Neutrophil progenitor cell therapy rescues host defense against Staphylococcus aureus in murine chronic granulomatous disease

Abstract

Despite advances in engineered adaptive immune cell therapies, current options for innate immune cell therapies are sparse. In this work, we demonstrate the utility of a neutrophil progenitor-based cell therapy. Murine conditionally-immortalized neutrophil progenitors (NPs) overcome the hurdles of alternative cell therapies by engrafting in the unconditioned host and substantially contributing to the host neutrophil population. Here we demonstrate the therapeutic value of NPs using a murine model of the primary immunodeficiency chronic granulomatous disease (CGD). Those with CGD are highly susceptible to infection with Staphylococcus aureus because of genetic mutations that impair neutrophil antimicrobial function. We find that the prophylactic treatment of CGD mice with transfused NPs rescue them from an otherwise lethal S. aureus pulmonary infection. In investigating the mechanisms behind the improved clearance of S. aureus and survival of CGD mice, our data suggests that the antimicrobial function of host CGD neutrophils is rescued by the presence of donor-derived wild-type neutrophils. We also observe that survival is improved to >50% in the CGD model when mice receive NPs post-infection. This work highlights the application of NPs to improving outcomes to acute bacterial infection in CGD, demonstrating the translational potential of conditionally-immortalized myeloid progenitors as a cellular therapy.