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

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.

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.

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.

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

Martin J. Blaser, Denise Kirschner The equilibria that allow bacterial persistence in human hosts . Nature, Vol 449, j18, October 2007, pp 483-489

Niyaz Ahmed, of the Pathogen Evolution Laboratory, Centre for DNA Fingerprinting and Diagnostics, India, gives his comments on the article at facultyof1000.com

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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.

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, October 2007, Volume 3, Issue 10

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

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

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: 4296-4314.

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

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

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

Simeone Marino, and Denise Kirschner, Mycobacterium tuberculosis as viewed through a computer , TRENDS in Microbiology Vol.13 No.5 May 2005

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, 4530 4535 PNAS March 22, 2005 vol. 102 no. 12

Victor DiRita of the University of Michigan, gives his comments on the article at facultyof1000.com

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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

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, Pages 357-376 2004.

Gerard Nau of the University of Pittsburgh Medical Center, gives his comments on the article at facultyof1000.com

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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):494-506, 2004.

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

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 .

Singer, B.H., D.E. Kirschner, Influence of Backward Bifurcation on Interpretation of R0 in a Model of Epidemic Tuberculosis with Reinfection Journal of Mathematical Biosciences and Engineering. Volume 1, Number 1, June 2004 pp. 81-93

Denise E. Kirschner, Reconstructing Microbial Pathogenesis ASM NEWS 67: Nov 11, 2001, pp. 566-573 (cover feature).