Variant enterovirus A71 found in immune- suppressed patient binds to heparan sulfate and exhibits neurotropism in B-cell-depleted mice

Enterovirus A71 (EV-A71) causes hand, foot, and mouth disease outbreaks with neurological complications and deaths. We previously isolated an EV-A71 variant in the stool, cerebrospinal fluid, and blood of an immunocompromised patient who had a leucine-to-arginine substitution on the VP1 capsid protein, resulting in increased heparin sulfate binding. We show here that this mutation increases the virus’s pathogenicity in orally infected mice with depleted B cells, which mimics the patient’s immune status, and increases susceptibility to neutralizing antibodies. However, a double mutant with even greater heparin sulfate affinity is not pathogenic, suggesting that increased heparin sulfate affinity may trap virions in peripheral tissues and reduce neurovirulence. This research sheds light on the increased pathogenicity of variant with heparin sulfate (HS)-binding ability in individuals with decreased B cell immunity.

肠道病毒A71型（Enterovirus A71, EV-A71）可引发手足口病暴发，并伴随神经系统并发症与死亡病例。此前，我们从一名免疫功能低下患者的粪便、脑脊液及血液样本中分离出一株EV-A71变异株，该患者的VP1衣壳蛋白（VP1 capsid protein）发生亮氨酸至精氨酸的氨基酸替换，使得该变异株的硫酸乙酰肝素（heparin sulfate）结合能力增强。本研究证实，该突变可在模拟该患者免疫状态的B细胞耗竭口服感染小鼠模型中，增强病毒的致病力，同时提升病毒对中和抗体（neutralizing antibodies）的敏感性。然而，一株硫酸乙酰肝素结合亲和力更强的双突变株却无致病能力，这提示硫酸乙酰肝素结合能力的增强可能会将病毒粒子滞留于外周组织，从而降低其神经毒力（neurovirulence）。本研究阐明了在B细胞免疫功能低下的个体中，具备硫酸乙酰肝素（HS）结合能力的变异株致病力增强的潜在机制。