Comparative Genomic Analysis of Buffalo (Bubalus bubalis) NOD1 and NOD2 Receptors and Their Functional Role in In-Vitro Cellular Immune Response

Abstract

Nucleotide binding and oligomerization domain (NOD)-like receptors (NLRs) are innate immune receptors that recognize bacterial cell wall components and initiate host immune response. Structure and function of NLRs have been well studied in human and mice, but little information exists on genetic composition and role of these receptors in innate immune system of water buffalo—a species known for its exceptional disease resistance. Here, a comparative study on the functional domains of NOD1 and NOD2 was performed across different species. The NOD mediated in-vitro cellular responses were studied in buffalo peripheral blood mononuclear cells, resident macrophages, mammary epithelial, and fibroblast cells. Buffalo NOD1 (buNOD1) and buNOD2 showed conserved domain architectures as found in other mammals. The domains of buNOD1 and buNOD2 showed analogy in secondary and tertiary conformations. Constitutive expressions of NODs were ubiquitous in different tissues. Following treatment with NOD agonists, peripheral lymphocytes showed an IFN-γ response along-with production of pro-inflammatory cytokines. Alveolar macrophages and mammary epithelial cells showed NOD mediated in-vitro immune response through NF-κB dependent pathway. Fibroblasts showed pro-inflammatory cytokine response following agonist treatment. Our study demonstrates that both immune and non-immune cells could generate NOD-mediated responses to pathogens though the type and magnitude of response depend on the cell types. The structural basis of ligand recognition by buffalo NODs and knowledge of immune response by different cell types could be useful for development of non-infective innate immune modulators and next generation anti-inflammatory compounds.

NOD2 silencing promotes cell apoptosis and inhibits drug resistance in chronic lymphocytic leukemia by inhibiting the NF‐κB signaling pathway

“…Studies have suggested that NOD2 participates in cell apoptosis by activating the NF-κB signaling pathway in many diseases. [16][17][18][19] Thus, we considered that NOD2 may modulate the NF-κB pathway in CLL. In addition, the STING website was used to predict the protein−protein interaction network among the top 20 differentially expressed genes, and the results revealed that NOD2 had a close relation with p53 and Bcl-2 (Figure 1D).…”

“…[28] Studies have suggested a role for NOD2 in the regulation of the NF-κB signaling pathway in many diseases. [17][18][19]29] NOD2 significantly activates the NF-κB signaling pathway and enhances antibacterial defenses, thereby increasing the expression of pro-inflammatory cytokines and defensins after stimulation with Escherichia coli. [24] Moreover, in our study, NOD2 silencing or inhibition of the NF-κB signaling pathway contributes to an elevation in ADR accumulation in CLL cells.…”