Interactions between Naïve and Infected Macrophages Reduce Mycobacterium tuberculosis Viability
Open accessAbstract
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 naïve macrophages produced an antimicrobial effect, but only if naïve 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 naïve macrophages. The antimicrobial effect of naïve 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 naïve 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 naïve 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.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Although macrophages killed by this cell death pathway are not efficiently phagocytosed by naive macrophages, this interaction still reduces the number of mycobacteria.
“Although MΦs killed by this cell death pathway are not efficiently phagocytosed by naive MΦs, this interaction still reduces the number of mycobacteria (154).”
From Macrophage defense mechanisms against intracellular bacteria (2015) · cites this paper as [154]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Repertoires of Autophagy in the Pathogenesis of Ocular Diseases
Li, Y., Jiang, Q. L., Cao, G.-F., Yao, J., & Yan, B. (2015) · Cellular Physiology and Biochemistry · doi:10.1159/000373980 · Cited by 16,351 · see citing works
Hornung, V., Bauernfeind, F., Halle, A., Samstad, E. O., Kono, H., Rock, K. L., Fitzgerald, K. A., & Latz, E. (2008) · Nature Immunology · doi:10.1038/ni.1631 · Cited by 3,065 · see citing works
Gutierrez, M. G., Master, S. S., Singh, S. B., Taylor, G. A., Colombo, M. I., & Deretic, V. (2004) · Cell · doi:10.1016/j.cell.2004.11.038 · Cited by 2,252 · see citing works
Ghiringhelli, F., Apetoh, L., Tesniere, A., Aymeric, L., Ma, Y., Ortiz, C., Vermaelen, K., Panaretakis, T., Mignot, G., Ullrich, E., et al. (2009) · Nature Medicine · doi:10.1038/nm.2028 · Cited by 1,898 · see citing works
Sturgill-Koszycki, S., Schlesinger, P. H., Chakraborty, P., Haddix, P. L., Collins, H. L., Fok, A. K., Allen, R. D., Gluck, S. L., Heuser, J., & Russell, D. G. (1994) · Science · doi:10.1126/science.8303277 · Cited by 1,302 · see citing works
Identification of nitric oxide synthase as a protective locus against tuberculosis
MacMicking, J. D., North, R. J., LaCourse, R., Mudgett, J. S., Shah, S. K., & Nathan, C. F. (1997) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.94.10.5243 · Cited by 1,180 · see citing works
The Role of the Granuloma in Expansion and Dissemination of Early Tuberculous Infection
Davis, J. M., & Ramakrishnan, L. (2009) · Cell · doi:10.1016/j.cell.2008.11.014 · Cited by 907 · see citing works
Unveiling the roles of autophagy in innate and adaptive immunity
Levine, B., & Deretic, V. P. (2007) · Nature reviews. Immunology · doi:10.1038/nri2161 · Cited by 903 · see citing works
Autophagy Controls IL-1β Secretion by Targeting Pro-IL-1β for Degradation
Harris, J., Hartman, M., Roche, C., Zeng, S. G., O'Shea, A., Sharp, F. A., Lambe, E. M., Creagh, E. M., Golenbock, D. T., Tschopp, J., et al. (2011) · Journal of Biological Chemistry · doi:10.1074/jbc.m110.202911 · Cited by 794 · see citing works
Self-citationToll‐like receptors control autophagy
Delgado, M. A., Elmaoued, R. A., Davis, A. S., Kyei, G., & Deretic, V. (2008) · The EMBO Journal · doi:10.1038/emboj.2008.31 · Cited by 744 · see citing works
Virulent Mycobacterium tuberculosis Strains Evade Apoptosis of Infected Alveolar Macrophages
