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Abstract：
The 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.
The 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.
We 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.
Our 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.
The 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.
We 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.
Our 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.
摘要：
■加纳结核分枝杆菌群（MTBC）5系（L5）感染的流行病学表明，与其他自我报告的种族相比，Ewes的患病率显着增加。在这种情况下，我们试图使用来自Ewe和Akan族志愿者血液的巨噬细胞与MTBCL4和L5菌株的离体感染来研究结核病(TB)感染的早期阶段.
■研究参与者由16个对照组成，其中自我报告的Akan和Ewe种族同样代表，以及20例治愈的结核病病例，包括11例Akans和9例Ewes。从健康对照和治愈的TB病例中分离外周血单核细胞。在用L4或L5特有菌株感染之前,分离CD14+单核细胞并分化成单核细胞衍生的巨噬细胞(MDM)。在感染后2小时(摄取)以及3和7天评估细菌负荷。
■我们观察到来自Ewes的MDM对吞噬L4菌株的能力更高（p<0.001），与L5相比，第7天的细菌负荷更高（p<0.001），尽管L5在EweMDMs中的复制率更高（倍数变化：1.4vs.1.2，p=0.03）。相反,在来自Akans的巨噬细胞内，我们观察到L5的吞噬摄取显著高于L4(p<0.001),在第7天也转化为更高的负荷(p=0.04)。然而,L4在AkanMDMs中的复制率高于L5（倍数变化：L4=1.2，L4=1.1，p=0.04）。虽然L4和L5的摄取在治愈的TB病例中没有显著差异,在EweMDMs的第7天，L4（p=0.02）和L5（p=0.02）的细菌负荷较高。
■我们的结果表明宿主种族（受宿主遗传多样性驱动），MTBC遗传多样性,和个体TB感染史共同作用调节MTBC巨噬细胞感染的结果。
■研究参与者由16个对照组成，其中自我报告的Akan和Ewe种族同样代表，以及20例治愈的结核病病例，包括11例Akans和9例Ewes。从健康对照和治愈的TB病例中分离外周血单核细胞。在用L4或L5特有菌株感染之前,分离CD14+单核细胞并分化成单核细胞衍生的巨噬细胞(MDM)。在感染后2小时(摄取)以及3和7天评估细菌负荷。
■我们观察到来自Ewes的MDM对吞噬L4菌株的能力更高（p<0.001），与L5相比，第7天的细菌负荷更高（p<0.001），尽管L5在EweMDMs中的复制率更高（倍数变化：1.4vs.1.2，p=0.03）。相反,在来自Akans的巨噬细胞内，我们观察到L5的吞噬摄取显著高于L4(p<0.001),在第7天也转化为更高的负荷(p=0.04)。然而,L4在AkanMDMs中的复制率高于L5（倍数变化：L4=1.2，L4=1.1，p=0.04）。虽然L4和L5的摄取在治愈的TB病例中没有显著差异,在EweMDMs的第7天，L4（p=0.02）和L5（p=0.02）的细菌负荷较高。
■我们的结果表明宿主种族（受宿主遗传多样性驱动），MTBC遗传多样性,和个体TB感染史共同作用调节MTBC巨噬细胞感染的结果。
