The effect of host genetics on in vitro performance of bovine monocyte-derived macrophages

Abstract

The dynamic interaction between the host and pathogens, along with environmental factors, influences the regulation of mammalian immune responses. Therefore, comprehensive in vivo immune-phenotyping during an active response to a pathogen can be complex and prone to confounding effects. Evaluating critical fundamental aspects of the immune system at a cellular level is an alternative approach to reduce this complexity. Therefore, the objective of the current study was to examine an in vitro model for functional phenotyping of bovine monocyte-derived macrophages (MDM), cells which play a crucial role at all phases of inflammation, as well influence downstream immune responses. As indicators of MDM function, phagocytosis and nitric oxide (NO −) production were tested in MDM of 16 cows in response to 2 common bacterial pathogens of dairy cows, Escherichia coli and Staphylococcus aureus. Notable functional variations were observed among the individuals (coefficient of variation: 33% for phagocytosis and 70% in the production of NO −). The rank correlation analysis revealed a significant, positive, and strong correlation (rho = 0.92) between NO − production in response to E. coli and S. aureus, and a positive but moderate correlation (rho = 0.58) between phagocytosis of E. coli and S. aureus. To gain further insight into this trait, another 58 cows were evaluated solely for NO − response against E. coli. The pedigree of the tested animals was added to the statistical model and the heritability was estimated to be 0.776. Overall, the finding of this study showed a strong effect of host genetics on the in vitro activities of MDM and the possibility of ranking Holstein cows based on the in vitro functional variation of MDM.

Transcriptomic Profiles of Monocyte-Derived Macrophages in Response to Escherichia coli is Associated with the Host Genetics

“…This cellular phenotype was strongly associated with host genetics. The heritability of NO − production was 77%, similar to the heritability of NO − production by peritoneal macrophages in mice 21,28 . These findings showed that NO production could be considered as a genetic index to classify MDMs.…”

“…These two groups were exposed to the same bacteria with exactly similar MOI in a similar environment. The only difference between these two groups was their genetic architecture as we have previously shown 21 .…”

“…Among enriched canonical pathways at 3 hours time point, "Fcγ Receptor-mediated Phagocytosis in Macrophages and Monocytes" is notable. We have previously shown a strong and significant correlation between NO − production and phagocytosis in bovine MDMs in response to E. coli and S. aureus 21 . The VEGF signalling pathway, enriched at 3 hours, regulates angiogenesis and lymphangiogenesis in the host during inflammation.…”

“…Blood samples were collected from the tail vein of 6 Holstein mid-lactating cows from the research herd at the University of Guelph. Based on our previous study 21 , these samples were divided into high (n = 3) and low (n = 3) responder groups based on in-vitro NO − response to E. coli. The average of NO − response 48 hours after the challenge was 13.1 µM (Standard Error: 0.66) and 5.3 µM (Standard Error: 0.47) for high and low responder groups, respectively (p-value of T-test between high and low responder groups was < 0.002) ( Supplementary Fig.…”

“…The study revealed notable individual variation in NO − production and also positive correlation between the phagocytic ability of MDMs and NO − production. Furthermore, the results showed that the genetics of the host determined 77% of the phenotypic variation in NO production 21 . However, it is not known if individual variation in production of NO − in response to one stimulant is associated with overall distinct proinflammatory profiles of macrophages, similar to distinct macrophage inflammatory profile in response to different stimulants.…”