Sex Differences in the Innate Immune Response to Pneumococcal Pneumonia

Abstract

Men are more likely to acquire and die from pneumonia compared to women, however the mechanism underlying this phenomenon is not yet fully understood. Thus, we explored sex differences in the innate immune system and immune response to Streptococcus pneumoniae infection (the most common bacterial cause of pneumonia). Female mice had greater survival compared to males after low- but not high-dose S. pneumoniae infection. RNAseq analysis of their lungs 6 hrs post infection (p.i.) revealed that chemokine signaling was differentially expressed during infection by sex. Using flow cytometry, we found that female mice had a stronger monocytic response while males had a neutrophilic response. Females had greater bone marrow monocyte progenitor counts at 18 hrs p.i. while males had more bone marrow neutrophils. Female bone marrow monocytes also had higher CCR2 expression at this time. Female mice recruited more monocytes to their lungs and had higher interstitial macrophage levels after infection, while males had more rapid neutrophil recruitment. Female lungs also had higher local inflammation after infection, but that males had higher persistent systemic inflammation after infection. Female monocytes and macrophages produced more tumor necrosis factor (TNF) after low- but not high-dose pneumococcal stimulation. Although male monocytes and macrophages had higher TNFR and TLR2 expression, male macrophages also had higher levels of NF-κB negative regulator expression (A20, Otulin, Cyld, Cezanne), perhaps explaining their depressed cytokine production. Monocyte depletion during infection diminished the female survival advantage, suggesting that monocyte recruitment is protective during infection. During aging, we highlighted how female mice appear to exhibit more dramatic changes in peripheral monocyte counts, bone marrow progenitor frequencies, bone marrow monocyte CCR2 expression. Furthermore, aging may increase baseline lung inflammation and monocyte TNF production after pathogenic stimulus in females but not males. Our findings highlight how biological sex impacts the murine immune system, and especially on monocytes.