Host aging induces a senescent-like phenotype in neutrophils with altered transcriptional responses to Streptococcus pneumoniae infection
Streptococcus pneumoniae is a Gram-positive commensal of the nasopharynx and highly virulent opportunistic pathogen in the respiratory tract. Despite the availability of multiple vaccines, S. pneumoniae remains a significant health burden especially in aged adults resulting in higher rates of serious disease progression, hospitalization, and death following infection. Polymorphonuclear leukocytes (PMNs) are among the first responders in the lung following S. pneumoniae infection. However, studies have indicated that PMNs of human and murine origin are dysfunctional in aged individuals. To identify mechanisms underlying this dysfunction and if it displays characteristics of immunosenescence previously observed in lymphocytes, we conducted RNA sequencing on PMNs in the lungs of young and old mice at 12 and 24 hours post pulmonary infection with S. pneumoniae. Our analysis indicated significant transcriptomic differences between the young and aged cohorts associated with decreased expression of many genes important for effector function including significant metabolic changes. These metabolic changes indicated that PMNS in the lungs of aged mice fail to upregulate glycolysis, which is necessary for anti-pneumococcal activity. Analysis of the transcription factors that may be regulating these differential transcriptomic changes to pneumococcal infection indicated differential regulation by E2f2 in aged mice, which appears to negatively regulate PMN differentiation. Importantly, analysis of PMNs in aged mice display context dependent senescent-like characteristics. Together this would suggest that in aged hosts PMNs display altered maturation and can adopt a senescent-like phenotype in the periphery, which contributes to defective gene expression changes required for normal anti-pneumococcal effector functions. Overall design: Bulk RNA-seq of murine neutrophils (PMNs) in the lungs of animals 12- and 24-hour post intratracheal infection with Streptococcus pneumoniae