Macrophage susceptibility to infection by Ghanaian Mycobacterium tuberculosis complex lineages 4 and 5 varies with self-reported ethnicity

Abstract

BackgroundThe epidemiology of Mycobacterium tuberculosis complex (MTBC) lineage 5 (L5) infections in Ghana revealed a significantly increased prevalence in Ewes compared to other self-reported ethnic groups. In that context, we sought to investigate the early phase of tuberculosis (TB) infection using ex vivo infection of macrophages derived from the blood of Ewe and Akan ethnic group volunteers with MTBC L4 and L5 strains.MethodsThe study participants consisted of 16 controls, among which self-reported Akan and Ewe ethnicity was equally represented, as well as 20 cured TB cases consisting of 11 Akans and 9 Ewes. Peripheral blood mononuclear cells were isolated from both healthy controls and cured TB cases. CD14+ monocytes were isolated and differentiated into monocyte-derived macrophages (MDMs) before infection with L4 or L5 endemic strains. The bacterial load was assessed after 2 hours (uptake) as well as 3 and 7 days post-infection.ResultsWe observed a higher capacity of MDMs from Ewes to phagocytose L4 strains (p < 0.001), translating into a higher bacillary load on day 7 (p < 0.001) compared to L5, despite the higher replication rate of L5 in Ewe MDMs (fold change: 1.4 vs. 1.2, p = 0.03) among the controls. On the contrary, within macrophages from Akans, we observed a significantly higher phagocytic uptake of L5 (p < 0.001) compared to L4, also translating into a higher load on day 7 (p = 0.04). However, the replication rate of L4 in Akan MDMs was higher than that of L5 (fold change: L4 = 1.2, L4 = 1.1, p = 0.04). Although there was no significant difference in the uptake of L4 and L5 among cured TB cases, there was a higher bacterial load of both L4 (p = 0.02) and L5 (p = 0.02) on day 7 in Ewe MDMs.ConclusionOur results suggest that host ethnicity (driven by host genetic diversity), MTBC genetic diversity, and individual TB infection history are all acting together to modulate the outcome of macrophage infections by MTBC.

Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania

“…Second, we did not investigate the phenotypes exhibited by MDMs from Tanzanians who did not have a history of TB infection, which would have informed on macrophage fitness in the general population. This is particularly relevant as trained immunity following BCG vaccination or TB disease can affect monocyte response upon re-stimulation or re-infection 67 , 68 . Third, while the sample size sufficed to draw conclusions on the impact of lineages overall, stratification by patients’ lineage led to small group sizes that may have limited our capacity to detect more subtle differences between patient groups.…”

Bacterial diversity dominates variable macrophage responses of tuberculosis patients in Tanzania

“…Second, we did not investigate the phenotypes exhibited by MDMs from Tanzanians who did not have a history of TB infection, which would have informed on macrophage fitness in the general population. This is particularly relevant as trained immunity following BCG vaccination or TB disease can affect monocyte response upon re-stimulation or re-infection (62,63). Third, while the sample size sufficed to draw conclusions on the impact of lineages overall, stratification by patients' lineage led to small group sizes that may have limited our capacity to detect more subtle differences between patient groups.…”