Systems virology of coxsackievirus B3 pathogenesis

An ERK–p38 subnetwork coordinates host-cell apoptosis and necrosis during coxsackievirus B3 infection. (2013) Cell Host Microbe, 13, 67-76. [link to article]

Coxsackievirus B3 (CVB3) is a cardiotropic positive-strand RNA virus that is a leading cause of viral myocarditis and heart failure in infants and young children. Nearly all work on CVB3 virology has focused on the docking interactions and gene products of the virus. Sparked by an early collaboration with the McManus laboratory (University of British Columbia), my group has taken a fundamentally different view of CVB3 pathogenesis as a systems-level perturbation of the host.

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).

Selected Publications

  1. 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]
  2. 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]
  3. 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]