| Multiscale computational modeling reveals a critical role for TNF-α receptor 1 dynamics in tuberculosis granuloma formation. | |
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MedLine Citation:
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PMID: 21321109 Owner: NLM Status: MEDLINE |
Abstract/OtherAbstract:
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Multiple immune factors control host responses to Mycobacterium tuberculosis infection, including the formation of granulomas, which are aggregates of immune cells whose function may reflect success or failure of the host to contain infection. One such factor is TNF-α. TNF-α has been experimentally characterized to have the following activities in M. tuberculosis infection: macrophage activation, apoptosis, and chemokine and cytokine production. Availability of TNF-α within a granuloma has been proposed to play a critical role in immunity to M. tuberculosis. However, in vivo measurement of a TNF-α concentration gradient and activities within a granuloma are not experimentally feasible. Further, processes that control TNF-α concentration and activities in a granuloma remain unknown. We developed a multiscale computational model that includes molecular, cellular, and tissue scale events that occur during granuloma formation and maintenance in lung. We use our model to identify processes that regulate TNF-α concentration and cellular behaviors and thus influence the outcome of infection within a granuloma. Our model predicts that TNF-αR1 internalization kinetics play a critical role in infection control within a granuloma, controlling whether there is clearance of bacteria, excessive inflammation, containment of bacteria within a stable granuloma, or uncontrolled growth of bacteria. Our results suggest that there is an interplay between TNF-α and bacterial levels in a granuloma that is controlled by the combined effects of both molecular and cellular scale processes. Finally, our model elucidates processes involved in immunity to M. tuberculosis that may be new targets for therapy. |
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Authors:
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Mohammad Fallahi-Sichani; Mohammed El-Kebir; Simeone Marino; Denise E Kirschner; Jennifer J Linderman |
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Publication Detail:
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Type: Journal Article; Research Support, N.I.H., Extramural Date: 2011-02-14 |
Journal Detail:
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Title: Journal of immunology (Baltimore, Md. : 1950) Volume: 186 ISSN: 1550-6606 ISO Abbreviation: J. Immunol. Publication Date: 2011 Mar |
Date Detail:
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Created Date: 2011-03-03 Completed Date: 2011-05-26 Revised Date: 2011-09-26 |
Medline Journal Info:
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Nlm Unique ID: 2985117R Medline TA: J Immunol Country: United States |
Other Details:
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Languages: eng Pagination: 3472-83 Citation Subset: AIM; IM |
Affiliation:
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Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, USA. |
Export Citation:
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| MeSH Terms | |
Descriptor/Qualifier:
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Computational Biology
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methods* Granuloma / immunology*, microbiology, pathology Humans Inflammation Mediators / chemistry, metabolism, physiology Ligands Models, Immunological* Molecular Dynamics Simulation* Mycobacterium tuberculosis / growth & development*, immunology*, pathogenicity Predictive Value of Tests Receptors, Tumor Necrosis Factor, Type I / chemistry, metabolism, physiology* Signal Transduction / immunology Tuberculosis, Pulmonary / immunology*, microbiology, pathology Tumor Necrosis Factor-alpha / chemistry, metabolism, physiology |
| Grant Support | |
ID/Acronym/Agency:
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N01 AI50018/AI/NIAID NIH HHS; R33 HL092844-01/HL/NHLBI NIH HHS; R33 HL092844-03/HL/NHLBI NIH HHS; R33 HL092853-01/HL/NHLBI NIH HHS; R33HL092844/HL/NHLBI NIH HHS; R33HL092853/HL/NHLBI NIH HHS |
| Chemical | |
Reg. No./Substance:
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0/Inflammation Mediators; 0/Ligands; 0/Receptors, Tumor Necrosis Factor, Type I; 0/Tumor Necrosis Factor-alpha |
| Comments/Corrections | |
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine
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