DataSheet_1_Congenital Zika Syndrome Is Associated With Interferon Alfa Receptor 1.docx

Host factors that influence Congenital Zika Syndrome (CZS) outcome remain elusive. Interferons have been reported as the main antiviral factor in Zika and other flavivirus infections. Here, we accessed samples from 153 pregnant women (77 without and 76 with CZS) and 143 newborns (77 without and 66 with CZS) exposed to ZIKV conducted a case-control study to verify whether interferon alfa receptor 1 (IFNAR1) and interferon lambda 2 and 4 (IFNL2/4) single nucleotide polymorphisms (SNPs) contribute to CZS outcome, and characterized placenta gene expression profile at term. Newborns carrying CG/CC genotypes of rs2257167 in IFNAR1 presented higher risk of developing CZS (OR=3.41; IC=1.35-8.60; Pcorrected=0.032). No association between IFNL SNPs and CZS was observed. Placenta from CZS cases displayed lower levels of IFNL2 and ISG15 along with higher IFIT5. The rs2257167 CG/CC placentas also demonstrated high levels of IFIT5 and inflammation-related genes. We found CZS to be related with exacerbated type I IFN and insufficient type III IFN in placenta at term, forming an unbalanced response modulated by the IFNAR1 rs2257167 genotype. Despite of the low sample size se findings shed light on the host-pathogen interaction focusing on the genetically regulated type I/type III IFN axis that could lead to better management of Zika and other TORCH (Toxoplasma, Others, Rubella, Cytomegalovirus, Herpes) congenital infections.

影响先天性寨卡综合征（Congenital Zika Syndrome, CZS）转归的宿主相关因素至今仍不明确。已有研究表明，干扰素是寨卡病毒及其他黄病毒感染中的主要抗病毒因子。本研究针对153名寨卡病毒暴露孕妇（其中77名所产新生儿无先天性寨卡综合征，76名所产新生儿罹患先天性寨卡综合征）及143名寨卡病毒暴露新生儿（其中77名无先天性寨卡综合征，66名罹患先天性寨卡综合征）开展病例对照研究，旨在验证α干扰素受体1（IFNAR1）与λ干扰素2、4（IFNL2/4）的单核苷酸多态性（SNPs）是否与先天性寨卡综合征转归相关，并对足月妊娠胎盘的基因表达谱进行特征分析。携带IFNAR1基因rs2257167位点CG/CC基因型的新生儿，罹患先天性寨卡综合征的风险显著升高（比值比OR=3.41；置信区间IC=1.35~8.60；校正后P值Pcorrected=0.032）。未发现IFNL基因单核苷酸多态性与先天性寨卡综合征存在关联。先天性寨卡综合征病例的胎盘组织中，IFNL2与干扰素刺激基因15（ISG15）的表达水平更低，而干扰素诱导蛋白5（IFIT5）的表达水平更高。携带rs2257167位点CG/CC基因型的胎盘组织，同样表现出IFIT5及炎症相关基因的高表达水平。本研究发现，足月妊娠胎盘组织中I型干扰素反应过度激活而III型干扰素应答不足，与先天性寨卡综合征密切相关，这种失衡的免疫应答受IFNAR1基因rs2257167位点基因型调控。尽管本研究样本量较小，但其研究结果阐明了以基因调控的I/III型干扰素轴为核心的宿主-病原体互作机制，可为寨卡病毒及其他TORCH（弓形虫、其他病原体、风疹病毒、巨细胞病毒、单纯疱疹病毒）先天性感染的临床管理提供新思路。