Human cytomegalovirus (HCMV) remains a significant cause of morbidity and mortality after Hematopoietic Stem Cell Transplantion (HSCT) and Solid Organ Transplantation (SOT). A commonly encountered clinical manifestation of HCMV infection in the HSCT or SOT recipient is myelosuppression. HCMV reactivation and use of the antiviral ganciclovir is associated with a number of cytopenias that increase the risk of secondary bacterial or fungal infections and require growth factor support or transfusion of blood products. Despite the clear clinical relevance of myelosuppression to the transplant recipient with HCMV infection, little is known about the mechanism(s) by which HCMV infection inhibits normal hematopoiesis. HCMV has been shown to inhibit hematopoiesis by the direct infection of hematopoietic progenitor cells (HPCs) and indirectly by the effectofinfectedHPCsonthemicroenvironmentsupportinghematopoiesis. We have recapitulated HCMV myelosuppression in vivo using a humanized mouse model. We furthershowinbothinvitroandinvivomodelsthattheadditionofincreasingnumbersofinfectedCD34+HPCs increases the degree of myelosuppression and that supernatant from infected CD34+ HPCs, as opposed to mock-infected HPCs, suppresses myelopoiesis. Further, Projects 1, 2, 3 and 4 have identified viral proteins andmiRNAsthatdirectlyaltersignalingandeitherpromoteorsuppresshematopoiesisinvitro.Therefore,we hypothesize that HCMV infection reprograms signaling and cytokine secretion in infected cells resulting in a microenvironmentthatinhibitshematopoiesisandcontributestoclinicalmyelosuppressionandhematopoietic failure.Totestourhypothesis,weproposeasystemsapproachtodefinethechangesinsignalingandcytokine secretionusingbothinvitroandinvivomodels.Weproposethefollowingspecificaims.
SpecificAim1. How doesHCMVinfectionofCD34+HPCsinvitroregulatehematopoiesis?WehypothesizethatHCMVsuppresses CD34+ HPC differentiation by altering signaling and secretion in the infected cell.
Specific Aim 2. How does HCMV regulate hematopoiesis in vivo? We hypothesize that HCMV infection alters the microenvironment for hematopoiesisinthehostorganism.
SpecificAim3. WhatarethemolecularsignaturesassociatedwithHCMV myelosuppression in HSCT and SOT patients? We hypothesize that HCMV-mediated changes in cytokine secretionimpedehematopoieticreconstitutioninHSCTandSOTpatients. IMPACT:Takentogether,ourprojectprovidesauniqueopportunitytomakeunprecedentedadvancements in our understanding of the mechanistic basis of HCMV-mediated myelosuppression. This advancement is driven by the development of the state-of-the-art huBLT mouse model and the identification of virus-host interactionsimpactinghematopoiesisandthekeycytokineandmolecularsignaturesthatpredictdisease.
PROJECT 5 NARRATIVE Human cytomegalovirus causes severe disease in allogeneic stem cell transplant and solid organ transplant patients. By defining the mechanisms of viral latency and reactivation within the host and how normal hematopoiesis occurs and how the virus upsets this critical process, we (as a group) will provide fundamental insight into the underlying viral pathogenesis, as well as open up new potential targets for therapeutic or pharmacological intervention.
| Collins-McMillen, Donna; Chesnokova, Liudmila; Lee, Byeong-Jae et al. (2018) HCMV Infection and Apoptosis: How Do Monocytes Survive HCMV Infection? Viruses 10: |
| 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; 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 : |
