Abstract
Peritonitis is a leading cause of severe sepsis in surgical intensive care units, as over 70% of patients diagnosed with peritonitis develop septic shock. A critical role of the immune system is to return to homeostasis after combating infection. S100A8/A9 (calprotectin) is an antimicrobial, pro-inflammatory protein used as a marker for diagnosis of inflammatory diseases. Here we describe the role of calprotectin on inflammatory collateral tissue damage (ICTD). WT and calprotectin-deficient in vivo Candida albicans disseminated peritonitis mice model, and primary macrophages were treated with recombinant calprotectin and the anti-inflammatory compound, paquinimod. The effects on ICTD and fungal clearance were investigated. Calprotectin-deficient mice developed less ICTD than wildtype mice. Injection of recombinant calprotectin resulted in increased ICTD and fungal clearance comparable to wildtype levels. Treatment with paquinimod, a specific inhibitor of calprotectin, abolished ICTD. The data indicated that calprotectin controls ICTD levels and host antimicrobial modulation at a systemic level during intra-abdominal candidiasis (ICA).
IMPORTANCE Fungal pathogens like C. albicans pose a significant burden on health at a global level comparable to malaria and tuberculosis. Despite the increasing antifungal drug resistance, fungi remain underestimated as pathogens. Fungal dissemination to organs during severe fungal systemic inflammation is often lethal for immunocompromised patients, particularly during intraabdominal surgeries where disseminating infections in patients can become life-threatening conditions with a matter of hours. This study utilizes in vivo techniques for recombinant protein therapy and pharmacological inhibition (paquinimod) to modulate activity of a systemic antimicrobial protein demonstrating that calprotectin controls the severity of fungal sepsis and hence provides an option for pharmacological intervention.