Plasma from patients with bacterial sepsis or severe COVID-19 induces suppressive myeloid cell production from hematopoietic progenitors in vitro
Miguel Reyes, Michael R. Filbin, Roby P. Bhattacharyya, Abraham Sonny, Arnav Mehta, Kianna Billman, Kyle R. Kays, Mayra Pinilla-Vera, Maura Benson, Lisa A. Cosimi, Deborah T. Hung, Bruce D. Levy, Alexandra–Chloé Villani, Moshe Sade-Feldman, Rebecca M. Baron, Marcia B. Goldberg, Paul C. Blainey, Nir Hacohen
Abstract
MS1 monocytes from healthy bone marrow hematopoietic stem and progenitor cells (HSPCs). We found that plasma from patients with bacterial sepsis or COVID-19 induced myelopoiesis in HSPCs in vitro and expression of the MS1 gene program in monocytes and neutrophils that differentiated from these HSPCs. Furthermore, we found that plasma concentrations of IL-6, and to a lesser extent IL-10, correlated with increased myeloid cell output from HSPCs in vitro and enhanced expression of the MS1 gene program. We validated the requirement for these two cytokines to induce the MS1 gene program through CRISPR-Cas9 editing of their receptors in HSPCs. Using this cellular model system, we demonstrated that induced MS1 cells were broadly immunosuppressive and showed decreased responsiveness to stimulation with a synthetic RNA analog. Our in vitro study suggests a potential role for systemic cytokines in inducing myelopoiesis during severe bacterial or SARS-CoV-2 infection.