Regulators of Neutrophilic Inflammation in Community Acquired Pneumonia

Community Acquired Pneumonia (CAP) remains amongst the leading causes of lethality worldwide, with Streptococcus pneumoniae (S.pn.) being its primary causative pathogen. During its lethal manifestation – severe CAP – a breakdown of the alveolar-endothelial lung barrier ensues. The importance of neutrophils in streptococcal clearance is widely accepted, however exacerbated neutrophil responses cause tissue damage and could be involved in fatal lung barrier breakdown. By analysis of serotype 2 & 3 (ST2 & ST3) S.pn.-infected C57BL/6J wild-type (WT) vs. microRNA-223 knockout (miR-223 ^–/–) mice, we aim to elucidate the role of the neutrophil regulator miR-223 in CAP. In vivo, a 10-fold increase in miR-223 expression was quantified in lung homogenates of WT mice 24h, 36h and 48h post-infection (p.i.) with S.pn. ST3 while a 2-fold increase was quantified following ST2 infection 24h p.i.. Both miR-223 ^–/– and WT mice infected transnasally with S.pn. ST3 exhibited a very severe disease course as evidenced by the bacterial burden in lungs and secondary lymphoid organs coupled to dramatic levels of cellular infiltrates in the lung, rendering miR-223 dispensable to disease course or outcome. In response to infection with S.pn. ST2 however, miR-223 ^–/– mice exhibited higher bacterial burden in the lungs, BAL and associated secondary lymphoid organs, contrastingly accompanied by higher neutrophilic influx into the lungs and bronchoalveolar lavage (BAL) 48h p.i.. Current and future analyses, including functional in vitro assays, inflammatory cytokine quantification and histopathological examinations, aim at revealing the reasons behind the high bacterial burden despite an elevated and sustained neutrophilic response in miR-223^–/– mice and will illuminate the precise role of miR-223 in CAP pathogenesis.

^*Authors contributed equally