Harnessing Trained Immunity as a Radiation Medical Countermeasure - PROJECT SUMMARY Radiation exposure causes acute and chronic injuries to cells, tissues, and organs that induce inflammatory and immune complications. Among the most serious complications is predisposition to life-threatening opportunistic infections due to hematopoietic and immune system damage. Long term effects referred to as delayed effects of acute radiation exposure (DEARE) can also occur leading to progressive organ system failure and increased risk of developing cancer or other chronic diseases. Our radiation MCM development research program centers on the concept of targeting innate immune pathways to induce protective anti-microbial immunity and restore immune system homeostasis. We discovered that treating mice with CpG-DNA, a Toll-like receptor 9 (TLR9) agonist found in bacteria and mitochondria, can restore anti-microbial immune function in mice exposed to immune-compromising total body irradiation (TBI) radiation doses. CpG-DNA induces trained immunity in mice via a mechanism involving mesenchymal stromal cells (MSC) effects on hematopoietic stem cells (HSC). The immune regenerative activity of CpG-DNA enhances anti-microbial immunity and reduces DEARE. As such, this project will address the next phases of developing CpG-DNA as a MCM strategy for radiation as well as radiation with traumatic injury. Given the complexity of radiation and traumatic injuries, we will use systems biology research methods to explore detailed changes in the hematopoietic and immune system. To implement translational potential, gender and natural immune “dirty” mice will be included in the experimental design of these pre-clinical studies. We hypothesize that CpG-DNA treatment will help regenerate hematopoietic system recovery by acting on bone marrow hematopoietic and progenitor cells to promote early and late recovery responses in people that may be exposed to radiation with or without trauma. Project aims will (1) systematically test, develop, and optimize CpG-DNA MCM treatment approaches for radiation injuries, (2) identify functional effects of CpG-DNA MCM treatments on infection and immune system recovery after radiation with and without trauma, (3) discover molecular and cellular mechanisms involved in the immune regenerating activity of CpG- DNA. We hypothesize that targeting innate pathways will signaling “upstream” networks to regenerate “downstream” injurious complications of radiation exposure by promoting homeostasis and recovery responses. We expect that the findings from this project will support future translation for CpG-DNA for use in immune compromised people exposed to radiation or other insults that suppress normal immune function and homeostasis.
