Interactions between naive and infected macrophages reduce Mycobacterium tuberculosis viability
UMass Chan Affiliations
Department of Medicine, Division of Pulmonary, Allergy and Critical Care MedicineDocument Type
Journal ArticlePublication Date
2011-11-18Keywords
AnimalsAutophagy
Cell Communication
Cells, Cultured
Coculture Techniques
Green Fluorescent Proteins
Host-Pathogen Interactions
Immunohistochemistry
Interleukin-18
Interleukin-1beta
Lysosome-Associated Membrane Glycoproteins
Macrophages
Mice
Mice, Inbred C57BL
Mice, Knockout
Microbial Viability
Microscopy, Confocal
Microtubule-Associated Proteins
Mycobacterium tuberculosis
Nitric Oxide Synthase Type II
Receptors, Interleukin-1
Receptors, Purinergic P2X7
Signal Transduction
Immunology and Infectious Disease
Life Sciences
Medicine and Health Sciences
Microbiology
Metadata
Show full item recordAbstract
A high intracellular bacillary load of Mycobacterium tuberculosis in macrophages induces an atypical lysosomal cell death with early features of apoptosis that progress to necrosis within hours. Unlike classical apoptosis, this cell death mode does not appear to diminish M. tuberculosis viability. We previously reported that culturing heavily infected macrophages with naive macrophages produced an antimicrobial effect, but only if naive macrophages were added during the pre-necrotic phase of M. tuberculosis-induced cell death. In the present study we investigated the mechanism of antimicrobial activity in co-cultures, anticipating that efferocytosis of bacilli in apoptotic bodies would be required. Confocal microscopy revealed frustrated phagocytosis of M. tuberculosis-infected macrophages with no evidence that significant numbers of bacilli were transferred to the naive macrophages. The antimicrobial effect of naive macrophages was retained when they were separated from infected macrophages in transwells, and conditioned co-culture supernatants transferred antimicrobial activity to cultures of infected macrophages alone. Antimicrobial activity in macrophage co-cultures was abrogated when the naive population was deficient in IL-1 receptor or when the infected population was deficient in inducible nitric oxide synthase. The participation of nitric oxide suggested a conventional antimicrobial mechanism requiring delivery of bacilli to a late endosomal compartment. Using macrophages expressing GFP-LC3 we observed the induction of autophagy specifically by a high intracellular load of M. tuberculosis. Bacilli were identified in LC3-positive compartments and LC3-positive compartments were confirmed to be acidified and LAMP1 positive. Thus, the antimicrobial effect of naive macrophages acting on M. tuberculosis in heavily-infected macrophages is contact-independent. Interleukin-1 provides an afferent signal that induces an as yet unidentified small molecule which promotes nitric oxide-dependent antimicrobial activity against bacilli in autolysosomes of heavily infected macrophages. This cooperative, innate antimicrobial interaction may limit the maximal growth rate of M. tuberculosis prior to the expression of adaptive immunity in pulmonary tuberculosis.Source
Hartman ML, Kornfeld H (2011) Interactions between Naïve and Infected Macrophages Reduce Mycobacterium tuberculosis Viability. PLoS ONE 6(11): e27972. doi:10.1371/journal.pone.0027972. Link to article on publisher's siteDOI
10.1371/journal.pone.0027972Permanent Link to this Item
http://hdl.handle.net/20.500.14038/39556PubMed ID
22125644Related Resources
Link to Article in PubMedRights
Copyright: © 2011 Hartman, Kornfeld. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.ae974a485f413a2113503eed53cd6c53
10.1371/journal.pone.0027972