Host-Pathogen Interactions in Persistent Infectious Diseases
The work in my laboratory focuses mainly on questions related to host-pathogen interactions in infectious diseases. This means defining both the immune responses and the microbial characteristics that lead to infection and disease. In particular, our main focus is studying persistent infections—infections that the host is not able to clear. The persistent pathogens we focus on include both bacteria (e.g. Helicobacter pylori and Mycobacterium tuberculosis) and HIV-1. Such pathogens have evolved strategies to evade or circumvent the host-immune response and our goal is to understand the complex dynamic involved in host-pathogen interactions, together with how perturbations to this interaction (via treatment with chemotherapies or immunotherapies) can lead to prolonged or permanent health of the patient. Drug-resistance and the effects of treatment can be efficiently studied in this setting.
Currently, our research focus is on the role of the host response in pathogenesis. The R01s funding our work aim to examine the immune responses in both HIV and TB infections in the lung . There are unique structures, granulomas, that are involved in the immune response to M. tuberculosis and we are developing methods to better understand their formation and function. In our HIV-1 studies, we are exploring the lung environment as an indicator of overall infection progression. This data could have a profound impact on our understanding the different disease trajectories seen in patients infected with persistent pathogens. We apply a host of computational tools from deterministic mathematical models to more discrete stochastic ones such as Agent Based Models and PDEs to examine spatial questions as well. Our broader goal is to develop a paradigm for understanding host-pathogen interactions leading to the pathogenesis of these persistent pathogens.
Denise E. Kirschner and Jennifer J. Linderman Mathematical and computational approaches can complement experimental studies of host pathogen interactions. Cellular Microbiology (2009) 11(4), doi:10.1111/j.1462-5822.2 009.01281.x, PMID: 19134115, PMCID: PMC2720090, NIHMSID: NIHMS113676
J.J. Linderman, T. Riggs, M. Pande, M. Miller, S. Marino, and D. Kirschner, “Characterizing the Dynamics of CD4+ T Cell Priming within a Lymph Node”. Journal of Immunology, Mar 2010; 184: 2873 – 2885, PMID: 20154206, PMCID: n/a, NIHMSID: NIHMS217408
Mohammad Fallahi-Sichani, Matt Schaller, Denise Kirschner, Steve L Kunkel, Jennifer J Linderman, “Identification of Key Processes that Control Tumor Necrosis Factor Availability in a Tuberculosis Granuloma”, PLoS Comput Biol 6(5) 2010, e1000778.doi:10.1371/ journal.pcbi.1000778, PMID: 20463877, PMCID: PMC2865521, NIHMSID: n/a
Kirschner, D Young, D and Flynn, J. Tuberculosis: Global Approaches to a Global Disease Current Opinions in Biotechnology Vol 21:524-531. 2010. PMID: 20637596
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 Volume 265, Issue 4, Pages 586-598 Journal of Theoretical Biology, August 2010, PMID: 20510249
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, PMID: 21197656, PMCID: 3110521
Fallahi-Sichani, M, El-Kebir, M, Marino, S, Kirschner, D*, Linderman, J. Multi-scale computational modeling reveals a critical role for TNF receptor 1 dynamics in tuberculosis granuloma formation Journal of Immunology, Journal of Immunology, Vol 186 (6) pps. 2011. (corresponding author).
Marino, S, El-Kebir, M, Kirschner, D. A hybrid multi-compartmental model of granuloma formation and T cell priming in Tuberculosis Journal of Theoretical Biology, Vol 280, 2011, pps. 50-62.
Guzzetta, G, Ajelli, M, Yang, Z, Merler, S, Furlanello, C, Kirschner, D. Modeling socio-demography to capture TB transmission in a low burden setting J. Theo. Biology, Nov 21 2011. 289:197-205. PMID: 21906603, PMCID: 3208139
Mirsky, H, Miller, M. Linderman, J and Kirschner, D. Systems Biology approaches toward understanding immune cell dynamics in lymph nodes, Journal of Theoretical Biology, Jan, ISSN 0022-5193, DOI: 10.1016/j.jtbi.2011.06.037., PMID: 21798267 2011.
Fallahi-Sichani, M, Flynn, JL, Linderman, JJ and Kirschner, D. Differential Risk of TB reactivation among anti-TNF therapies is due to drug binding kinetics and permeability. Journal of Immunology (in press), 2012.
Young, D, Stark, J and Kirschner, D. Systems Biology Of Persistent Infection: tuberculosis as a case study. Nature Reviews Microbiology, July 2008, p. 520-526 Vol. 6., PMID: 18536727, PMCID: n/a, NIHMSID: n/a