Publication Date:
2013-12-18
Description:
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.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961847/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3961847/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Cambier, C J -- Takaki, Kevin K -- Larson, Ryan P -- Hernandez, Rafael E -- Tobin, David M -- Urdahl, Kevin B -- Cosma, Christine L -- Ramakrishnan, Lalita -- DP1 MH099901/MH/NIMH NIH HHS/ -- DP1 OD006782/OD/NIH HHS/ -- R01 AI036396/AI/NIAID NIH HHS/ -- R01 AI054503/AI/NIAID NIH HHS/ -- R01 AI076327/AI/NIAID NIH HHS/ -- R37 AI054503/AI/NIAID NIH HHS/ -- England -- Nature. 2014 Jan 9;505(7482):218-22. doi: 10.1038/nature12799. Epub 2013 Dec 15.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Immunology, University of Washington, Seattle, Washington 98195, USA. ; Department of Microbiology, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Immunology, University of Washington, Seattle, Washington 98195, USA [2] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA. ; Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Immunology, University of Washington, Seattle, Washington 98195, USA [2] Seattle Biomedical Research Institute, Seattle, Washington 98109, USA [3] Department of Pediatrics, University of Washington, Seattle, Washington 98195, USA. ; 1] Department of Immunology, University of Washington, Seattle, Washington 98195, USA [2] Department of Microbiology, University of Washington, Seattle, Washington 98195, USA [3] Department of Medicine, University of Washington, Seattle, Washington 98195, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/24336213" target="_blank"〉PubMed〈/a〉
Keywords:
Animals
;
Female
;
Glycolipids/immunology/metabolism
;
*Immune Evasion
;
Lipids/biosynthesis/immunology
;
Macrophages/cytology/immunology/metabolism/*microbiology
;
Membrane Lipids/*metabolism
;
Mice
;
Mice, Inbred C57BL
;
Mycobacterium/pathogenicity/*physiology
;
Mycobacterium tuberculosis/pathogenicity/physiology
;
Receptors, CCR2/metabolism
;
Toll-Like Receptors/immunology/metabolism
;
Virulence/immunology
;
Zebrafish/microbiology
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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