Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark; Department of Clinical Immunology, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark.
Department of Clinical Immunology, Aarhus University Hospital, Aarhus, Denmark; Danish Big Data Centre for Environment and Health (BERTHA), Aarhus University, Aarhus, Denmark.
EBioMedicine. 2024 Nov;109:105406. doi: 10.1016/j.ebiom.2024.105406. Epub 2024 Oct 21.
The CC chemokine receptor 5 (CCR5) is a suggested receptor for Staphylococcus aureus leukotoxin ED. Homozygosity for the Δ32 deletion (CCR5Δ32) protects against human immunodeficiency virus infection and possibly also against leukotoxin ED. We examined the impact of CCR5Δ32 on the susceptibility to S. aureus infection, all-cause infections, and S. aureus nasal carriage, respectively, and on the concentrations of circulating chemokines in blood donors.
We included 95,406 participants from the Danish Blood Donor Study (DBDS) genotyped for >650,000 single nucleotide polymorphisms. The CCR5Δ32 (rs333, MAF: 0.12) was imputed from a reference panel and validated. Infectious outcomes were identified by diagnosis codes and redeemed prescription of antibiotics in national health registers. Data on S. aureus nasal carriage and forty-seven inflammatory biomarkers were available for 6721 and 7811 participants, respectively. Cox, logistic, and linear regression models adjusted for relevant confounders were used to explore said associations.
During more than 700,000 person-years of observation, we found that CCR5Δ32 was associated with neither an increased risk of redeemed dicloxacillin, hospital-treated S. aureus-associated infection (replicated in 345,996 Icelanders), redeemed antibiotics, all-cause infection, and nor with S. aureus nasal carriage. We discovered an association between CCR5Δ32 and elevated CCL4 concentrations, which were 1.26-fold higher in Δ32-heterozygotes (95%-CI: 1.23-1.30) and 2.64-fold higher in Δ32-homozygotes (95%-CI: 2.41-2.90) compared with wildtype homozygotes. Conversely, concentrations of CCL2, CXCL-10, and CCL11 were slightly lower among Δ32-heterozygotes.
Results from this CCR5Δ32 high-prevalent cohort do not support the idea that CCR5Δ32 affects the risk of S. aureus carriage or infection to any relevant degree, in this northern European context. CCL4 was the main chemokine affected by CCR5Δ32 and was observed in higher concentration among Δ32-carriers. This study cannot rule out that S. aureus is a previous driver of CCR5Δ32 selection.
The Health Research Fund of Central Denmark Region, Aarhus University, Danish Administrative Regions, Bio- and Genome Bank Denmark, Danish Blood Donor Research Foundation, Aase & Ejnar Danielsens Foundation, Højmosegård Grant, National Institute of Allergy and Infectious Diseases, and A.P. Møller Foundation for the Advancement of Medical Science.
CC 趋化因子受体 5（CCR5）被认为是金黄色葡萄球菌白细胞毒素 ED 的受体。CCR5Δ32 缺失（CCR5Δ32）纯合子可预防人类免疫缺陷病毒感染，也可能预防白细胞毒素 ED。我们分别研究了 CCR5Δ32 对金黄色葡萄球菌感染、全因感染和金黄色葡萄球菌鼻腔携带的易感性的影响，以及对献血者血液中循环趋化因子浓度的影响。
我们纳入了来自丹麦献血者研究（DBDS）的 95406 名参与者，这些参与者的基因型超过 650000 个单核苷酸多态性。CCR5Δ32（rs333，MAF：0.12）由参考面板推断并验证。通过诊断代码和国家健康登记处 redeemed 抗生素处方确定感染性结局。6721 名参与者可获得金黄色葡萄球菌鼻腔携带数据，7811 名参与者可获得 47 种炎症生物标志物数据。使用 Cox、逻辑和线性回归模型，对相关混杂因素进行调整，以探讨这些关联。
在超过 700000 人年的观察期内，我们发现 CCR5Δ32 既不会增加 redeemed dicloxacillin、金黄色葡萄球菌相关感染的住院治疗风险（在 345996 名冰岛人中得到复制）、也不会增加 redeemed 抗生素、全因感染或金黄色葡萄球菌鼻腔携带的风险。我们发现 CCR5Δ32 与 CCL4 浓度升高之间存在关联，Δ32 杂合子的 CCL4 浓度升高 1.26 倍（95%-CI：1.23-1.30），Δ32 纯合子升高 2.64 倍（95%-CI：2.41-2.90），与野生型纯合子相比。相反，CCL2、CXCL-10 和 CCL11 的浓度在 Δ32 杂合子中略低。
在这种北欧环境中，来自 CCR5Δ32 高流行率队列的结果并不支持 CCR5Δ32 会影响金黄色葡萄球菌携带或感染风险的观点。CCL4 是受 CCR5Δ32 影响的主要趋化因子，在 CCR5Δ32 携带者中观察到更高浓度的 CCL4。本研究不能排除金黄色葡萄球菌是 CCR5Δ32 选择的先前驱动因素。
丹麦中部地区健康研究基金、奥胡斯大学、丹麦行政区域、生物和基因组银行丹麦、丹麦献血者研究基金会、Aase & Ejnar Danielsens 基金会、Højmosegård 赠款、美国国立过敏和传染病研究所和 A.P. 莫勒基金会医学进步。
