Department of Microbiology and Immunology, Loyola University Chicago, Maywood, Illinois, USA.
Department of Microbiology and Immunology, University of Iowa, Iowa City, Iowa, USA.
mBio. 2020 Feb 11;11(1):e02764-19. doi: 10.1128/mBio.02764-19.
Coronaviruses (CoVs) are common human and animal pathogens that can transmit zoonotically and cause severe respiratory disease syndromes. CoV infection requires spike proteins, which bind viruses to host cell receptors and catalyze virus-cell membrane fusion. Several CoV strains have spike proteins with two receptor-binding domains, an S1A that engages host sialic acids and an S1B that recognizes host transmembrane proteins. As this bivalent binding may enable broad zoonotic CoV infection, we aimed to identify roles for each receptor in distinct infection stages. Focusing on two betacoronaviruses, murine JHM-CoV and human Middle East respiratory syndrome coronavirus (MERS-CoV), we found that virus particle binding to cells was mediated by sialic acids; however, the transmembrane protein receptors were required for a subsequent virus infection. These results favored a two-step process in which viruses first adhere to sialic acids and then require subsequent engagement with protein receptors during infectious cell entry. However, sialic acids sufficiently facilitated the later stages of virus spread through cell-cell membrane fusion, without requiring protein receptors. This virus spread in the absence of the prototype protein receptors was increased by adaptive S1A mutations. Overall, these findings reveal roles for sialic acids in virus-cell binding, viral spike protein-directed cell-cell fusion, and resultant spread of CoV infections. CoVs can transmit from animals to humans to cause serious disease. This zoonotic transmission uses spike proteins, which bind CoVs to cells with two receptor-binding domains. Here, we identified the roles for the two binding processes in the CoV infection process. Binding to sialic acids promoted infection and also supported the intercellular expansion of CoV infections through syncytial development. Adaptive mutations in the sialic acid-binding spike domains increased the intercellular expansion process. These findings raise the possibility that the lectin-like properties of many CoVs contribute to facile zoonotic transmission and intercellular spread within infected organisms.
冠状病毒（CoV）是常见的人畜共患病原体，可通过动物传播并导致严重的呼吸道疾病综合征。CoV 感染需要刺突蛋白，该蛋白与宿主细胞受体结合并催化病毒-细胞膜融合。几种 CoV 株的刺突蛋白具有两个受体结合域，一个 S1A 与宿主唾液酸结合，另一个 S1B 识别宿主跨膜蛋白。由于这种二价结合可能使广泛的人畜共患 CoV 感染成为可能，我们旨在确定每个受体在不同感染阶段的作用。我们专注于两种β冠状病毒，鼠 JHM-CoV 和人类中东呼吸综合征冠状病毒（MERS-CoV），发现病毒粒子与细胞的结合是由唾液酸介导的；然而，跨膜蛋白受体是随后病毒感染所必需的。这些结果支持两步过程，即病毒首先附着在唾液酸上，然后在感染细胞进入时需要与蛋白受体后续结合。然而，唾液酸通过促进细胞-细胞膜融合的后期阶段来充分促进病毒的传播，而不需要蛋白受体。在没有原型蛋白受体的情况下，这种病毒传播通过 S1A 突变的适应性增加。总的来说，这些发现揭示了唾液酸在病毒-细胞结合、病毒刺突蛋白指导的细胞-细胞融合以及 CoV 感染的传播中的作用。CoV 可从动物传播到人类，引起严重疾病。这种人畜共患病的传播使用刺突蛋白，该蛋白通过两个受体结合域与细胞结合。在这里，我们确定了两个结合过程在 CoV 感染过程中的作用。与唾液酸的结合促进了感染，并且通过合胞体发育也支持了 CoV 感染的细胞间扩展。刺突糖结合域中的适应性突变增加了细胞间扩展过程。这些发现提出了这样一种可能性，即许多 CoV 的凝集素样特性有助于它们在感染的生物体中易于发生人畜共患传播和细胞间传播。
