Shifts in receptors during submergence of an encephalitic arbovirus

Affiliations

• Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
• World Reference Center for Emerging Viruses and Arboviruses, University of Texas Medical Branch, Galveston, TX, USA.
• Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA.
• Institute for Human Infections and Immunity, University of Texas Medical Branch, Galveston, TX, USA.
• Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
• Department of Neurology, F. M. Kirby Neurobiology Center, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
• MicRoN Core, Harvard Medical School, Boston, MA, USA.
• Department of Microbiology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA. jonathan_abraham@hms.harvard.edu.
• Department of Medicine, Division of Infectious Diseases, Brigham and Women's Hospital, Boston, MA, USA. jonathan_abraham@hms.harvard.edu.
• Center for Integrated Solutions in Infectious Diseases, Broad Institute of Harvard and MIT, Cambridge, MA, USA. jonathan_abraham@hms.harvard.edu.

PMID: 39048821 DOI: 10.1038/s41586-024-07740-2

Abstract

Western equine encephalitis virus (WEEV) is an arthropod-borne virus (arbovirus) that frequently caused major outbreaks of encephalitis in humans and horses in the early twentieth century, but the frequency of outbreaks has since decreased markedly, and strains of this alphavirus isolated in the past two decades are less virulent in mammals than strains isolated in the 1930s and 1940s1-3. The basis for this phenotypic change in WEEV strains and coincident decrease in epizootic activity (known as viral submergence3) is unclear, as is the possibility of re-emergence of highly virulent strains. Here we identify protocadherin 10 (PCDH10) as a cellular receptor for WEEV. We show that multiple highly virulent ancestral WEEV strains isolated in the 1930s and 1940s, in addition to binding human PCDH10, could also bind very low-density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2), which are recognized by another encephalitic alphavirus as receptors4. However, whereas most of the WEEV strains that we examined bind to PCDH10, a contemporary strain has lost the ability to recognize mammalian PCDH10 while retaining the ability to bind avian receptors, suggesting WEEV adaptation to a main reservoir host during enzootic circulation. PCDH10 supports WEEV E2-E1 glycoprotein-mediated infection of primary mouse cortical neurons, and administration of a soluble form of PCDH10 protects mice from lethal WEEV challenge. Our results have implications for the development of medical countermeasures and for risk assessment for re-emerging WEEV strains.

西部马脑炎病毒（WEEV）是一种由文字播的人畜共患病毒，在20世纪早期曾频繁引发人类和马匹脑炎的大规模疫情。然而，自那时以来，疫情的频率显著下降，过去二十年中分离出的WEEV毒株在哺乳动物中的致病性也低于1930年代和1940年代分离的毒株。关于这种表型变化的基础以及流行活动的减少（称为病毒沉没）尚不清楚，也不清楚高致病性毒株是否有可能重新出现。在这项研究中，我们鉴定出原钙粘附蛋白10（PCDH10）作为WEEV的细胞受体。我们发现，1930年代和1940年代分离的多种高度致病的祖传WEEV毒株除了能结合人类PCDH10外，还能结合极低密度脂蛋白受体（VLDLR）和载脂蛋白E受体2（ApoER2），这些受体也被另一种脑炎性α病毒识别。然而，虽然我们研究的大多数WEEV毒株能结合PCDH10，但一种现代毒株已经失去了识别哺乳动物PCDH10的能力，而仍能结合鸟类受体，这表明WEEV在恩诺图库传播期间已适应了主要的宿主。PCDH10支持WEEV E2-E1糖蛋白介导的初级小鼠皮质神经元感染，且施用溶解形式的PCDH10能保护小鼠免受致命的WEEV挑战。我们的结果对医学对策的开发和对潜在重新出现的WEEV毒株的风险评估具有重要意义。

References 

• Bergren, N. A. et al. Western equine encephalitis virus: evolutionary analysis of a declining alphavirus based on complete genome sequences. J. Virol. 88, 9260–9267 (2014).
• Logue, C. H. et al. Virulence variation among isolates of Western equine encephalitis virus in an outbred mouse model. J. Gen. Virol. 90, 1848–1858 (2009).
• Bergren, N. A. et al. Submergence of Western equine encephalitis virus: evidence of positive selection argues against genetic drift and fitness reductions. PLoS Pathog. 16, e1008102 (2020).
• Clark, L. E. et al. VLDLR and ApoER2 are receptors for multiple alphaviruses. Nature 602, 475–480 (2022).
• Arechiga-Ceballos, N. & Aguilar-Setien, A. Alphaviral equine encephalomyelitis (Eastern, Western and Venezuelan). Rev. Sci. Tech. 34, 491–501 (2015).