NOD1 and NOD2 regulation of pulmonary innate immunity to Legionella pneumophila

Abstract

The role of nucleotide‐binding oligomerization domain‐1 (NOD1) and nucleotide‐binding oligomerization domain‐2 (NOD2), cytoplasmic receptors which detect bacterial cell wall molecules, in pulmonary innate immune responses is poorly understood. We determined that both NOD1 and NOD2 detect heat‐killed Legionella and stimulate NF‐κb and IFN‐β promoter activity using an in vitro luciferase reporter system. We next infected NOD1‐ and NOD2‐deficient animals with aerosolized Legionella pneumophila. At 3 days post infection, Nod1−/− mice had impaired bacterial clearance compared to WT controls. In addition, at 4 h and 24 h, Nod1−/− mice had impaired neutrophil recruitment to the alveolar space. In contrast, increased lung neutrophils were seen in the Nod2−/− animals at 24 h. Analysis of cytokine production at 4 h post infection revealed a significant decrease in proinflammatory cytokines in the Nod1−/− animals when compared to WT animals. In contrast, increased 4‐h proinflammatory cytokines were seen in the Nod2−/− animals. Furthermore, the lungs of both Nod1−/− and Nod2−/− mice had significantly increased pro‐inflammatory cytokine levels at 24 h, suggesting possible suppressive roles for later stages of infection. Together, our data suggest that although both NOD1 and NOD2 can detect Legionella, these receptors modulate the in vivo pulmonary immune response differently.

The Type II Secretion System of Legionella pneumophila Dampens the MyD88 and Toll-Like Receptor 2 Signaling Pathway in Infected Human Macrophages

“…The noninflammasome NLRs NOD1 and NOD2 are stimulated during L. pneumophila infection. This has been shown in the context of lung infection of knockout mice and infected BMD macrophages obtained from knockout mice as well as a human epithelial cell line (33,(40)(41)(42)(43). The activation of the MAPK and NF-B pathways is in part dependent upon NOD signaling, which is contingent upon RIP2 (44,45).…”

Innate Instruction of CD4+ T Cell Immunity in Respiratory Bacterial Infection

“…In contrast, active induction of predominantly Th2 responses via cytosolic recognition of peptidoglycans by Nod 1 and Nod2 was demonstrated in in vivo studies (52,53). Furthermore, L. pneumophila-derived peptidoglycans were shown to activate Nod1 and Nod2 (10,54). Both Nod1 and Nod2 activate NF-kΒ-signaling pathways through the adapter serine-threonine kinase Rip2 and MAPK through CARD9.…”

“…L. pneumophila modulates the host cell via cytosolic injection of virulence factors through its Icm/Dot type IV secretion system (T4SS) (5), which enables the bacterium to replicate in a specialized nondegradative vacuole (6). It triggers transmembrane TLRs (7,8), as well as cytosolic NLRs (9,10), and induces a potent inflammatory response, leading to the subsequent initiation of a robust adaptive immune response in the host. Abs of the IgG and IgA isotype were shown to protect from L. pneumophila infection, and CD4 T cells were crucial for Ab isotype switch (11,12).…”

Molecular characterization, expression, and functional analysis of NOD1 in Qingyuan partridge chicken

“…The CARD domain of NOD1 binds the CARD domain of RIP2 through homophilic CARD-CARD interactions (Correa et al, 2012) and induces NFkB. Several studies have shown that NOD1 detects the minimal tri-DAP structure of Gramnegative bacteria, including Salmonella typhimurium, Legionella pneumophila, and Shigella flexneri (Berrington et al, 2010;Keestra et al, 2011;Robertson and Girardin, 2013). In order to examine whether Salmonella infection activates chNOD1 signaling in chicken, Salmonella enteritidis was used to infect Qingyuan partridge chickens.…”