Data_Sheet_1_Association between heavy metals exposure and persistent infections: the mediating role of immune function.docx

IntroductionPersistent infections caused by certain viruses and parasites have been associated with multiple diseases and substantial mortality. Heavy metals are ubiquitous environmental pollutants with immunosuppressive properties. This study aimed to determine whether heavy metals exposure suppress the immune system, thereby increasing the susceptibility to persistent infections.
MethodsUsing data from NHANES 1999–2016, we explored the associations between heavy metals exposure and persistent infections: Cytomegalovirus (CMV), Epstein–Barr Virus (EBV), Hepatitis C Virus (HCV), Herpes Simplex Virus Type–1 (HSV–1), Toxoplasma gondii (T. gondii), and Toxocara canis and Toxocara cati (Toxocara spp.) by performing logistic regression, weighted quantile sum (WQS) and Bayesian kernel machine regression (BKMR) models. Mediation analysis was used to determine the mediating role of host immune function in these associations.
ResultsLogistic regression analysis revealed positive associations between multiple heavy metals and the increased risk of persistent infections. In WQS models, the heavy metals mixture was associated with increased risks of several persistent infections: CMV (OR: 1.58; 95% CI: 1.17, 2.14), HCV (OR: 2.94; 95% CI: 1.68, 5.16), HSV–1 (OR: 1.25; 95% CI: 1.11, 1.42), T. gondii (OR: 1.97; 95% CI: 1.41, 2.76), and Toxocara spp. (OR: 1.76; 95% CI: 1.16, 2.66). BKMR models further confirmed the combined effects of heavy metals mixture and also identified the individual effect of arsenic, cadmium, and lead. On mediation analysis, the systemic immune inflammation index, which reflects the host’s immune status, mediated 12.14% of the association of mixed heavy metals exposure with HSV–1 infection.
DiscussionThe findings of this study revealed that heavy metals exposure may increase susceptibility to persistent infections, with the host’s immune status potentially mediating this relationship. Reducing exposure to heavy metals may have preventive implications for persistent infections, and further prospective studies are needed to confirm these findings.

引言
某些病毒与寄生虫引发的持续感染与多种疾病及较高死亡率密切相关。重金属是一类普遍存在的环境污染物，同时具有免疫抑制特性。本研究旨在探讨重金属暴露是否会抑制机体免疫系统，进而提升宿主对持续感染的易感性。

方法
本研究利用1999-2016年美国国家健康与营养调查（National Health and Nutrition Examination Survey, NHANES）数据，探讨重金属暴露与以下持续感染的关联：巨细胞病毒（Cytomegalovirus, CMV）、EB病毒（Epstein–Barr Virus, EBV）、丙型肝炎病毒（Hepatitis C Virus, HCV）、1型单纯疱疹病毒（Herpes Simplex Virus Type–1, HSV–1）、刚地弓形虫（Toxoplasma gondii, T. gondii）以及犬弓首线虫与猫弓首线虫（弓首线虫属, Toxocara spp.）。研究采用logistic回归、加权分位数和（weighted quantile sum, WQS）与贝叶斯核机器回归（Bayesian kernel machine regression, BKMR）模型开展分析，并通过中介分析明确宿主免疫功能在上述关联中的中介作用。

结果
Logistic回归分析显示，多种重金属暴露与持续感染风险升高呈正相关。在WQS模型中，重金属混合暴露与多种持续感染风险升高显著相关：巨细胞病毒（CMV，比值比OR=1.58，95%置信区间CI：1.17~2.14）、丙型肝炎病毒（HCV，OR=2.94，95%CI：1.68~5.16）、1型单纯疱疹病毒（HSV–1，OR=1.25，95%CI：1.11~1.42）、刚地弓形虫（T. gondii，OR=1.97，95%CI：1.41~2.76）以及弓首线虫属（Toxocara spp.，OR=1.76，95%CI：1.16~2.66）。BKMR模型进一步验证了重金属混合暴露的联合效应，同时识别出砷、镉与铅的单独效应。中介分析结果显示，反映宿主免疫状态的全身免疫炎症指数在重金属混合暴露与HSV–1感染的关联中起到了12.14%的中介作用。

讨论
本研究结果表明，重金属暴露可能提升宿主对持续感染的易感性，而宿主免疫状态可能在该关联中发挥中介作用。降低重金属暴露或可为持续感染的预防提供潜在干预方向，未来仍需开展前瞻性研究以验证本研究结论。