HoxB8‐conditional Neutrophil Progenitor Transplant Provides a Therapeutic Benefit for S. aureusPulmonary Infection in a Murine Model of Chronic Granulomatous Disease (CGD)

Abstract

CGD is a congenital disease marked by neutrophil dysfunction leading to increased infectious susceptibility. Despite prophylactic treatment with antimicrobial agents, outcomes for CGD patients are troubling with a typical lifespan of 30‐40 years due to breakthrough infections. As we strive to stay ahead of the impacts of drug‐resistant microbes, it is reasonable to consider cellular therapeutics which replace immune cells to treat CGD and other immunodeficiencies. We hypothesize that a conditionally‐immortalized neutrophil progenitor cell line has a translational application as a therapy for immune compromised hosts. This cell line was first generated by Wang, et al. through inducing ectopic expression of the transcription factor HoxB8 in murine bone marrow stem cells. Induction of HoxB8 leads to exponential growth of cells, while withdrawal leads to differentiation into neutrophil‐like cells. We have found that unconditioned transplant of HoxB8 progenitors lead to robust engraftment in the bone marrow. Engrafted progenitor cells differentiate in vivointo donor‐derived neutrophils found circulating in the peripheral blood. Donor neutrophils are also recruited to the lungs of mice infected with Staphylococcus aureus. Using a novel fluorescent killing assay, we demonstrate that donor‐derived neutrophils can kill pulmonary S. aureus both in vitro and in vivo with comparable efficiency to wild type host neutrophils. Strikingly, our results find that treatment with HoxB8‐conditional progenitors improves survival of CGD animals infected with S. aureus from 0% to >50%. This work demonstrates the potential of conditionally‐immortalized neutrophil progenitors as a novel cellular therapy in the context of neutrophil dysfunction.