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   Immune Modeling of Tuberculosis

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Pariksheet Nanda, Maral Budak, Christian T. Michael, Kathryn Krupinsky, and Denise E. Kirschner, Development and Analysis of Multiscale Models for Tuberculosis: From Molecules to Populations, Springer Nature Switzerland AG 2024 M. Aguiar et al. (eds.), Predicting Pandemics in a Globally Connected World, Volume 2, Modeling and Simulation in Science, Engineering and Technology, DOI: n/a, PMID: n/a, PMCID: n/a,

Maral Budak, Laura E. Via, Danielle M. Weiner, Clifton E. Barry III, Pariksheet Nanda, Gabrielle Michael, Khisimuzi Mdluli, Denise Kirschner, A systematic efficacy analysis of tuberculosis treatment with BPaL-containing regimens using a multiscale modeling approach, CPT Pharmacometrics Syst Pharmacol., February 7, 2024;00:1-13., DOI: 10.1002/psp4.13117, PMID: 38404200, PMCID: n/a,

Christian T. Michael, Sayed Ahmad Almohri, Jennifer J. Linderman, and Denise E. Kirschner, A framework for multi-scale intervention modeling: virtual cohorts, virtual clinical trials, and model-to-model comparisons, Frontiers in Biology Systems, January 22, 2024, vol 3, DOI: 10.3389/fsysb.2023.1283341, PMID: n/a, PMCID: n/a,

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Soorya Janakiraman, Sophie Engels, Pariksheet Nanda, Maral Budak, Talia Greenstein, Mariana Pereira Moraes, Bree B. Aldridge, and Denise E. Kirschner, Semi-automated colony-forming unit counting for biosafety level 3 laboratories, Star Protocols, September 15, 2023, DOI: 10.1016/j.xpro.2023.102442, PMID: 37549035, PMCID: 10424145,

Pariksheet Nanda, Maral Budak, Christian T. Michael, Kathryn Krupinsky, Denise E. Kirschner, Development and Analysis of Multiscale Models for Tuberculosis: From Molecules to Populations, Predicting Pandemics in a Globally Connected World, Volume 2, (in press.) eds. Maira Aguiar, Nicola Bellomo, and Mark Chaplain, DOI: n/a, PMID: n/a, PMCID: n/a,

Maral Budak, Joseph M. Cicchese, Pauline Maiello, H. Jacob Borish, Alexander G. White, Harris B. Chishti, Jaime Tomko, L. James Frye, Daniel Fillmore, Kara Kracinovsky, Jennifer Sakal, Charles A. Scanga, Philana Ling Lin, Veronique Dartois, Jennifer J. Linderman, JoAnne L. Flynn, Denise E. Kirschner, Optimizing tuberculosis treatment efficacy: Comparing the standard regimen with Moxifloxacin-containing regimens, PLoS Comp Bio, (June 15, 2023), DOI: 10.1371/journal.pcbi.1010823, PMID: 37319311, PMCID: 10306236,

Louis R. Joslyn, JoAnne L. Flynn, Denise E. Kirschner, and Jennifer J. Linderman, Concomitant immunity to M. tuberculosis infection, Scientific Reports, (2022) 12:20731, DOI: 10.1038/s41598-022-24516-8, PMID: 36456599, PMCID: 9713124,

Nicole L. Grant, Pauline Maiello, Edwin Klein, Philana Ling Lin, H. Jacob Borish, Jaime Tomko, L. James Frye, Alexander G. White, Denise E. Kirschner, Joshua T. Mattila, JoAnne L. Flynn, T cell transcription factor expression evolves over time in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques, Cell Reports: Volume 39, ISSUE 7, 110826, May 17 (2022), DOI: 10.1016/j.celrep.2022.110826, PMID: 35584684, PMCID: 9169877,

Louis R. Joslyn, Jennifer J. Linderman, Denise E. Kirschner, A virtual host model of Mycobacterium tuberculosis infection identifies early immune events as predictive of infection outcomes, Journal of Theoretical Biology (2022), DOI: 10.1016/j.jtbi.2022.111042, PMID: 35114195, PMCID: 9169921,

Supplementary Material

Online Supplement

Caitlin Hult, Joshua T. Mattila, Hannah P. Gideon, Jennifer J. Linderman, and Denise E. Kirschner, Neutrophil Dynamics Affect Mycobacterium tuberculosis Granuloma Outcomes and Dissemination, Front. Immunol., 05 October 2021, DOI: 10.3389/fimmu.2021.712457, PMID: 34675916, PMCID: 8525425

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Joseph M Cicchese, Awanti Sambarey, Denise Kirschner, Jennifer J Linderman, Sriram Chandrasekaran, A multi-scale pipeline linking drug transcriptomics with pharmacokinetics predicts in vivo interactions of tuberculosis drugs, Sci Rep 11, 5643 (2021), DOI: 10.1038/s41598-021-84827-0, PMID: 33707554, PMCID: 7971003

