sentinels and orchestrators of the immune response, and their pathogenic role as reservoirs for microbial persistence. In this article, the principal strategies used by M. tuberculosis to subvert the MPS compartment are presented along with emerging concepts.
    Full-text · Article · Aug 2014 · Cold Spring Harbor Perspectives in Medicine
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