Regulators of Neutrophilic Inflammation in Community Acquired Pneumonia

Community Acquired Pneumonia (CAP) remains one of the front running causes of lethality worldwide, with an estimated 1.6 million deaths provoked by its leading causative pathogen, Streptococcus pneumoniae (S. pn).

After its commencement as an acute pathogen driven local infection, a breakdown of the alveolar-endothelial lung barrier may ensue, resulting in systemic CAP which leads to the spread of bacteria into secondary lymphoid organs and sepsis; ultimately becoming fatal. The series of events, mechanisms and triggers leading to lung barrier dysfunction remains to be elucidated, hence the discovery of novel clinical and molecular biomarkers remains critical for diagnostic and prognostic purposes.

Recent studies have shown that microRNA-223 (miR-223) directly targets CXCL2 and CCL3 for endogenous degradation. In line with this finding, we have observed an increased influx of neutrophils into the lungs and bronchoalveolar lavage of S. pn infected miR-223^–/– mice compared to wild type (WT) mice, 48h post infection π. Concordantly, we have also detected significantly enhanced miR-223 expression in lung homogenates of WT mice 24h pi with S. pn serotypes 2 & 3. Moreover, miR-223^–/– mice suffered from more severe illness despite evident neutrophilia, as evidenced by the increased weight loss and higher bacterial burden in the lungs and secondary lymphoid organs 48h pi.

By analysis of S. pn infected mice (WT vs. miR-223 ^–/–) at various time points, we aim to bring light to the role of miR-223 in CAP. Other aims include understanding the temporal and cellular expression pattern in myeloid cells, host/pathogenic factors influencing miR-223 regulation, specific roles of miR-223 in neutrophil homeostasis, and discovering new mechanistic roles of miR-223 in S. pn pathogenesis.

Martin Witzenrath^*, Geraldine Nouailles^*

*Authors contributed equally