Keane, J., Remold, H. G., & Kornfeld, H. (2000) · The Journal of Immunology · doi:10.4049/jimmunol.164.4.2016 · Cited by 542 · see citing works
Self-citationArmstrong, J. A., & Hart, P. D. (1975) · The Journal of Experimental Medicine · doi:10.1084/jem.142.1.1 · Cited by 537 · see citing works
Henson, P. M. (1971) · PubMed · Cited by 514 · see citing works
Infection by Mycobacterium tuberculosis promotes human alveolar macrophage apoptosis
Keane, J., Balcewicz-Sablinska, M. K., Remold, H. G., Chupp, G. L., Meek, B., Fenton, M. J., & Kornfeld, H. (1997) · Infection and Immunity · doi:10.1128/iai.65.1.298-304.1997 · Cited by 512 · see citing works
Self-citationGiacomini, E., Iona, E., Ferroni, L., Miettinen, M., Fattorini, L., Orefici, G., Julkunen, I., & Coccia, E. M. (2001) · The Journal of Immunology · doi:10.4049/jimmunol.166.12.7033 · Cited by 431 · see citing works
P2X7 Receptor Differentially Couples to Distinct Release Pathways for IL-1β in Mouse Macrophage
Pelegrı́n, P., Barroso-Gutierrez, C., & Surprenant, A. (2008) · The Journal of Immunology · doi:10.4049/jimmunol.180.11.7147 · Cited by 413 · see citing works
Lammas, D. A., Stober, C. B., Harvey, C. J., Kendrick, N., Panchalingam, S., & Kumararatne, D. S. (1997) · Immunity · doi:10.1016/s1074-7613(00)80364-7 · Cited by 393 · see citing works
Ponpuak, M., Davis, A. S., Roberts, E. A., Delgado, M. A., Dinkins, C., Zhao, Z., Virgin, H. W., Kyei, G. B., Johansen, T., Vergne, I., et al. (2010) · Immunity · doi:10.1016/j.immuni.2010.02.009 · Cited by 308 · see citing works
Flesch, I. E. A., & Kaufmann, S. H. E. (1991) · Infection and Immunity · doi:10.1128/iai.59.9.3213-3218.1991 · Cited by 280 · see citing works
Interferon Gamma Activated Macrophages Kill Mycobacteria by Nitric Oxide Induced Apoptosis
Herbst, S., Schaible, U. E., & Schneider, B. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0019105 · Cited by 277 · see citing works
Henson, P. M. (1971) · PubMed · Cited by 251 · see citing works
Lee, J., Remold, H. G., Ieong, M. H., & Kornfeld, H. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.176.7.4267 · Cited by 238 · see citing works
Self-citationThe Immunologic Release of Constituents from Neutrophil Leukocytes
Henson, P. M. (1971) · The Journal of Immunology · doi:10.4049/jimmunol.107.6.1547 · Cited by 218 · see citing works
Macrophage Apoptosis in Tuberculosis
Lee, J., Hartman, M., & Kornfeld, H. (2009) · Yonsei Medical Journal · doi:10.3349/ymj.2009.50.1.1 · Cited by 179 · see citing works
Self-citationMacrophage apoptosis in mycobacterial infections
Fratazzi, C., Arbeit, R. D., Carini, C., Balcewicz-Sablinska, M. K., Keane, J., Kornfeld, H., & Remold, H. G. (1999) · Journal of Leukocyte Biology · doi:10.1002/jlb.66.5.763 · Cited by 171 · see citing works
Self-citationDiabetic Mice Display a Delayed Adaptive Immune Response to Mycobacterium tuberculosis
Vallerskog, T., Martens, G. W., & Kornfeld, H. (2010) · The Journal of Immunology · doi:10.4049/jimmunol.1000304 · Cited by 165 · see citing works
Self-citationMechanism of nitric oxide-dependent killing of Mycobacterium bovis BCG in human alveolar macrophages
Nozaki, Y., Hasegawa, Y., Ichiyama, S., Nakashima, I., & Shimokata, K. (1997) · Infection and Immunity · doi:10.1128/iai.65.9.3644-3647.1997 · Cited by 158 · see citing works
Biswas, D., Qureshi, O. S., Lee, W.-Y. J., Croudace, J. E., Mura, M., & Lammas, D. A. (2008) · BMC Immunology · doi:10.1186/1471-2172-9-35 · Cited by 156 · see citing works