Jess A. Millar, J R. Butler, Stephanie Evans, Joshua T. Mattila, Jennifer J. Linderman, JoAnne L. Flynn, and Denise E. Kirschner, Spatial organization and recruitment of non-specific T cells may limit T cell-macrophage interactions within Mycobacterium tuberculosis granulomas, Front. Immunol. 11:613638, Jan 20 2021, DOI: 10.3389/fimmu.2020.613638, PMID: 33552077, PMCID: 7855029

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Errata Summary

Corrected table for spatial organization paper - updated table 2

Corrected figure for spatial organization paper [flattened 5x5]

Stephanie Evans, J. Russell Butler, Joshua T. Mattila, Denise E. Kirschner, Systems biology predicts that fibrosis in tuberculous granulomas may arise through macrophage-to-myofibroblast transformation, PLoS Computational Biology (2020), DOI: 10.1371/journal.pcbi.1008520, PMID: 33370784, PMCID: 7793262

Eileen A Wong, Stephanie Evans, Carolyn R Kraus, Kathleen D Engelman, Pauline Maiello, Walter J Flores, Anthony M Cadena, Edwin Klein, Kayla Thomas, Alexander G White, Chelsea Causgrove, Brianne Stein, Jaime Tomko, Joshua T Mattila, Hannah Gideon, P Ling Lin, Keith A Reimann, Denise E Kirschner, JoAnne L Flynn, IL-10 Impairs Local Immune Response in Lung Granulomas and Lymph Nodes during Early Mycobacterium tuberculosis Infection, J Immunol, Feb 1 2020; 204(3):644-659, DOI: 10.4049/jimmunol.1901211, PMID: 31862711, PMCID: 6981067

Louis R. Joslyn, Marissa Renardy, Caleb Weissman, Nicole L. Grant, JoAnne L. Flynn, J. Russ Butler, and Denise E. Kirschner, Temporal and spatial analyses of TB granulomas to predict long-term outcomes, in "Complex Systems and Computational Biology Approaches to Acute Inflammation". An, G.; Vodovotz, Y., eds. New York, NY: Springer. 2020, DOI: 10.1007/978-3-030-56510-7, PMID: (exempt), PMCID: (exempt), , ,

Joseph M. Cicchese, Véronique Dartois, Denise E. Kirschner, and Jennifer J. Linderman, Both Pharmacokinetic Variability and Granuloma Heterogeneity Impact the Ability of the First-Line Antibiotics to Sterilize Tuberculosis Granulomas, Front. Pharmacol., 24 March 2020, DOI: 10.3389/fphar.2020.00333, PMID: 32265707, PMCID: 7105635

Timothy Wessler, Louis R. Joslyn, H. Jacob Borish, Hannah P. Gideon, JoAnne L. Flynn, Denise E. Kirschner, Jennifer J. Linderman, A computational model tracks whole-lung Mycobacterium tuberculosis infection and predicts factors that inhibit dissemination, PLoS Comput Biol 16(5): e1007280., 2020, DOI: 10.1371/journal.pcbi.1007280, PMID: 32433646, PMCID: 7239387

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Jansy Sarathy, Landry Blanc, Nadine Alvarez-Cabrera, Paul O'Brien, Isabela Dias-Freedman, Marizel Mina, Matthew Zimmerman, Firat Kaya, Hsin-Pin Ho Liang, Brendan Prideaux, Jillian Dietzold, Padmini Salgame, Rada Savic, Jennifer Linderman, Denise Kirschner, Elsje Pienaar, Véronique Dartois, Fluoroquinolone efficacy against tuberculosis is driven by penetration into lesions and activity against resident bacterial populations, Online 25 February 2019, Antimicrobial Agents and Chemotherapy, DOI: 10.1128/AAC.02516-18, PMID: 30803965, PMCID: 6496041

Marissa Renardy, Caitlin Hult, Stephanie Evans, Jennifer J. Linderman, and Denise E. Kirschner, Global sensitivity analysis of biological multi-scale models, Curr Opin Biomed Eng. 2019 Sep; 11: 109-116, Volume 11, DOI: 10.1016/j.cobme.2019.09.012, PMID: 32864523, PMCID: 7450543

Marissa Renardy, Timothy Wessler, Silvia Blemker, Jennifer Linderman, Shayn Peirce, Denise Kirschner, Data-Driven Model Validation Across Dimensions, Bull Math Biol (2019), Pages 1-14, DOI: 10.1007/s11538-019-00590-4, PMID: 30830675, PMCID: 6494696

Sophie J. Rhodes, Gwenan M. Knight, Denise E. Kirschner, Richard G. White, Thomas G. Evans, Dose finding for new vaccines: The role for immunostimulation/immunodynamic modelling, Journal of Theoretical Biology, Volume 465, 21 March 2019, Pages 51-55, DOI: 10.1016/j.jtbi.2019.01.017, PMID: 30639297, PMCID: 6860008

