Cited by 269Tuberculosis Research and EpidemiologyImmune Response and InflammationImmune responses and vaccinations

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Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

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Rajaram, Murugesan V. S., Ni, Bin, Morris, Jessica D., Brooks, Michelle N., Carlson, Tracy K., Bakthavachalu, Baskar, Schoenberg, Daniel R., Torrelles, Jordi B., Schlesinger, Larry S.·2011·Proceedings of the National Academy of Sciences

DOI 10.1073/pnas.1112660108PMC PMC3198317

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Abstract

Contact of Mycobacterium tuberculosis (M.tb) with the immune system requires interactions between microbial surface molecules and host pattern recognition receptors. Major M.tb-exposed cell envelope molecules, such as lipomannan (LM), contain subtle structural variations that affect the nature of the immune response. Here we show that LM from virulent M.tb (TB-LM), but not from avirulent Myocobacterium smegmatis (SmegLM), is a potent inhibitor of TNF biosynthesis in human macrophages. This difference in response is not because of variation in Toll-like receptor 2-dependent activation of the signaling kinase MAPK p38. Rather, TB-LM stimulation leads to destabilization of TNF mRNA transcripts and subsequent failure to produce TNF protein. In contrast, SmegLM enhances MAPK-activated protein kinase 2 phosphorylation, which is critical for maintaining TNF mRNA stability in part by contributing microRNAs (miRNAs). In this context, human miRNA miR-125b binds to the 3' UTR region of TNF mRNA and destabilizes the transcript, whereas miR-155 enhances TNF production by increasing TNF mRNA half-life and limiting expression of SHIP1, a negative regulator of the PI3K/Akt pathway. We show that macrophages incubated with TB-LM and live M.tb induce high miR-125b expression and low miR-155 expression with correspondingly low TNF production. In contrast, SmegLM and live M. smegmatis induce high miR-155 expression and low miR-125b expression with high TNF production. Thus, we identify a unique cellular mechanism underlying the ability of a major M.tb cell wall component, TB-LM, to block TNF biosynthesis in human macrophages, thereby allowing M.tb to subvert host immunity and potentially increase its virulence.

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Authors: Rajaram, M. V. S., Ni, B., Morris, J. D., Brooks, M. N., Carlson, T. K., Bakthavachalu, B., Schoenberg, D. R., Torrelles, J. B., & Schlesinger, L. S.
Affiliations: Center for Microbial Interface Biology,
Integrated Biomedical Science Graduate Program,
Center for RNA Biology and Department of Molecular and Cellular Biochemistry,
The Ohio State University (US)
ORCID: Rajaram, Murugesan V. S.
Ni, Bin
Bakthavachalu, Baskar
Schoenberg, Daniel R.
Torrelles, Jordi B.
Schlesinger, Larry S.
Venue: Proceedings of the National Academy of Sciences
Publisher: National Academy of Sciences
Published: 2011-10-03
Volume: 108
Issue: 42
Pages: 17408-17413
ISSN: 0027-8424 (ISSN-L)
1091-6490
DOI: 10.1073/pnas.1112660108
PMC: PMC3198317
OpenAlex: W2101417884
Cited by: 269
References: 43
Citations by year: 2026: 4 · 2025: 9 · 2024: 3 · 2023: 20 · 2022: 15 · 2021: 20 · 2020: 19 · 2019: 16 · 2018: 19 · 2017: 18 · 2016: 35 · 2015: 26 · 2014: 23 · 2013: 26 · 2012: 16
FWCI: 14.09
Type: journal article
Language: en
Open access: bronze
doi.org
Locations: Proceedings of the National Academy of Sciences (publishedVersion)
Europe PMC (PubMed Central) (publishedVersion)
PubMed Central (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health (8k01od011077-03)
National Institute of General Medical Sciences (R01GM038277, GM038277)
National Institute of Allergy and Infectious Diseases (AI059639, R01AI059639, AI-052458, R01AI052458, R21AI059639, R21AI052458)
Topics: Health Sciences › Medicine › Infectious Diseases › Tuberculosis Research and Epidemiology
Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
Life Sciences › Immunology and Microbiology › Immunology › Immune responses and vaccinations
Keywords: Mycobacterium tuberculosis, lipomannan, macrophages, MAPKAPK2, miR-125b, miR-155, 3' untranslated region, SHIP1, PI3K/Akt signaling, Mycobacterium smegmatis, virulence, host immune evasion
MeSH terms: Humans, Lipopolysaccharides, Macrophages, Mycobacterium tuberculosis, Phosphorylation, Promoter Regions, Genetic, Tumor Necrosis Factor-alpha, Virulence, RNA Stability, MAP Kinase Signaling System, MicroRNAs, p38 Mitogen-Activated Protein Kinases, MAP Kinase Kinase 2, Proto-Oncogene Proteins c-akt, Toll-Like Receptor 2, In Vitro Techniques

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Mycobacterium tuberculosis lipomannan blocks TNF biosynthesis by regulating macrophage MAPK-activated protein kinase 2 (MK2) and microRNA miR-125b

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