Systems virology of coxsackievirus B3 pathogenesis
By exploiting the polypharmacology of host-cell signaling inhibitors, we have uncovered novel posttranslational and autocrine mechanisms during acute CVB3 infection (1). Moreover, we have shown that dynamic changes in the host-cell signaling network are sufficient to predict the outcome of acute infection to within 97% accuracy (2). Combinatorial perturbation of the most-informative host-cell pathways reduced CVB3 transmission by 1000-fold and revealed new mechanisms of cytotoxicity during infection. Ongoing work is focused on systems-level analysis of signaling dysfunction during chronic CVB3 infection in an in vitro model. Chronic CVB3 infection ultimately leads to dilated cardiomyopathy and the need for heart transplantation in infected patients. We seek to determine whether systems-biology approaches can have the same impact on virology as they have had on cancer biology (3).
- Jensen KJ, Garmaroudi FS, Zhang J, Lin J, Boroomand S, Zhang M, Luo Z, Yang D, Luo H, McManus BM*, and Janes KA*. (2013) An ERK–p38 subnetwork coordinates host-cell apoptosis and necrosis during coxsackievirus B3 infection. Cell Host Microbe, 13, 67-76. [Link to Article]
- Lopacinski AB*, Sweatt AJ*, Smolko CM, Gray-Gaillard E, Borgman CA, Shah M†, Janes KA†. (2021) Modeling the complete kinetics of coxsackievirus B3 reveals human determinants of host-cell feedback. Cell Systems, 12, 304. [Link to Article]
- Garmaroudi FS, Marchant D, Si X, Khalili A, Bashashati A, Wong BW, Tabet A, Ng RT, Murphy K, Luo H, Janes KA*, McManus BM*. (2010) Pairwise network mechanisms in the host signaling response to coxsackievirus B3 infection. Proc Natl Acad Sci, 107, 17053-8 [Link to Article]
- Shah M, Smolko CM, Kinicki S, Chapman ZD, Brautigan DL, Janes KA. (2017) Profiling subcellular phosphatase responses to coxsackievirus B3 infection of cardiomyocytes. Mol Cell Proteomics, 16, S244-S262. [Link to Article]