Simeone Marino, Caitlin Hult, Paul Wolberg, Jennifer J. Linderman, Denise E. Kirschner, The Role of Dimensionality in Understanding Granuloma Formation, Computation 2018, 6, 58, DOI: 10.3390/computation6040058, PMID: 31258937, PMCID: 6599587

(This article belongs to the Special Issue: Computational Modeling in Inflammation and Regenerative Medicine edited by Profs. Dr. Yoram Vodovotz and Dr. Rami Namas)

Eileen A. Wong, Louis Joslyn, Nicole L. Grant, Edwin Klein, Philana Ling Lin, Denise E. Kirschner, JoAnne L. Flynn, Low Levels of T Cell Exhaustion in Tuberculous Lung Granulomas, Infect Immun 86:e00426-18, 2018, DOI: 10.1128/IAI.00426-18, PMID: 29891540, PMCID: 6105875

Louis R. Joslyn, Elsje Pienaar, Robert M. DiFazio, Sara Suliman, Benjamin M. Kagina, JoAnne L. Flynn, Thomas J. Scriba, Jennifer J. Linderman, Denise E. Kirschner, Integrating Non-human Primate, Human, and Mathematical Studies to Determine the Influence of BCG Timing on H56 Vaccine Outcomes, Frontiers in Microbiology, 17 August 2018, Volume 9, Article 1734, DOI: 10.3389/fmicb.2018.01734, PMID: 30177914, PMCID: 6109686

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Joseph M. Cicchese, Timothy Wessler, Joshua T. Mattila, Stephanie Evans, Caitlin Hult, Louis R. Joslyn, Jess A. Millar, Simeone Marino, Nicholas A. Cilfone, Jennifer J. Linderman, Denise E. Kirschner, Dynamic balance of pro- and anti-inflammatory signals controls disease and limits pathology, Immunological Reviews. 2018; 1-21, DOI: 10.1111/imr.12671, PMID: 30129209, PMCID: 6292442

Elsje Pienaar, Jennifer J. Linderman, Denise E. Kirschner, Emergence and selection of isoniazid and rifampin resistance in tuberculosis granulomas, PLoS One. 2018 May 10;13(5):e0196322, DOI: 10.1371/journal.pone.0196322, PMID: 29746491, PMCID: 5944939

Warsinske HC, Pienaar E, Linderman JJ, Mattila JT and Kirschner DE, Deletion of TGF-β1 Increases Bacterial Clearance by Cytotoxic T Cells in a Tuberculosis Granuloma Model, Front. Immunol. 8:1843, Accepted December 2017, DOI: 10.3389/fimmu.2017.01843, PMID: 29326718, PMCID: 5742530

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Hayley C. Warsinske, Robert M. DiFazio, Jennifer J. Linderman, JoAnne L. Flynn, Denise E. Kirschner, Identifying mechanisms driving formation of granuloma-associated fibrosis during Mycobacterium tuberculosis infection, Journal of Theoretical Biology, Volume 429, 21 September 2017, Pages 1-17, DOI: 10.1016/j.jtbi.2017.06.017, PMID: 28642013, PMCID: 5576548

Elsje Pienaar, Jansy Sarathy, Brendan Prideaux, Jillian Dietzold, Véronique Dartois, Denise E. Kirschner, Jennifer J. Linderman, Comparing efficacies of moxifloxacin, levofloxacin and gatifloxacin in tuberculosis granulomas using a multi-scale systems pharmacology approach, PLOS: Computational Biology, Published: August 17, 2017, DOI: 10.1371/journal.pcbi.1005650, PMID: 28817561, PMCID: 5560534

Biomedical Picture of the Day

Joseph M. Cicchese, Elsje Pienaar, Denise E. Kirschner, Jennifer J. Linderman, Applying Optimization Algorithms to Tuberculosis Antibiotic Treatment Regimens, Cellular and Molecular Bioengineering, pp 1-13, 30 August 2017, Pages 1-17, DOI: 10.1007/s12195-017-0507-6, PMID: 29276546, PMCID: 5737793

Article featured on Journal cover

Denise Kirschner, Elsje Pienaar, Simeone Marino, Jennifer J. Linderman, A review of computational and mathematical modeling contributions to our understanding of Mycobacterium tuberculosis within-host infection and treatment, CURRENT OPINION Systems Biology 2017, 3:170-185, DOI: 10.1016/j.coisb.2017.05.014, PMID: 30714019, PMCID: 6354243

Online Supplement

Simeone Marino, Denise E. Kirschner, A Multi-Compartment Hybrid Computational Model Predicts Key Roles for Dendritic Cells in Tuberculosis Infection, Academic Editors: Gennady Bocharov, Olga Solovyova and Vitaly Volpert, Computation 2016, 4, 39, DOI: 10.3390/computation4040039, PMID: 28989808, PMCID: 5627612

