Altered neutrophil homeostasis in sepsis survivors correlates with increased susceptibility to Streptococcus pneumoniae infection 4240

Description Sepsis survivors exhibit immune dysfunction and profound hematological changes thus increasing a patient’s risk for recurrent infections and hospital readmission. Using a cecal-ligation and puncture model (CLP; causing 50-70% mortality), followed by S. pneumoniae (Sp) intranasal challenge, we evaluated mechanisms driving increased susceptibility to subsequent infection. Whereas sham controls uniformly survived, CLP mice exhibited 100% morality when challenged day 20 post-surgery. CLP mice also exhibited uncontrolled Sp growth in the bronchoalveolar lavage fluid (BALF) whereas sham effectively cleared Sp. Although neutrophils were increased in the BALF of both sham and CLP mice, only CLP mice exhibited increased neutrophils in the blood, spleen, and liver. Sp challenge did not elicit an increase of bone marrow (BM) neutrophils in sham or CLP mice, and transcriptomics of BM showed that genes involved in myeloid cell homeostasis were downregulated in CLP mice. Increased susceptibility was, in part, due to defects of the hematopoietic compartment as recipients of BM from CLP mice were more susceptible to Sp infection. Recipients of CLP BM exhibited increased BM neutrophils, but reduced neutrophils in the blood and peripheral tissues during Sp challenge, suggesting impaired infection-induced neutrophil mobilization. Our data suggests that sepsis induces long-term changes to granulocyte production and homeostasis, thus contributing to increased susceptibility to Sp infection. Funding Sources 5R35GM131842 Topic Categories Innate Immune Responses and Host Defense: Cellular Mechanisms (INC)