Distinct Roles for Sialoside and Protein Receptors in Coronavirus Infection

Qing, Enya; Hantak, Michael; Perlman, Stanley; Gallagher, Tom

Finally, this report illuminates understanding of CoV pathogenesis. Among the CoVs, the JHM-CoV strain is known for causing lethal brain infection, even in mice that lack the principal MHV receptor, CEACAM1a (30) . JHM spike was identified to be the major contributor to this phenotype (30) , and JHM-CoV, but not the related A59-CoV, spread interneuronally both in vivo and within in vitro cultures of central nervous system (CNS)-derived cells (89, 90) . Notably, neural cell membranes are known for their abundant sialic acid content (72) . These findings, combined with evidence that cell-tocell syncytial spread correlates with pathogenesis in several infection models (30, 62, 63, (73) (74) (75) , prompts a hypothesis that JHM-CoV sialic acid binding potential accounts for an interneuronal syncytial spread that is rapidly lethal. A prediction is that variants of JHM-CoV exhibiting enhanced sialic acid affinity will have unusually high neurovirulence. Similarly, the MERS-CoV strain causes lethal pneumonia, and here it is significant that antibodies specific for the MERS-CoV S1A domains both neutralize the virus and reduce infection and pathogenesis in a mouse MERS-CoV model system (55, 59, 76) . Conceivably, these antibodies interfere with sialic acid binding, reducing expansion of MERS-CoV that may take place via cell-cell fusion. Variants of MERS-CoV with enhanced cell binding may be useful in assessing the in vivo significance of the findings presented in this report.