Elsje Pienaar, William M. Matern, Jennifer J. Linderman, Joel S. Bader, Denise E. Kirschner, Multiscale Model of Mycobacterium tuberculosis Infection Maps Metabolite and Gene Perturbations to Granuloma Sterilization Predictions, Infect Immun. 2016 Apr 22;84(5):1650-69. Print 2016 May., DOI: 10.1128/IAI.01438-15, PMID: 26975995, PMCID: 4862722

Supplemental Information - Supplement1

Simeone Marino, Hannah P. Gideon, Chang Gong, Shawn Mankad, John T. McCrone, Philana Ling Lin, Jennifer J. Linderman, JoAnne L. Flynn, Denise E. Kirschner, Computational and Empirical Studies Predict Mycobacterium tuberculosis-Specific T Cells as a Biomarker for Infection Outcome, PLoS Computational Biology, 2016, DOI: 10.1371/journal.pcbi.1004804, PMID: 27065304, PMCID: 4827839

Cordelia Ziraldo, Chang Gong, Denise E. Kirschner, and Jennifer J. Linderman, Strategic Priming with Multiple Antigens can Yield Memory Cell Phenotypes Optimized for Infection with Mycobacterium tuberculosis: A Computational Study, Frontiers in Microbiology, 2016, Volume 6, Article 1477, DOI: 10.3389/fmicb.2015.01477, PMID: 26779136, PMCID: 4701940

Jennifer J. Linderman, Denise E. Kirschner, In silico models of M. tuberculosis infection provide a route to new therapies, Drug Discovery Today: Disease Models, Volume 15, Spring 2015, Pages 37-41, DOI: 10.1016/j.ddmod.2014.02.006, PMID: 26904139, PMCID: 4758993

Elsje Pienaar, Véronique Dartois, Jennifer J. Linderman, Denise E. Kirschner, In silico evaluation and exploration of antibiotic tuberculosis treatment regimens, BMC Systems Biology 2015, 9:79, DOI: 10.1186/s12918-015-0221-8, PMID: 26578235, PMCID: 4650854

Jennifer J. Linderman, Nicholas A. Cilfone, Elsje Pienaar, Chang Gong, Denise E. Kirschner, A Multi-scale Approach to Designing Therapeutics for Tuberculosis, Integrative Biology (2015), DOI: 10.1039/C4IB00295D, PMID: 25924949, PMCID: 4436084

Cilfone, N, Pienaar, E, Thurber, G, Kirschner, D and Linderman, JJ., A systems pharmacology approach towards the design of inhaled formulations of rifampicin and isoniazid for treatment of tuberculosis, CPT Pharmacometrics Syst. Pharmacol. (2015) 4, e22, DOI: 10.1002/psp4.22, PMID: 26225241, PMCID: 4394619

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Gong, Chang, Linderman, J and Kirschner, D., A population model capturing dynamics of tuberculosis granulomas predicts infection outcomes, Mathematical Biosciences and Engineering, pp: 625-642, Volume 12, Issue 3, June 2015, DOI: 10.3934/mbe.2015.12.625, PMID: 25811559, PMCID: 4447319

Nicholas A. Cilfone, Christopher B. Ford, Simeone Marino, Joshua T. Mattila, Hannah P. Gideon, JoAnne L. Flynn, Denise E. Kirschner and Jennifer J. Linderman, Computational Modeling Predicts IL-10 Control of Lesion Sterilization by Balancing Early Host Immunity-Mediated Antimicrobial Responses with Caseation during Mycobacterium tuberculosis Infection, J Immunol. 2015 Jan 15;194(2):664-77 DOI: 10.4049/jimmunol.1400734, PMID: 25512604, PMCID: 4283220

Hannah Priyadarshini Gideon, JiaYao Phuah, Amy J. Myers, Bryan D. Bryson, Mark A. Rodgers, M. Teresa Coleman, Pauline Maiello, Tara Rutledge, Simeone Marino, Sarah M. Fortune, Denise E. Kirschner, Philana Ling Lin, JoAnne L. Flynn, Variability in Tuberculosis Granuloma T Cell Responses Exists, but a Balance of Pro- and Anti-inflammatory Cytokines Is Associated with Sterilization, PLOS: Pathogens, January 22, 2015 DOI: 10.1371/journal.ppat.1004603, PMID: 25611466, PMCID: 4303275

Elsje Pienaar, Nicholas A. Cilfone, Philana Ling Lin, Veronique Dartois, Joshua T. Mattila, J. Russell Butler, JoAnne L. Flynn, Denise E. Kirschner, Jennifer J. Linderman, A computational tool integrating host immunity with antibiotic dynamics to study tuberculosis treatment, Journal of Theoretical Biology (2015), pp. 166-179, published online: 24-DEC-2014 DOI: 10.1016/j.jtbi.2014.11.021, PMID: 25497475, PMCID: 4332617

