Description of Research Interests – Jay R. Radke, Ph.D.


Research in my laboratory is focused on understanding how two human adenovirus (Ad) genes (E1A and E1B) modulate both the host innate immune response and cell death pathways. The ultimate goal of our research is to develop novel treatments for virus induced acute respiratory distress syndrome (ARDS) and for improving the efficacy of oncolytic adenoviruses for treating cancer. We have described a novel, immunorepressive activity of Ad infected dying cells (termed Ad CPE corpses) that modulate the Ad-induced, innate immune response. Ad CPE corpse repression of macrophage-mediated inflammatory responses requires expression of the Ad protein, E1B 19/20K. Ad CPE corpses resulting from infection with Ad that lack E1B 19K, fail to repress Ad-induced macrophage pro-inflammatory responses and, in contrast, can induce increases in such responses. Ad14p1 is an emergent strain of Ad14 that induces a strong inflammatory response during infection that can result in severe, acute lung injury and, in some cases, ARDS. Studies showed reduced E1B 20K expression in virally infected human cells, when compared with wild type (wt) Ad14 infection. As a result, Ad14p1 CPE corpses fail to repress pro-inflammatory macrophage responses, whereas wt Ad14 CPE corpses are markedly immunorepressive. Syrian hamsters are permissive for human adenoviruses. Infection of Syrian hamsters revealed that Ad14p1 infection induces a patchy bronchopneumonia that is not seen following infection with Ad14. Ad14p1 infected hamsters also show up-regulation of pro-inflammatory cytokines, consistent with our in vitro model system. Currently, we are developing new methods to characterize the innate immune response in the lungs of Ad14p1 lungs and testing novel mechanisms through which Ad14 CPE corpses repress pro-inflammatory macrophage responses. With the goal to developing novel methods to treat viral and non-viral induced ARDS. The second focus of my research is understanding how stable expression of E1A (outside the context of viral infection) alters cellular apoptotic pathways, which results in cellular sensitivity to both innate immune effector cells, chemotherapeutic drugs and other apoptosis inducing agents as well as to innate immune effector cells such as activated macrophages and natural killer cells. We have demonstrated that E1A sensitizes cells to apoptosis induced by intrinsic injuries by enhancing caspase-2 activation through the PIDDosome. It appears that PIDDosome mediated caspase-2 activation is also required for macrophage and NK induced cell death of E1A expressing cells. We are currently trying to identify how E1A expression regulates PIDDosome formation and its activation of caspase-2.



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