Mycobacteria Inhibit Nitric Oxide Synthase Recruitment to Phagosomes during Macrophage Infection
Miller, B. H., Fratti, R. A., Poschet, J. F., Timmins, G. S., Master, S. S., Burgos, M. V., Marletta, M. A., & Deretic, V. P. (2004) · Infection and Immunity · doi:10.1128/iai.72.5.2872-2878.2004 · Cited by 152 · see citing works
Mycobacterium tuberculosis Induces an Atypical Cell Death Mode to Escape from Infected Macrophages
Lee, J., Repasy, T., Papavinasasundaram, K. G., Sassetti, C. M., & Kornfeld, H. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018367 · Cited by 121 · see citing works
Self-citationMechanism of Inducible Nitric Oxide Synthase Exclusion from Mycobacterial Phagosomes
Davis, A. S., Vergne, I., Master, S. S., Kyei, G. B., Chua, J., & Deretic, V. P. (2007) · PLoS Pathogens · doi:10.1371/journal.ppat.0030186 · Cited by 114 · see citing works
Placido, R., Auricchio, G., Falzoni, S., Battistini, L., Colizzi, V., Brunetti, E., Virgilio, F. D., & Mancino, G. (2006) · Cellular Immunology · doi:10.1016/j.cellimm.2007.02.001 · Cited by 89 · see citing works
Roberson, S. M., & Walker, W. S. (1988) · Cellular Immunology · doi:10.1016/0008-8749(88)90236-5 · Cited by 81 · see citing works
Morello, S., Ito, K., Yamamura, S., Lee, K., Jazrawi, E., deSouza, P., Barnes, P. J., Cicala, C., & Adcock, I. M. (2006) · The Journal of Immunology · doi:10.4049/jimmunol.177.10.7173 · Cited by 80 · see citing works
Autophagy in Immune Defense Against Mycobacterium tuberculosis
Vergne, I., Singh, S., Roberts, E., Kyei, G., Master, S., Harris, J., Haro, S. D., Naylor, J., Davis, A., Delgado, M., et al. (2006) · Autophagy · doi:10.4161/auto.2830 · Cited by 79 · see citing works
Guinea pig neutrophil–macrophage interactions during infection with Mycobacterium tuberculosis
Sawant, K. V., Cho, H., Lyons, M. J., Ly, L. H., & McMurray, D. N. (2010) · Microbes and Infection · doi:10.1016/j.micinf.2010.05.009 · Cited by 22 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Programmed cell death as a defence against infection
Jørgensen, I., Rayamajhi, M., & Miao, E. A. (2017) · Nature reviews. Immunology · doi:10.1038/nri.2016.147 · Cited by 1,014 · see citing works
Macrophage defense mechanisms against intracellular bacteria
Weiss, G., & Schaible, U. E. (2015) · Immunological Reviews · doi:10.1111/imr.12266 · Cited by 989 · see citing works
Autophagy protects against active tuberculosis by suppressing bacterial burden and inflammation
Castillo, E. F., Dekonenko, A., Arko‐Mensah, J., Mandell, M. A., Dupont, N., Jiang, S., Delgado-Vargas, M., Timmins, G. S., Bhattacharya, D., Yang, H., et al. (2012) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1210500109 · Cited by 451 · see citing works
Modulation of inflammation by autophagy: Consequences for human disease
Netea-Maier, R. T., Plantinga, T. S., van de Veerdonk, F. L., Smit, J. W., & Netea, M. G. (2016) · Autophagy · doi:10.1080/15548627.2015.1071759 · Cited by 349 · see citing works
Efferocytosis Is an Innate Antibacterial Mechanism
Martin, C. J., Booty, M. G., Rosebrock, T. R., Nunes-Alves, C., Desjardins, D. M., Keren, I., Fortune, S. M., Remold, H. G., & Behar, S. M. (2012) · Cell Host & Microbe · doi:10.1016/j.chom.2012.06.010 · Cited by 285 · see citing works
Dallenga, T. K., Repnik, U., Corleis, B., Eich, J., Reimer, R., Griffiths, G. W., & Schaible, U. E. (2017) · Cell Host & Microbe · doi:10.1016/j.chom.2017.09.003 · Cited by 231 · see citing works