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Simeone Marino, Nicholas A. Cilfone, Joshua T. Mattila, Jennifer J. Linderman, JoAnne L. Flynn, and Denise E. Kirschner, Macrophage Polarization Drives Granuloma Outcome during Mycobacterium tuberculosis Infection, Infect. Immun. January 2015 83:324-338; Accepted manuscript posted online, 3 November 2014, DOI: 10.1128/IAI.02494-14, PMID: 25368116, PMCID: 4288886

Nicholas A. Cilfone, Cory R. Perry, Denise E. Kirschner, Jennifer J. Linderman, Multi-Scale Modeling Predicts a Balance of Tumor Necrosis Factor-α and Interleukin-10 Controls the Granuloma Environment during Mycobacterium tuberculosis Infection, PLOS One, July 15, 2013, 8(7):e68680, Volume 8, Issue 7, DOI: 10.1371/journal.pone.0068680, PMID: 23869227, PMCID: 3711807

Joshua T. Mattila, Olabisi O. Ojo, Diane Kepka-Lenhart, Simeone Marino, Jin Hee Kim, Seok Yong Eum, Laura E. Via, Clifton E. Barry III, Edwin Klein, Denise E. Kirschner, Sidney M. Morris, Jr., Philana Ling Lin, JoAnne L. Flynn, Microenvironments in Tuberculous Granulomas Are Delineated by Distinct Populations of Macrophage Subsets and Expression of Nitric Oxide Synthase and Arginase Isoforms, J Immunol 2013 191:773-784; published ahead of print June 7, 2013, DOI: 10.4049/jimmunol.1300113, PMID: 23749634, PMCID: 3746594

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Myers AJ, Marino S, Kirschner DE, Flynn JL, Inoculation Dose of Mycobacterium tuberculosis Does Not Influence Priming of T Cell Responses in Lymph Nodes, J Immunol. 2013 Apr 1 [Epub ahead of print], DOI: 10.4049/jimmunol.1203465, PMID: 23547119, PMCID: 3674545

M. El-Kebir, M. van der Kuip, A.M. van Furth, D.E. Kirschner, Computational modeling of tuberculous meningitis reveals an important role for tumor necrosis factor-α, JTB 2013, pp 43-53, DOI: 10.1016/j.jtbi.2013.03.008, PMID: 23542051, PMCID: 3821557

Giorgio Guzzetta, Denise Kirschner, The Roles of Immune Memory and Aging in Protective Immunity and Endogenous Reactivation of Tuberculosis, PLOS 2013, DOI: 10.1371/journal.pone.0060425, PMID: 23580062, PMCID: 3620273

Repasy T, Lee J, Marino S, Martinez N, Kirschner DE, Hendricks G, Baker S, Wilson AA, Kotton DN, Kornfeld H. Intracellular Bacillary Burden Reflects a Burst Size for Mycobacterium tuberculosis In Vivo, PLOS Pathogens 2013, DOI: 10.1371/journal.ppat.1003190, PMID: 23436998, PMCID: 3578792

Fallahi-Sichani M, Marino S, Flynn JL, Linderman JJ, Kirschner DE., A systems biology approach for understanding granuloma formation and function in tuberculosis, Editors: Johnjoe McFadden, Dany Beste and Andrzej Kierzek, Systems Biology of Tuberculosis, Springer (NY) 2013, DOI: 10.1007/978-1-4614-4966-9_7, PMID: (exempt), PMCID: (exempt)

The website of the book that contains the above article: Systems Biology of Tuberculosis

Marino S, Fallahi-Sichani M, Linderman JJ, Kirschner DE, Mathematical models of anti-TNF therapies and their correlation with tuberculosis, In Antibody-mediated Drug Delivery Systems: Concepts, Technology and Applications, Y. Pathak and S. Benita, eds., John Wiley and Sons, Inc., 2012, Hoboken, New Jersey, 83-104, Published Online: 23 APR 2012, DOI: 10.1002/9781118229019.ch5, PMID: (exempt), PMCID: (exempt)

Fallahi-Sichani M, Linderman JJ, Kirschner DE, NF-kB signaling dynamics play a key role in infection control in tuberculosis, Frontiers in Physiology, June 2012, Volume 3, Article 170, DOI: 10.3389/fphys.2012.00170, PMID: 22685435, PMCID: 3368390

Fallahi-Sichani M, Flynn JL, Linderman JJ, Kirschner DE, Differential risk of tuberculosis reactivation among anti-TNF therapies is due to drug binding kinetics and permeability and not apoptotic and cytolytic activities, J. Immunology, 2012, The Journal of Immunology, April 1, vol. 188, no. 7, pp. 3169-3178, DOI: 10.4049/jimmunol.1103298, PMID: 22379032, PMCID: 3311778

