Immune Resolution Dilemma: Host Antimicrobial Factor S100A8/A9 Modulates Inflammatory Collateral Tissue Damage During Disseminated Fungal Peritonitis.

Madhu Shankar,Sandra Holmberg,Thomas Vogl,Emelie Backman,Maria Joanna Niemiec,Constantin F Urban,Nathalie Uwamahoro,Johannes Roth

doi:10.3389/fimmu.2021.553911

Madhu Shankar, Sandra Holmberg + Show 6 more

Open Access

https://doi.org/10.3389/fimmu.2021.553911

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Abstract

Intra-abdominal infection (peritonitis) is a leading cause of severe disease 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 and pro-inflammatory protein complex used as a biomarker for diagnosis of numerous inflammatory disorders. Here we describe the role of S100A8/A9 in inflammatory collateral tissue damage (ICTD). Using a mouse model of disseminated intra-abdominal candidiasis (IAC) in wild-type and S100A8/A9-deficient mice in the presence or absence of S100A9 inhibitor paquinimod, the role of S100A8/A9 during ICTD and fungal clearance were investigated. S100A8/A9-deficient mice developed less ICTD than wild-type mice. Restoration of S100A8/A9 in knockout mice by injection of recombinant protein resulted in increased ICTD and fungal clearance comparable to wild-type levels. Treatment with paquinimod abolished ICTD and S100A9-deficient mice showed increased survival compared to wild-type littermates. The data indicates that S100A8/A9 controls ICTD levels and antimicrobial activity during IAC and that targeting of S100A8/A9 could serve as promising adjunct therapy against this challenging disease.

Highlights

In surgical patients, peritonitis frequently results in severe sepsis, in the intensive care unit [1], where more than 70% of patients suffering from this complication may succumb to death within 72 h [2]
WT and S100A9-/- mice were IP-infected with C. albicans and fungal dissemination into different organs was determined 24 h post infection (Figure 1A)
This work characterizes the role of S100A8/A9 on host resolution of inflammation in an experimental model of disseminated C. albicans

Summary

Introduction

Peritonitis frequently results in severe sepsis, in the intensive care unit [1], where more than 70% of patients suffering from this complication may succumb to death within 72 h [2]. Peritonitis is characterized by an inflamed membrane of the abdominal cavity, the Calprotectin Modulates Collateral Tissue Damage peritoneum, and is caused by endogenous microbes of the gastrointestinal microbiota [4]. Intra-abdominal surgery frequently originates peritonitis [5]. The surgical disruption of mucosal barriers facilitates microbial translocation from the gut lumen into the peritoneal cavity and from there into circulation [1, 6]. The microbial spread leads to deep-seated infections by gut-colonizing organisms, such as the yeast Candida albicans [7]. Intra-abdominal candidiasis (IAC) is the most common non-mucosal fungal disease among hospitalized patients and is associated with fungal cells disseminating to the liver and other organs via lymphatics or bloodstream [8]. Liver tissue damage and leukocytosis are hallmarks of deep-seated and systemic C. albicans infections [9]. IAC remains challenging to diagnose and results in high mortality rates from 25% to 60% [5]

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