Nucleotide-Binding Oligomerization Domain Protein 2-Deficient Mice Control Infection with Mycobacterium tuberculosis

Abstract

Nucleotide-binding oligomerization domain proteins (NODs) are modular cytoplasmic proteins implicated in the recognition of peptidoglycan-derived molecules. NOD2 has recently been shown to be important for host cell cytokine responses to Mycobacterium tuberculosis, to synergize with Toll-like receptor 2 (TLR2) in mediating these responses, and thus to serve as a nonredundant recognition receptor for M. tuberculosis. Here, we demonstrate that macrophages and dendritic cells from NOD2-deficient mice were impaired in the production of proinflammatory cytokines and nitric oxide following infection with live, virulent M. tuberculosis. Mycolylarabinogalactan peptidoglycan (PGN), the cell wall core of M. tuberculosis, stimulated macrophages to release tumor necrosis factor (TNF) and interleukin-12p40 in a partially NOD2-dependent manner, and M. tuberculosis PGN required NOD2 for the optimal induction of TNF. However, NOD2-deficient mice were no more susceptible to infection with virulent M. tuberculosis than wild-type mice: they controlled the replication of M. tuberculosis in lung, spleen, and liver as well as wild-type mice, and both genotypes displayed similar lung pathologies. In addition, mice doubly deficient for NOD2 and TLR2 were similarly able to control an M. tuberculosis infection. Thus, NOD2 appears to participate in the recognition of M. tuberculosis by antigenpresenting cells in vitro yet is dispensable for the control of the pathogen during in vivo infection.

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

“…Because of the critical link between type 1 cytokines and NO production in antimycobacterial immunity, we also measured NO levels. Consistent with findings reported by Gandotra and colleagues, Nod2 deficiency was associated with significantly reduced NO production in unstimulated and stimulated cells (17).…”

“…Consistent with findings reported by Gandotra and colleagues (17), the mycobacterial burden in both the lungs and spleen was unaffected by Nod2 status at both 4 and 8 wk after M. tuberculosis pulmonary infection (Fig. 2A).…”

“…Consistently, these studies have shown that defects in NOD2 signaling lead to impaired in vitro mycobacterial recognition by human-or murine-derived macrophages (16 -19). Furthermore, Gandotra and colleagues reported that Nod2-deficient mice exhibit decreased innate antimycobacterial immunity following M. tuberculosis infection; however, the bacterial burden in the first months after challenge did not differ as a function of Nod2 status (17). More recently, human NOD2 variants were found to be associated with susceptibility to tuberculosis in an African American population (20).…”

Silencing Suppressor of Cytokine Signaling-1 (SOCS1) in Macrophages Improves Mycobacterium tuberculosis Control in an Interferon-γ (IFN-γ)-dependent Manner

“…The NOD2 pathway is also involved in mycobacterial recognition (43). Diminished levels of SOCS1 mRNA were observed in NOD2 Ϫ/Ϫ BCG-infected BMM, compared with WT controls (Fig.…”

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 .…”