Alcorn Maria D H, Sun Chengqun, Gilliland Theron C, Lukash Tetyana, Crasto Christine M, Raju Saravanan, Diamond Michael S, Weaver Scott C, Klimstra William B
Department of Immunology, University of Pittsburgh, Pittsburgh, PA, USA.
Center for Vaccine Research, University of Pittsburgh, Pittsburgh, PA, USA.
Nat Commun. 2025 Aug 5;16(1):7227. doi: 10.1038/s41467-025-62513-3.
Naturally circulating strains of eastern equine encephalitis virus (EEEV) bind heparan sulfate (HS) receptors and this interaction has been linked to neurovirulence. Previous studies associated EEEV-HS interactions with three positively charged amino acid clusters on the E2 glycoprotein. One of these sites has recently been reported to be critical for binding EEEV to the very-low-density lipoprotein receptor (VLDLR), an EEEV receptor protein. The proteins apolipoprotein E receptor 2 (ApoER2) isoforms 1 and 2, and LDLR have also been shown to function as EEEV receptors. Herein, we investigate the individual contribution of each HS interaction site to EEEV HS- and protein receptor-dependent infection in vitro and EEEV replication in animals. We show that each site contributes to both EEEV-HS and EEEV-protein receptor interactions, providing evidence that altering these interactions can affect disease in mice and eliminate mosquito infectivity. Thus, multiple HS-binding sites exist in EEEV E2, and these sites overlap functionally with protein receptor interaction sites, with each type of interaction contributing to tissue infectivity and disease phenotypes.
东部马脑炎病毒（EEEV）的自然循环毒株与硫酸乙酰肝素（HS）受体结合，这种相互作用与神经毒力有关。先前的研究将EEEV-HS相互作用与E2糖蛋白上的三个带正电荷的氨基酸簇联系起来。最近有报道称，这些位点之一对于EEEV与极低密度脂蛋白受体（VLDLR，一种EEEV受体蛋白）的结合至关重要。载脂蛋白E受体2（ApoER2）亚型1和2以及低密度脂蛋白受体（LDLR）也已被证明可作为EEEV受体发挥作用。在此，我们研究了每个HS相互作用位点对体外EEEV HS和蛋白受体依赖性感染以及动物体内EEEV复制的个体贡献。我们表明，每个位点都对EEEV-HS和EEEV-蛋白受体相互作用有贡献，这表明改变这些相互作用会影响小鼠疾病并消除蚊子的感染性。因此，EEEV E2中存在多个HS结合位点，这些位点在功能上与蛋白受体相互作用位点重叠，每种相互作用类型都对组织感染性和疾病表型有贡献。
