S100A9 is indispensable for survival of pneumococcal pneumonia in mice

Abstract

S100A8/A9 has important immunomodulatory roles in antibacterial defense, but its relevance in focal pneumonia caused by Streptococcus pneumoniae (S. pneumoniae) is understudied. We show that S100A9 was significantly increased in BAL fluids of patients with bacterial but not viral pneumonia and correlated with procalcitonin and sequential organ failure assessment scores. Mice deficient in S100A9 exhibited drastically elevated Zn2+ levels in lungs, which led to bacterial outgrowth and significantly reduced survival. In addition, reduced survival of S100A9 KO mice was characterized by excessive release of neutrophil elastase, which resulted in degradation of opsonophagocytically important collectins surfactant proteins A and D. All of these features were attenuated in S. pneumoniae-challenged chimeric WT→S100A9 KO mice. Similarly, therapy of S. pneumoniae-infected S100A9 KO mice with a mutant S100A8/A9 protein showing increased half-life significantly decreased lung bacterial loads and lung injury. Collectively, S100A9 controls central antibacterial immune mechanisms of the lung with essential relevance to survival of pneumococcal pneumonia. Moreover, S100A9 appears to be a promising biomarker to distinguish patients with bacterial from those with viral pneumonia. Trial registration: Clinical Trials register (DRKS00000620).

The oxidative stress response of Streptococcus pneumoniae: its contribution to both extracellular and intracellular survival

“…Notably, a significant release of CP has been observed during the course of pneumococcal infections ( Raquil et al, 2008 ). In an infection model involving mice lacking S100A9, it was observed that pneumococcal pneumonia worsened ( Ostermann et al, 2023 ). The sequestration of Mn 2+ by CP plays a crucial role in the defense against infection and is a vital component of the innate immune response to bacterial pathogens.…”

Elevated level of circulating calprotectin correlates with severity and high mortality in patients with COVID‐19

“…Calprotectin could modulate cyclooxygenase activity to regulate the expression of prostaglandin analogs, promoting the adhesion of phagocytes to the vascular endothelium and thrombi formation 13,14 . Moreover, it has potent antimicrobial effects against various bacterial and fungal pathogens 15 . As an acute phase reactant, the expression level of calprotectin is often increased following infection, trauma, and inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease, serving as a biomarker to help with the diagnosis.…”

“… 13 , 14 Moreover, it has potent antimicrobial effects against various bacterial and fungal pathogens. 15 As an acute phase reactant, the expression level of calprotectin is often increased following infection, trauma, and inflammatory diseases such as rheumatoid arthritis, ankylosing spondylitis, and inflammatory bowel disease, serving as a biomarker to help with the diagnosis. In particular, fecal calprotectin has become one of the most important indicators for monitoring inflammatory bowel disease.…”