The Long Pentraxin PTX3 Controls Klebsiella Pneumoniae Severe Infection.

Fatemeh Asgari,Sadaf Davoudian,Alberto Mantovani,Matteo Stravalaci,Domenico Supino,Federica Riva,Fabio Pasqualini,Camilla Recordati,Nadia Polentarutti,Marialuisa Barbagallo,Andrea Mariancini,Alessia Giordano,Chiara Perucchini,Thierry Roger,Elena Magrini,Cecilia Garlanda,Raffaella Parente,Andrea Doni,Rémi Porte ,Sébastien Jaillon ,Cornelis Van’t Veer

doi:10.3389/fimmu.2021.666198

Abstract

Klebsiella pneumoniae is a common pathogen in human sepsis. The emergence of multidrug-resistant K. pneumoniae strains represents a major clinical challenge in nosocomial and community acquired infections. The long pentraxin PTX3, a key component of humoral innate immunity, is involved in resistance to selected pathogens by promoting opsonophagocytosis. We investigated the relevance of PTX3 in innate immunity against K. pneumoniae infections using Ptx3 -/- mice and mouse models of severe K. pneumoniae infections. Local and systemic PTX3 expression was induced following K. pneumoniae pulmonary infection, in association with the up-regulation of TNF-α and IL-1β. PTX3 deficiency in mice was associated with higher bacterial burden and mortality, release of pro-inflammatory cytokines as well as IL-10 in the lung and systemically. The analysis of the mechanisms responsible of PTX3-dependent control of K. pneumoniae infection revealed that PTX3 did not interact with K. pneumoniae, or promote opsonophagocytosis. The comparison of susceptibility of wild-type, Ptx3-/-, C3-/- and Ptx3-/-/C3-/- mice to the infection showed that PTX3 acted in a complement-independent manner. Lung histopathological analysis showed more severe lesions in Ptx3 -/- mice with fibrinosuppurative, necrotizing and haemorrhagic bronchopneumonia, associated with increased fibrin deposition in the lung and circulating fibrinogen consumption. These findings indicate that PTX3 contributes to the control of K. pneumoniae infection by modulating inflammatory responses and tissue damage. Thus, this study emphasizes the relevance of the role of PTX3 as regulator of inflammation and orchestrator of tissue repair in innate responses to infections.

Highlights

Klebsiella pneumoniae is a Gram-negative bacillus belonging to the family of Enterobacteriaceae, normally colonizing the colon and the oropharynx in humans
These results suggest an association between K. pneumoniae infection-induced inflammation and Pentraxin 3 (PTX3) expression
The present study was designed to address the role of the long pentraxin PTX3 in innate resistance to K. pneumoniae infection, taking advantage of PTX3-deficient mice and well-established in vivo models of K. pneumoniae severe infection

Summary

Introduction

Klebsiella pneumoniae is a Gram-negative bacillus belonging to the family of Enterobacteriaceae, normally colonizing the colon and the oropharynx in humans. Overuse of antibiotics has promoted the emergence of multidrug-resistant K. pneumoniae strains, which are frequently isolated in nosocomial and community-acquired infections [2, 3]. Community-acquired pneumonia (CAP) is the most common cause of sepsis and K. pneumoniae is one of the known causative pathogens for CAP with high mortality rates [1, 4, 5]. Sepsis is defined as a life-threatening organ dysfunction caused by a dysregulated host response to an infection with the worldwide mortality rate of almost 11 million individuals per year [6,7,8]. The balance between pro and anti-inflammatory responses contributes to the patient outcome in sepsis [9]. In addition to all the complications that sepsis per se brings in clinical setting, the emergence of antibiotic resistant K. pneumoniae strains becomes a notable concern in public health

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