Apoptosis inhibition by intracellular bacteria and its consequence on host immunity
Behar, S. M., & Briken, V. (2019) · Current Opinion in Immunology · doi:10.1016/j.coi.2019.05.007 · Cited by 84 · see citing works
Choi, J.-A., Lim, Y.-J., Cho, S.-N., Lee, J.-H., Jeong, J. A., Kim, E., Park, J. B., Kim, S., Park, H. S., Kim, H.-J., et al. (2013) · Cell Death and Disease · doi:10.1038/cddis.2013.489 · Cited by 81 · see citing works
Verma, N. K., Conroy, J., Lyons, P. E., Coleman, J., O'Sullivan, M. P., Kornfeld, H., Kelleher, D., & Volkov, Y. (2012) · Toxicology and Applied Pharmacology · doi:10.1016/j.taap.2012.08.023 · Cited by 68 · see citing works
Self-citationLawlor, C., O’Connor, G., O’Leary, S. M., Gallagher, P., Cryan, S., Keane, J., & O’Sullivan, M. P. (2016) · PLoS ONE · doi:10.1371/journal.pone.0149167 · Cited by 58 · see citing works
Pérez‐Flores, J. G., García‐Curiel, L., Pérez-Escalante, E., Contreras‐López, E., Aguilar-Lira, G. Y., Angel‐Jijón, C., González-Olivares, L. G., Santillán, E. S. B., Ocampo, I. O. S., Guerrero-Solano, J. A., et al. (2025) · Applied Sciences · doi:10.3390/app15073516 · Cited by 67 · see citing works
Lysosomes, Lysosomal Storage Diseases, and Inflammation
Simonaro, C. M. (2016) · Journal of Inborn Errors of Metabolism and Screening · doi:10.1177/2326409816650465 · Cited by 51 · see citing works
Combined Active Humoral and Cellular Immunization Approaches for the Treatment of Synucleinopathies
Rockenstein, E. M., Ostroff, G. R., Dikengil, F., Rus, F., Mante, M., Florio, J. B., Adame, A., Trinh, I., Kim, C., Overk, C., et al. (2017) · Journal of Neuroscience · doi:10.1523/jneurosci.1170-17.2017 · Cited by 49 · see citing works
Khan, N., Vidyarthi, A., Javed, S., & Agrewala, J. N. (2016) · Frontiers in Microbiology · doi:10.3389/fmicb.2016.00328 · Cited by 44 · see citing works
Reinforcing the Functionality of Mononuclear Phagocyte System to Control Tuberculosis
Pahari, S., Kaur, G., Negi, S., Aqdas, M., Das, D. K., Bashir, H., Singh, S., Nagare, M., Khan, J., & Agrewala, J. N. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.00193 · Cited by 39 · see citing works
P2RX7 at the Host-Pathogen Interface of Infectious Diseases
Soare, A., Freeman, T. L., Min, A. K., Malik, H. S., Osota, E. O., & Swartz, T. H. (2021) · Microbiology and Molecular Biology Reviews · doi:10.1128/mmbr.00055-20 · Cited by 25 · see citing works
The Role of Autophagy-Related Proteins in Candida albicans Infections
Tam, J. M., Mansour, M. K., Acharya, M., Sokolovska, A., Timmons, A. K., Lacy‐Hulbert, A., & Vyas, J. M. (2016) · Pathogens · doi:10.3390/pathogens5020034 · Cited by 28 · see citing works
Saquib, N. M., Jamwal, S. V., Midha, M. K., Verma, H. N., & Manivel, V. (2015) · International Journal of Proteomics · doi:10.1155/2015/270438 · Cited by 21 · see citing works
Kwon, S., Lim, C. J., Jung, J., Kim, H. J., Park, K., Shin, J. W., Huh, C., Park, K. C., & Na, J. (2018) · Journal of Dermatological Treatment · doi:10.1080/09546634.2018.1544407 · Cited by 20 · see citing works
Andersson, A.-M., Larsson, M., Stendahl, O. I., & Blomgran, R. (2019) · Journal of Innate Immunity · doi:10.1159/000500861 · Cited by 19 · see citing works
Deng, Y.-H., He, H., & Zhang, B. (2013) · Journal of Microbiology Immunology and Infection · doi:10.1016/j.jmii.2012.11.005 · Cited by 18 · see citing works
