Middle East respiratory syndrome coronavirus (MERS-CoV) utilizes dipeptidyl peptidase 4 (DPP4) as an entry receptor. While bat, camel, and human DPP4 support MERS-CoV infection, several DPP4 orthologs, including mouse, ferret, hamster, and guinea pig DPP4, do not. Previous work revealed that glycosylation of mouse DPP4 plays a role in blocking MERS-CoV infection. Here, we tested whether glycosylation also acts as a determinant of permissivity for ferret, hamster, and guinea pig DPP4. We found that, while glycosylation plays an important role in these orthologs, additional sequence and structural determinants impact their ability to act as functional receptors for MERS-CoV. These results provide insight into DPP4 species-specific differences impacting MERS-CoV host range and better inform our understanding of virus-receptor interactions associated with disease emergence and host susceptibility.

IMPORTANCE MERS-CoV is a recently emerged zoonotic virus that is still circulating in the human population with an ∼35% mortality rate. With no available vaccines or therapeutics, the study of MERS-CoV pathogenesis is crucial for its control and prevention. However, in vivo studies are limited because MERS-CoV cannot infect wild-type mice due to incompatibilities between the virus spike and the mouse host cell receptor, mouse DPP4 (mDPP4). Specifically, mDPP4 has a nonconserved glycosylation site that acts as a barrier to MERS-CoV infection. Thus, one mouse model strategy has been to modify the mouse genome to remove this glycosylation site. Here, we investigated whether glycosylation acts as a barrier to infection for other nonpermissive small-animal species, namely, ferret, guinea pig, and hamster. Understanding the virus-receptor interactions for these DPP4 orthologs will help in the development of additional animal models while also revealing species-specific differences impacting MERS-CoV host range.

中东呼吸综合征冠状病毒（MERS-CoV）利用二肽基肽酶4（DPP4）作为进入受体。尽管蝙蝠，骆驼和人DPP4支持MERS-CoV感染，但DPP4直系同源物（包括小鼠，雪貂，仓鼠和豚鼠DPP4）却不支持。先前的工作表明，小鼠DPP4的糖基化在阻断MERS-CoV感染中起作用。在这里，我们测试了糖基化是否也可作为雪貂，仓鼠和豚鼠DPP4介电常数的决定因素。我们发现，尽管糖基化在这些直系同源物中起重要作用，但其他序列和结构决定簇影响它们充当MERS-CoV功能性受体的能力。

重要事项MERS-CoV是一种新近出现的人畜共患病毒，目前仍在人群中传播，死亡率约为35％。在没有可用的疫苗或治疗剂的情况下，MERS-CoV发病机理的研究对其控制和预防至关重要。但是，体内由于MERS-CoV由于病毒刺突与小鼠宿主细胞受体小鼠DPP4（mDPP4）之间的不相容性而无法感染野生型小鼠，因此研究非常有限。具体而言，mDPP4具有一个非保守的糖基化位点，可作为MERS-CoV感染的屏障。因此，一种小鼠模型策略是修饰小鼠基因组以去除该糖基化位点。在这里，我们研究了糖基化是否对其他非许可的小动物物种（如雪貂，豚鼠和仓鼠）造成感染的障碍。了解这些DPP4直系同源物的病毒-受体相互作用将有助于开发其他动物模型，同时还揭示影响MERS-CoV宿主范围的物种特异性差异。