Sepsis-induced alterations to the microenvironment promotes maladaptive emergency granulopoiesis and susceptibility to Streptococcus pneumoniae 2253166

Abstract

Abstract Introduction Sepsis survivors exhibit immune dysfunction and profound hematological changes that increase a patient’s risk for recurrent infections and hospital readmission. Methods Using a cecal-ligation and puncture model (CLP; causing 50-70% mortality), followed by Streptococcus pneumoniae (Spn) intranasal challenge, we evaluated mechanisms driving increased susceptibility to secondary infection. Results Sham-surgery controls uniformly survived Spn infection, whereas CLP survivors exhibited 100% morality when challenged day 20 or 40 post-surgery, revealing long-term susceptibility to Spn infection. Neutrophils were increased in the bronchoalveolar lavage fluid (BALF) of both sham and CLP mice, however, only CLP mice exhibited significantly increased neutrophils in the blood, spleen, and liver. Following challenge, CLP mice exhibited maladaptive emergency granulopoiesis evidenced by systemic neutrophilia, expansion of bone marrow (BM) hematopoietic stem and progenitor cells (HSPCs) and marked reduction of mature neutrophils in the BM. Using BM transplantation, we found that sepsis-induced alterations to the microenvironment were sufficient to promote maladaptive emergency granulopoiesis during intranasal Spn challenge. Sepsis survivors challenged with Spn exhibited increased stromal cell populations and osteoblastic progenitors, suggesting profound BM niche remodeling, that correlated with robust splenic extramedullary granulopoiesis. Susceptibility to pneumonia was not due to lung-specific damage as CLP survivors were unable to control intravenous Spn infection. Conclusion Therefore, despite robust granulopoiesis and increased neutrophils, particularly splenic neutrophils, sepsis results in long-term neutrophil dysfunction. Our data demonstrate that sepsis drives durable changes to the microenvironment that support maladaptive granulopoieses programs and increased susceptibility to Spn and pneumonia. Funding Source 5R35GM131842 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)