P2X7 receptor is essential for cross-dressing of bone marrow-derived dendritic cells
Barrera‐Avalos, C., Briceño, P., Valdés, D., Imarai, M., Leiva‐Salcedo, E., Rojo, L. E., Milla, L. A., Huidobro-Toro, J. P., Robles-Planells, C., Escobar, A. F., et al. (2021) · iScience · doi:10.1016/j.isci.2021.103520 · Cited by 17 · see citing works
Mathie, H. A., Jensen, K., Stevens, J. M., Glass, E. J., & Hope, J. C. (2019) · Journal of Microbiological Methods · doi:10.1016/j.mimet.2019.105779 · Cited by 12 · see citing works
Epigenetic Control of Autophagy Related Genes Transcription in Pulpitis via JMJD3
Yin, B., Ma, Q., Zhao, L., Song, C., Wang, C., Yu, F., Shi, Y., & Ye, L. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.654958 · Cited by 5 · see citing works
Eklund, D. (2013) · Linköping University Electronic Press eBooks · doi:10.3384/diss.diva-100890 · Cited by 1 · see citing works
Efferocytosis is an Innate Antibacterial Mechanism of Mycobacterium tuberculosis Control
Martin, C. J. (2012) · Digital Access to Scholarship at Harvard (DASH) (Harvard University)
M.tb Killing by Macrophage Innate Immune Mechanisms: A Dissertation
Hartman, M. (2011) · The Journal of the American Medical Association (JAMA) Network (American Medical Association) · doi:10.13028/8kch-xp86
Self-citation
- Authors
- Hartman, M. L., & Kornfeld, H.
- Affiliations
- University of Massachusetts Chan Medical School (US)
- Corresponding author
- Kornfeld, Hardy
- ORCID
- Kornfeld, Hardy
- Venue
- PLoS ONE
- Publisher
- Public Library of Science (PLoS)
- Published
- 2011-11-18
- Volume
- 6
- Issue
- 11
- Pages
- e27972
- ISSN
- 1932-6203 (ISSN-L)
- PMC
- PMC3220711
- OpenAlex
- W2013552849
- Cited by
- 27
- References
- 36
- Citations by year
- 2025: 1 · 2021: 3 · 2019: 3 · 2018: 2 · 2017: 3 · 2016: 4 · 2015: 3 · 2013: 3 · 2012: 4
- FWCI
- 1.73
- Type
- journal article
- Language
- en
- Open access
- gold
- doi.org
- Locations
- PLoS ONE (publishedVersion, cc-by)
- Europe PMC (PubMed Central) (publishedVersion, cc-by)
- PubMed Central (publishedVersion, cc-by)
- PubMed (publishedVersion)
- eScholarship@UMassChan (submittedVersion, cc-by)
- DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
- Figshare (submittedVersion, cc-by)
- Funders
- National Institutes of Health
- University of Massachusetts Medical School
- National Heart, Lung, and Blood Institute (R01HL064884, R01 HL064664)
- Topics
- Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
- Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
- Health Sciences › Medicine › Epidemiology › Autophagy in Disease and Therapy
- Keywords
- Mycobacterium tuberculosis, macrophage co-culture, infected macrophages, apoptosis, necrosis, frustrated phagocytosis, efferocytosis, autophagy, nitric oxide, inducible nitric oxide synthase, interleukin-1, autolysosomes, bacterial load, innate immunity, pulmonary tuberculosis
- MeSH terms
- Animals, Autophagy, Cell Communication, Cells, Cultured, Immunohistochemistry, Macrophages, Mice, Inbred C57BL, Microtubule-Associated Proteins, Mycobacterium tuberculosis, Signal Transduction, Receptors, Interleukin-1, Mice, Knockout, Microscopy, Confocal, Coculture Techniques, Interleukin-18, Green Fluorescent Proteins, Microbial Viability, Mice, Lysosomal Membrane Proteins, Lysosomal-Associated Membrane Protein 1, Nitric Oxide Synthase Type II, Interleukin-1beta, Host-Pathogen Interactions, Receptors, Purinergic P2X7
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
