Role of Nucleotide-Binding Oligomerization Domain-Containing (NOD) 2 in Host Defense during Pneumococcal Pneumonia.

Tijmen J Hommes,Sandrine Florquin,Hester J Bootsma,Miriam H Van Lieshout,Cornelis Van ‘T Veer,Tom Van Der Poll,Alex F De Vos,Peter W Hermans,Eliane Namie Miyaji

doi:10.1371/journal.pone.0145138

Abstract

Streptococcus (S.) pneumoniae is the most common causative pathogen in community-acquired pneumonia. Nucleotide-binding oligomerization domain-containing (NOD) 2 is a pattern recognition receptor located in the cytosol of myeloid cells that is able to detect peptidoglycan fragments of S. pneumoniae. We here aimed to investigate the role of NOD2 in the host response during pneumococcal pneumonia. Phagocytosis of S. pneumoniae was studied in NOD2 deficient (Nod2 -/-) and wild-type (Wt) alveolar macrophages and neutrophils in vitro. In subsequent in vivo experiments Nod2 -/- and Wt mice were inoculated with serotype 2 S. pneumoniae (D39), an isogenic capsule locus deletion mutant (D39Δcps) or serotype 3 S. pneumoniae (6303) via the airways, and bacterial growth and dissemination and the lung inflammatory response were evaluated. Nod2 -/- alveolar macrophages and blood neutrophils displayed a reduced capacity to internalize pneumococci in vitro. During pneumonia caused by S. pneumoniae D39 Nod2 -/- mice were indistinguishable from Wt mice with regard to bacterial loads in lungs and distant organs, lung pathology and neutrophil recruitment. While Nod2 -/- and Wt mice also had similar bacterial loads after infection with the more virulent S. pneumoniae 6303 strain, Nod2 -/- mice displayed a reduced bacterial clearance of the normally avirulent unencapsulated D39Δcps strain. These results suggest that NOD2 does not contribute to host defense during pneumococcal pneumonia and that the pneumococcal capsule impairs recognition of S. pneumoniae by NOD2.

Highlights

Invading pathogens are sensed by a wide array of pattern recognition receptors (PRRs) that initiate the innate immune response and shape adaptive immunity [1]
NOD2 deficiency reduces the capacity of alveolar macrophages and neutrophils to phagocytose S. pneumoniae in vitro
Since NOD2 has been shown to promote phagocytosis of Staphylococcus aureus [14], we first tested the capacity of Nod2-/- and Wt leukocytes to internalize S. pneumoniae (D39) in vitro

Summary

Introduction

Invading pathogens are sensed by a wide array of pattern recognition receptors (PRRs) that initiate the innate immune response and shape adaptive immunity [1]. Role of NOD2 in Pneumococcal Pneumonia oligomerization domain (NOD)-like receptors (NLRs) are a family of intracellular PRRs that recognize specific microbial components [2]. NOD1 and NOD2 are prominent members of this family. NOD2 recognizes bacterial molecules that are produced during the synthesis and/or degradation of peptidoglycan and is considered to act as a general sensor for most bacteria [3]. NOD2 signals through the adaptor protein receptor interacting protein (RIP), resulting in nuclear factor (NF)-κB translocation to the nucleus and the subsequent production and release of proinflammatory mediators, thereby triggering an immune response aimed at restricting bacterial growth

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