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Simeone Marino, Mohammed El-Kebir, Denise Kirschner, A hybrid multi-compartment model of granuloma formation and T cell priming in Tuberculosis. Journal of Theoretical Biology 280 (2011) pp. 50-62., DOI: 10.1016/j.jtbi.2011.03.022, PMID: 21443879, PMCID: 3740747,

Supplemental Information - Supplement1

Fallahi-Sichani, M, El-Kebir, M, Marino, S, Kirschner, D*, Linderman, J. Multi-scale computational modeling reveals a critical role for TNF-α receptor 1 dynamics in tuberculosis granuloma formation. Journal of Immunology, 2011, March 15, vol. 186, no. 6, pp 3472-3483 (corresponding author)., DOI: 10.4049/jimmunol.1003299, PMID: 21321109, PMCID: 3127549

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Marino, S Linderman, J and Kirschner, D. A Multi-faceted Approach to Modeling the immune response in Tuberculosis. WIRES Systems Biology and Medicine 2011, Volume 3, Issue 4, pp. 479-489, July/August, DOI: 10.1002/wsbm.131, PMID: 21197656, PMCID: 3110521

Denise E Kirschner, Douglas Young, and JoAnne L Flynn, Tuberculosis: global approaches to a global disease. Current Opinion in Biotechnology 2010, 21, pp 524-531, DOI: 10.1016/j.copbio.2010.06.002, PMID: 20637596, PMCID: 2943033

Simeone Marino, Amy Myers, JoAnne L. Flynn, Denise E. Kirschner, TNF and IL-10 are major factors in modulation of the phagocytic cell environment in lung and lymph node in tuberculosis: A next-generation two-compartmental model. Journal of Theoretical Biology 265 (2010), pp 586-598, DOI: 10.1016/j.jtbi.2010.05.012, PMID: 20510249, PMCID: 3150786

Supplemental Information - Supplement1

Mohammad Fallahi-Sichani, Matthew A. Schaller, Denise E. Kirschner, Steven L. Kunkel, Jennifer J. Linderman, Identification of Key Processes that Control Tumor Necrosis Factor Availability in a Tuberculosis Granuloma. PLoS Computational Biology, May 2010, Volume 6, Issue 5, (published online only), PMID: 20463877, PMCID: 2865521

Denise E. Kirschner and Jennifer J. Linderman, Mathematical and computational approaches can complement experimental studies of host pathogen interactions. Cellular Microbiology (2009) 11(4), pp 531-539, DOI: 10.1111/j.1462-5822.2009.01281.x, PMID: 19134115, PMCID: 2720090

J. Christian J. Ray, JoAnne L. Flynn, and Denise E. Kirschner, Synergy between Individual TNF-Dependent Functions Determines Granuloma Performance for Controlling Mycobacterium tuberculosis Infection. Journal of Immunology, 2009, 182: pp 3706-3717, DOI: 10.4049/jimmunol.0802297, PMID: 19265149, PMCID: 3182770.

Errata - Table 1 | For Movies and Supplemental Information - Supplement Set 1

Amy L. Bauer, Ian B. Hogue, Simeone Marino, and Denise E. Kirschner, The Effects of HIV Infection on Latent Tuberculosis . Math. Model. Nat. Phenom. Vol. 3, No. 7, 2008, pp. 229-266, PMID: n/a, PMCID: n/a

Stewart T. Chang, Jennifer J. Linderman, and Denise E. Kirschner, Effect of Multiple Genetic Polymorphisms on Antigen Presentation and Susceptibility to Mycobacterium tuberculosis Infection , with supporting text, Infection and Immunity, July 2008, pp. 3221-3232, Vol. 76, No. 7, Copyright 2008, American Society for Microbiology, PMID: 18443099, PMCID: 2446740

Douglas Young, Jaroslav Stark, Denise Kirschner, Systems biology of persistent infection: tuberculosis as a case study . Nature Reviews: Systems Microbiology, July 2008, p. 520-526 Vol. 6, Copyright 2008, Macmillian Publishers Limited, PMID: 18536727, PMCID: n/a

Soumya D. Chakravarty, Guofeng Zhu, Ming C. Tsai, Vellore P. Mohan, Simeone Marino, Denise E. Kirschner, Luqi Huang, JoAnne Flynn, and John Chan, Tumor Necrosis Factor Blockade in Chronic Murine Tuberculosis Enhances Granulomatous Inflammation and Disorganizes Granulomas in the Lungs . Infection and Immunity, Mar. 2008, p. 916-926 Vol. 76, No. 3, Copyright 2008, American Society for Microbiology, PMID: 18212087, PMCID: 2258824

Ray, JCJ, Wang, J., Chan, J., and Kirschner, D. The timing of TNF and IFN-γ signaling affects macrophage activation strategies during Mycobacterium tuberculosis infection . The Journal of Theoretical Biology, 2008, Vol 252, pp. 24-38, DOI: 10.1016/j.jtbi.2008.01.010, PMID: 18321531, PMCID: 2459258

A Systems Biology Markup Language file of the model used in the above project is available here (1).

