Polymorphisms in the P2X7 receptor, and differential expression of Toll-like receptor-mediated cytokines and defensins, in a Canadian Indigenous group

• Published in: Scientific Reports
• Main Authors: Semple, Catlin, Choi, Ka-Yee Grace, Kroeker, Andrea, Denechezhe, Lizette, Orr, Pamela, Mookherjee, Neeloffer, Larcombe, Linda
• Other Authors: Lynne Ransby – Gerry Hodson Infectious Disease Research Fund Dr. Paul H.T. Thorlakson Foundation Fund, Research Manitoba
• Format: Article in Journal/Newspaper
• Language: English
• Published: Springer Science and Business Media LLC 2019
• Subjects: Multidisciplinary; First Nations; inuit
• Online Access: http://dx.doi.org/10.1038/s41598-019-50596-0; http://www.nature.com/articles/s41598-019-50596-0.pdf; http://www.nature.com/articles/s41598-019-50596-0

Abstract Canadian Indigenous peoples (First Nations and Inuit) exhibit a high burden of infectious diseases including tuberculosis influenced by societal factors, and biological determinants. Toll-like receptor (TLR)-mediated innate immune responses are the first line of defence against infections. We examined the production of a panel of 30 cytokines in peripheral blood-derived mononuclear cells (PBMC) isolated from Indigenous and non-Indigenous participants, following stimulation with five different TLR ligands. The levels of TLR-induced pro-inflammatory cytokines such as IL-12/23p40, IL-16, and IFN-γ, and chemokines (MCP-4, MDC and eotaxin) were different between Indigenous compared to non-Indigenous participants. Antimicrobial cationic host defence peptides (CHDP) induced by TLR activation are critical for resolution of infections and modulate the TLR-to-NFκB pathway to alter downstream cytokine responses. Therefore, we examined the expression of human CHDP defensins and cathelicidin in PBMC. mRNA expression of genes encoding for def-A1 and def-B1 were significantly higher following stimulation with TLR ligands in Indigenous compared to non-Indigenous participants. The purinergic receptor P2X7 known to be activated by ATP released following TLR stimulation, is a receptor for CHDP. Therefore, we further examined single nucleotide polymorphisms (SNP) in P2X7. Indigenous participants had a significantly higher percentage of a P2X7 SNP which is associated with reduced function and lower ability to clear infections. These results suggest that a higher frequency of non-functional P2X7 receptors may influence the activity of downstream immune mediators required for resolution of infections such as pro-inflammatory cytokines and CHDP defensins, thus contributing to higher burden of infections in Indigenous population.