Critical Role of NOD2 in Regulating the Immune Response to Staphylococcus aureus

Abstract

ABSTRACT NOD2 (the nucleotide-binding oligomerization domain containing protein 2) is known to be involved in host recognition of bacteria, although its role in the host response to Staphylococcus aureus infection is unknown. NOD2-deficient ( Nod2 −/− ) mice and wild-type (WT) littermate controls were injected intraperitoneally with S. aureus suspension (10 7 bacteria/g of body weight), and their survival was monitored. Cultured bone marrow-derived neutrophils were harvested from Nod2 −/− and WT mice and tested for cytokine production and phagocytosis. Compared to WT mice, Nod2 −/− mice were significantly more susceptible to S. aureus infection (median survival of 1.5 days versus >5 days; P = 0.003) and had a significantly higher bacterial tissue burden. Cultured bone marrow-derived neutrophils from Nod2 −/− and WT mice had similar levels of peritoneal neutrophil recruitment and intracellular killing, but bone marrow-derived neutrophils from Nod2 −/− mice had significantly reduced ability to internalize fluorescein-labeled S. aureus. Nod2 −/− mice had significantly higher levels of Th1-derived cytokines in serum (tumor necrosis factor alpha, gamma interferon, and interleukin-2 [IL-2]) compared to WT mice, whereas the levels of Th2-derived cytokines (IL-1β, IL-4, IL-6, and IL-10) were similar in Nod2 −/− and WT mice. Thus, mice deficient in NOD2 are more susceptible to S. aureus . Increased susceptibility is due in part to defective neutrophil phagocytosis, elevated serum levels of Th1 cytokines, and a higher bacterial tissue burden.