Simeone Marino, Dhruv Sud, Hillarie Plessner, Philana Ling Lin, John Chan, JoAnne L. Flynn, Denise E. Kirschner Differences in Reactivation of Tuberculosis Induced from Anti-TNF Treatments Are Based on Bioavailability in Granulomatous Tissue . PLoS Computational Biology, Oct 2007, Vol 3, Issue 10, pp. 1909-1924, DOI: 10.1371/journal.pcbi.0030194, PMID: 17953477, PMCID: 2041971

Martin J. Blaser, Denise Kirschner The equilibria that allow bacterial persistence in human hosts . Nature, Vol 449, j18, October 2007, pp 483-489, PMID: 17943121, PMCID: (exempt)

Niyaz Ahmed, of the Pathogen Evolution Laboratory, Centre for DNA Fingerprinting and Diagnostics, India, gives his comments on the article at
This is a provocative yet legitimate proposal on how pathogenic bacteria adapt to their co-evolved hosts across a wide array of conditions linked to biology of both the host and pathogen, over huge evolutionary timescales. The authors focus on the concept that persistence represents finely negotiated, well balanced host- microbial interests, culminating in a long-term equilibrium whose maintenance requires a series of evolved, nested equilibria leading to the overall homeostasis. To support their assumption the authors harness observed pathobiology of three dreaded pathogens (H. pylori, S. typhi and M. tuberculosis). Based on the fact that genomic and biological features of these 'specialist' bacteria are quite diverse, authors generalize their model for other pathogens as well. If it is so, this model may also fit to commensals and other 'generalist' bacteria who might have accompanied humans in various capacities throughout their association. This dogma may therefore be relevant in understanding acquisition and/or attenuation of virulence with the change in human history and ecology. Although this is a largely speculative treatise, I am sure it will provide a foundation for future experimental evidence.
Raymond Mejia, of the National Heart, Lung and Blood Institute (NHLBI), and the National Institutes of Health (NIH), gives his comments on the article at
This study uses a mathematical model to explain bacterial persistence in a host population. Symbiosis is characterized by existence of evolutionary stable states that permit homeostasis. The model is applied to three bacteria with human hosts, H. pylori, S. typhi, and M. tuberculosis, and can be utilized to investigate how virulence may vary with changes in human ecology.

Hillarie L. Plessner, P. Ling Lin,Tadahiko Kohno,James S. Louie,Denise Kirschner,John Chan,and JoAnne L. Flynn Neutralization of Tumor Necrosis Factor (TNF) by Antibody but not TNF Receptor Fusion Molecule Exacerbates Chronic Murine , The Journal of Infectious Diseases, vol. 195, no. 112007, June 1, 2007, pp. 1643-1650, PMID: 17471434, PMCID: (exempt)

Denise Kirschner, The Multi-scale Immune Response to Pathogens: M. tuberculosis as an Example , In Silico Immunology, Springer US, pp. 289-311, 2007, DOI 10.1007/978-0-387-39241-7, PMID: n/a, PMCID: (exempt)

Dhruv Sud, Carolyn Bigbee, JoAnne L. Flynn, and Denise E. Kirschner, Contribution of CD8+ T Cells to Control of Mycobacterium tuberculosis Infection, The Journal of Immunology, 2006, 176: pp 4296-4314, PMID: 16547267, PMCID: (exempt)

Correction to above paper

Denise Kirschner, Victor DiRita, JoAnne L. Flynn, Overcoming Math Anxiety: Malthus Meets Koch , (cover article) ASM News, Vol 71, No 8, August 2005, pp. 357-362, PMID: n/a, PMCID: (exempt)

Suman Ganguli, David Gammack, Denise E. Kirschner, A Metapopulation Model of Granuloma Formation in the Lung During Infection with Mycobacterium Tuberculosis , Mathematical Biosciences and Engineering, Volume 2, Number 3, Aug 2005 - pp. 535-560, PMID: 20369939, PMCID: (exempt)

P. Ling Lin, Denise Kirschner, JoAnne L. Flynn, Modeling pathogen and host: in vitro, in vivo and in silico models of latent Mycobacterium tuberculosis infection, Drug Discovery Today: Disease Models, Vol 2, Issue 2 - 2005 - pp. 149-154, PMID: n/a, PMCID: (exempt)

Simeone Marino, and Denise Kirschner, Mycobacterium tuberculosis as viewed through a computer, TRENDS in Microbiology Vol.13 No.5, pp 206-211, May 2005, PMID: 15866037, PMCID: (exempt)

Stewart T. Chang, Jennifer J. Linderman, and Denise E. Kirschner "Multiple mechanisms allow Mycobacterium tuberculosis to continuously inhibit MHC class II-mediated antigen presentation by macrophages", with supporting text, pp 4530-4535, PNAS March 22, 2005 vol. 102 no. 12., DOI: 10.1073/pnas.0500362102, PMID: 15767567, PMCID: 555518

