The primary goal of this Core is to generate humanized mice that can be used to test HCMV latency and reactivation as well as hematopoiesis using HCMV mutants generated in Projects 1-5. The long-term goal of Core A is to generate huBLT mice to answer in vivo questions of HCMV latency, reactivation and hematopoiesis based on in vitro CMV models proposed in the various studies embedded in the Program Project. First, the Core will generate huBLT mice to analyze HCMV mutants generated in Projects 1-4 for their ability to establish and maintain latency and reactivate following treatment with G-CSF and AMD-3100. Once Projects 1-4 will have identified signaling pathways and/or secreted factors that are important for HCMV latency and reactivation, Core A will validate them using chemical inhibitors, neutralizing antibodies, recombinant HCMV expressing shRNAs and/or addition of cytokines/growth factors required for reactivation. Second, the Core will analyze hematopoiesis in huBLT mice infected with WT HCMV (Project 5) or viral mutants (Projects 1-4) and then will validate the results using chemical inhibitors, neutralizing antibodies, recombinant HCMV expressing shRNAs and/or addition of cytokines/growth factors required for hematopoiesis.
Human Cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality after Solid Organ Transplantation (SOT) and Hematopoietic Stem Cell Transplantation (HSCT), and myelosuppression is a common clinical manifestation of HCMV infection in these patients. The goal of this Program Project Grant (PPG) proposal is to determine mechanisms involved in HCMV latency, reactivation as well as bone marrow graft rejection and hematopoiesis. Core A will be instrumental in providing an animal model (humanized BLT mice) required to extend and validate the in vitro findings of Projects 1-5 in a unique in vivo setting.
|Crawford, Lindsey B; Kim, Jung Heon; Collins-McMillen, Donna et al. (2018) Human Cytomegalovirus Encodes a Novel FLT3 Receptor Ligand Necessary for Hematopoietic Cell Differentiation and Viral Reactivation. MBio 9:|
|Collins-McMillen, Donna; Chesnokova, Liudmila; Lee, Byeong-Jae et al. (2018) HCMV Infection and Apoptosis: How Do Monocytes Survive HCMV Infection? Viruses 10:|
|Collins-McMillen, Donna; Stevenson, Emily V; Kim, Jung Heon et al. (2017) HCMV utilizes a non-traditional STAT1 activation cascade via signaling through EGFR and integrins to efficiently promote the motility, differentiation, and polarization of infected monocytes. J Virol :|