Muramyl Dipeptide Induces NOD2-Dependent Ly6Chigh Monocyte Recruitment to the Lungs and Protects Against Influenza Virus Infection

Abstract

Bacterial peptidoglycan-derived muramyl dipeptide (MDP) and derivatives have long-recognized antiviral properties but their mechanism of action remains unclear. In recent years, the pattern-recognition receptor NOD2 has been shown to mediate innate responses to MDP. Here, we show that MDP treatment of mice infected with Influenza A virus (IAV) significantly reduces mortality, viral load and pulmonary inflammation in a NOD2-dependent manner. Importantly, the induction of type I interferon (IFN) and CCL2 chemokine was markedly increased in the lungs following MDP treatment and correlated with a NOD2-dependent enhancement in circulating monocytes. Mechanistically, the protective effect of MDP could be explained by the NOD2-dependent transient increase in recruitment of Ly6Chigh “inflammatory” monocytes and, to a lesser extent, neutrophils to the lungs. Indeed, impairment in both Ly6Chigh monocyte recruitment and survival observed in infected Nod2-/- mice treated with MDP was recapitulated in mice deficient for the chemokine receptor CCR2 required for CCL2-mediated Ly6Chigh monocyte migration from the bone marrow into the lungs. MDP-induced pulmonary monocyte recruitment occurred normally in IAV-infected and MDP-treated Ips-1-/- mice. However, IPS-1 was required for improved survival upon MDP treatment. Finally, mycobacterial N-glycolyl MDP was more potent than N-acetyl MDP expressed by most bacteria at reducing viral burden while both forms of MDP restored pulmonary function following IAV challenge. Overall, our work sheds light on the antiviral mechanism of a clinically relevant bacterial-derived compound and identifies the NOD2 pathway as a potential therapeutic target against IAV.

XIAP variants in male Crohn's disease

“…This is supported by the observation that Xiap -deficient mice exhibit impaired NOD2 function and susceptibility to bacterial infections in a manner resembling that observed for Nod2 -deficient mice 46 56 57. Recent findings of a critical role of NOD2 in viral recognition58 59 and the crosstalk between viruses and bacteria60 61 thereby suggest that NOD2-dependent immunodeficiency in patients with XIAP variants may extend to enteropathogenic viruses with potential implications for the pathogenesis of CD. However, despite a clear association between NOD2 variants and IBD, particularly in patients homozygous for NOD2 risk alleles,54 it remains to be investigated whether intestinal inflammation in patients harbouring XIAP mutations is indeed related to NOD dysfunction.…”

NLRX1 prevents mitochondrial induced apoptosis and enhances macrophage antiviral immunity by interacting with influenza virus PB1-F2 protein

“…For histopathologic examination, lungs were fixed by inflation and immersion in buffered formalin and subjected to H&E staining. Airway hyperreactivity in response to methacholine was evaluated using the flexiVent apparatus and flexiVent 5.1 software as previously described (44).…”

Inflammatory monocyte effector mechanisms

“…Hematopoietic cells can also participate to CCL2 production through TLR and type I interferon-dependent cytosolic pathways (48). Triggering of cytosolic Nod2 via bacterialderived MDP can also induce the secretion of type I IFN and CCL2, and the mobilization of Ly6C + monocytes from the bone-marrow (19, 49). …”