Victor DiRita of the University of Michigan, gives his comments on the article at
This interesting paper uses mathematical modeling to explore the mechanisms controlling antigen presentation in macrophages infected with Mycobacterium tuberculosis (Mtb). With their model, the authors test hypotheses -- some of them in apparent conflict with each other -- generated from experimental approaches in different labs. By simulating these experimental protocols, the model makes clear that several mechanisms alter antigen presentation in Mtb infected cells. Notable among the findings is the significant delay of about 10 hours seen with mechanisms that alter antigen presentation by affecting class II expression. Furthermore, the model simulations suggest that in the time scale of the experimental approaches previously used, antigen processing and peptide loading could not have accounted for reductions in antigen presentation observed, thus raising the caveat that experimental findings can be biased by the approaches used to generate them. The best math modeling papers are able shed light on biological mechanisms and to guide new experiments, and this paper does both.

David Gammack, Jose L. Segovia-Juarez, Suman Ganguli, Simeone Marino, and Denise Kirschner, Understanding the Immune Response in Tuberculosis Using Different Mathematical Models and Biological Scales, SIAM Journal of Multiscale Modeling and Simulation, Vol. 3, No. 2, pp. 312-345, 2005, PMID: n/a, PMCID: (exempt)

Jose L. Segovia-Juarez, Suman Ganguli, and Denise Kirschner, Identifying control mechanism of granuloma formation during M. tuberculosis infection using an agent based model , Journal of Theoretical Biology. 231, Issue 3, pp 357-376, 2004, PMID: 15501468, PMCID: (exempt)

Errata - The Table in this paper has a small error: The correct T cell movement rate is 2 micrometers/minute.

See for movies and supplementary material.

Gerard Nau of the University of Pittsburgh Medical Center, gives his comments on the article at
This paper is perhaps the most helpful discussion of mathematical modeling applied to biological questions, in this case granuloma formation, that I have read. The descriptive narrative is accessible to biologists when detailed mathematical proofs would make most of us uncomfortable. Although highly dependent on existing experimental data, mathematical modeling is likely to become more popular in biological research for two reasons. First, it permits a critical analysis and manipulation of variables that affect biological process under study. Second, models can highlight areas of experimentation that must be pursued. In this case, slowing of growth rate appears to help M. tuberculosis in its interactions with the host.

S. Marino, S. Pawar, C.L. Fuller, T.A. Reinhart, J.L. Flynn, D.E. Kirschner, Dendritic Cell Trafficking and Antigen Presentation in the Human Immune Response to Mycobacterium Tuberculosis , Journal of Immunology, Jul 1;173(1): pp 494-506, 2004, PMID: 15210810, PMCID: (exempt)

S. Marino, D.E. Kirschner, The Human Immune Response to Mycobacterium Tuberculosis in Lung and Lymph Node , Journal of Theoretical Biology, Vol 227: pp 463-486, 2004, PMID: 15038983, PMCID: (exempt)

D. Gammack, C.R. Doering, D.E. Kirschner, Macrophage response to Mycobacterium tuberculosis infection Journal of Mathematical Biology. Published online: 20 August 2003, In print: Vol 48(2) February 2004, Pages:218-242, PMID: 14745511, PMCID: (exempt)

Denise E. Kirschner, Reconstructing Microbial Pathogenesis ASM NEWS 67: Nov 11, 2001, pp. 566-573 (cover feature), PMID: n/a, PMCID: (exempt)

Wigginton J and Kirschner D. A Model to Predict Cell-Mediated Immune Regulatory Mechanisms During Human Infection with Mycobacterium tuberculosis , J. Immunology 166: pp 1951-1976, 2001, PMID: 11160244, PMCID: (exempt)

Parameter File.

Kirschner D and Freter R. Mathematical Models of Persistent Bacterial Infections.  In: Nataro J, Blaser MJ, and Cunningham-Rungles S. (eds): Persistant Bacterial Infections, for ASM Press Publications, Washington, DC, 2000, pp. 79-99, PMID: n/a, PMCID: (exempt)

Kirschner D, Buchman T. Mathematical modeling in surgical research.  in: Surg Res, Ed: WW Souba and D. Wilmore, (Academic Press, San Diego, 2000) pp. 1105-1115, PMID: n/a, PMCID: (exempt)

Kirschner D. Dynamics of co-infection with M. tuberculosis and HIV-1.  Theor Popul Biol, 55: pp 94-109, 1999, PMID: 9925811, PMCID: (exempt)

Kirschner D. Timebomb: The Global Epidemimc of Multi-drug Resistant TB.  Nature Med. 7: pp 1173-1174, 2001, PMID: n/a, PMCID: (exempt)

In honor of Professor Glen F. Webb's 65th birthday, we would like to refer you to a special issue of Mathematical Modeling of Natural Phenomena dedicated to Glen.


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