NOD2-Deficient Mice Have Impaired Resistance to Mycobacterium tuberculosis Infection through Defective Innate and Adaptive Immunity

Abstract

NOD2/CARD15 mediates innate immune responses to mycobacterial infection. However, its role in the regulation of adaptive immunity has remained unknown. In this study, we examined host defense, T cell responses, and tissue pathology in two models of pulmonary mycobacterial infection, using wild-type and Nod2-deficient mice. During the early phase of aerosol infection with Mycobacterium tuberculosis, Nod2−/− mice had similar bacterial counts but reduced inflammatory response on histopathology at 4 and 8 wk postchallenge compared with wild-type animals. These findings were confirmed upon intratracheal infection of mice with attenuated Mycobacterium bovis bacillus Calmette-Guérin. Analysis of the lungs 4 wk after bacillus Calmette-Guérin infection demonstrated that Nod2−/− mice had decreased production of type 1 cytokines and reduced recruitment of CD8+ and CD4+ T cells. Ag-specific T cell responses in both the spleens and thoracic lymph nodes were diminished in Nod2−/− mice, indicating impaired adaptive antimycobacterial immunity. The immune regulatory role of NOD2 was not restricted to the lung since Nod2 disruption also led to reduced type 1 T cell activation following i.m. bacillus Calmette-Guérin infection. To determine the importance of diminished innate and adaptive immunity, we measured bacterial burden 6 mo after aerosol infection with M. tuberculosis and followed a second infected group for assessment of survival. Nod2−/− mice had a higher bacterial burden in the lungs 6 mo after infection and succumbed sooner than did wild-type controls. Taken together, these data indicate that NOD2 mediates resistance to mycobacterial infection via both innate and adaptive immunity.

Deciphering the genetic architecture of variation in the immune response toMycobacterium tuberculosisinfection

“…5 B and C), and the same genetic variants are nominally associated with pulmonary TB in the GWAS data (Table S1). RIPK2 encodes an adapter protein of the NOD2-dependent signaling pathway, which is a key pathway involved in the regulation of host responses to MTB infection (44)(45)(46). ATP6V0A2 encodes a subunit of the vesicular proton-ATPase (v-ATPase) (47).…”

NOD2 deletion promotes cardiac hypertrophy and fibrosis induced by pressure overload

“…NOD2 is an intracellular receptor for the bacterial cell wall component muramyl dipeptide, 12,13 and contributes to innate antimycobacterial immunity. 23 NOD2 signaling has an important role in inflammation. 11,24 NOD2 may represent a new therapeutic target in liver diseases.…”

Broadening Our View About the Role of Mycobacterium tuberculosis Cell Envelope Components During Infection: A Battle for Survival

“…Zhang et al, 2009). Studies done in vitro using different models and in vivo using the mouse model dispute the significance of Nod2 in controlling M.tb growth during infection (Divangahi et al, 2008;Gandotra et al, 2007). However, recent studies using human macrophages align with the human polymorphism studies showing that Nod2 plays a role in controlling proinflammation and M.tb intracellular growth .…”