Matsugo Hiromichi, Kitamura Tomoya, Takahashi Naohiro, Chambers James, Ichikawa Ayano, Katayama Misa, Li Kaixin, Sekine Wataru, Ohira Kosuke, Ishida Hiroho, Takenaka-Uema Akiko, Uchida Kazuyuki, Shimojima Masayuki, Horimoto Taisuke, Murakami Shin
Laboratory of Veterinary Microbiology, Graduate School of Agricultural and Life Sciences, University of Tokyo, Tokyo, Japan.
African Swine Fever Unit, National Agriculture and Food Research Organization (NARO), National Institute of Animal Health, Tokyo, Japan.
J Virol. 2025 Jul 22;99(7):e0072725. doi: 10.1128/jvi.00727-25. Epub 2025 Jun 17.
Betacoronaviruses, which have caused three human outbreaks within the last two decades, are thought to originate from bats, raising the concern that bat coronaviruses could cause a novel human outbreak in the future. To determine whether the bat merbecovirus EjCoV-3 strain, previously detected in in Japan, has the potential to infect humans, we analyzed its cellular entry mechanism. Cellular entry of EjCoV-3 via the spike protein requires protease treatment and is mediated by an unknown receptor, other than DPP4 or ACE2. We generated cultivable recombinant EjCoV-3 using bacterial artificial chromosome-based reverse genetics and found that it efficiently replicated in human respiratory and intestinal cell cultures as well as nasal ciliated epithelium in hamsters. These findings suggest that bat merbecovirus with ACE2- and DPP4-independent cell entry has the potential to cause human infections, highlighting the importance of extensive bat surveillance for pandemic preparedness.
Betacoronaviruses, including severe acute respiratory syndrome coronavirus (SARS-CoV), Middle East respiratory syndrome coronavirus (MERS-CoV), and SARS-CoV-2, have caused three significant outbreaks in the past two decades and are believed to have originated from bats. To investigate the potential for future outbreaks, we generated a Japanese bat-derived MERS-related coronavirus, designated EjCoV-3, using reverse genetics. Our results showed that EjCoV-3 does not utilize ACE2 and DPP4, cell entry receptors for SARS-CoV and MERS-CoV, as a means of infection. However, we found that EjCoV-3 is the first bat merbecovirus capable of efficiently replicating in human respiratory cells and the respiratory tract of hamsters. These findings provide new insight into the potential for MERS-related coronaviruses that do not use ACE2 and DPP4 to infect the human respiratory tract, highlighting the importance of preparedness for outbreaks caused by these viruses.
在过去二十年中引发了三次人类疫情的β冠状病毒被认为起源于蝙蝠，这引发了人们对蝙蝠冠状病毒未来可能引发新的人类疫情的担忧。为了确定之前在日本检测到的蝙蝠默贝病毒EjCoV-3毒株是否具有感染人类的潜力，我们分析了其细胞进入机制。EjCoV-3通过刺突蛋白进入细胞需要蛋白酶处理，并且由除DPP4或ACE2之外的未知受体介导。我们使用基于细菌人工染色体的反向遗传学方法构建了可培养的重组EjCoV-3，发现它能在人类呼吸道和肠道细胞培养物以及仓鼠的鼻纤毛上皮中有效复制。这些发现表明，具有不依赖ACE2和DPP4的细胞进入机制的蝙蝠默贝病毒有可能导致人类感染，凸显了广泛监测蝙蝠对于防范大流行的重要性。
包括严重急性呼吸综合征冠状病毒（SARS-CoV）、中东呼吸综合征冠状病毒（MERS-CoV）和严重急性呼吸综合征冠状病毒2（SARS-CoV-2）在内的β冠状病毒在过去二十年中引发了三次重大疫情，并且被认为起源于蝙蝠。为了调查未来疫情爆发的可能性，我们利用反向遗传学方法构建了一种源自日本蝙蝠的与MERS相关的冠状病毒，命名为EjCoV-3。我们的结果表明，EjCoV-3不利用SARS-CoV和MERS-CoV的细胞进入受体ACE2和DPP4作为感染途径。然而，我们发现EjCoV-3是第一种能够在人类呼吸道细胞和仓鼠呼吸道中有效复制的蝙蝠默贝病毒。这些发现为不利用ACE2和DPP4的与MERS相关的冠状病毒感染人类呼吸道的可能性提供了新的见解，凸显了防范这些病毒引发疫情的重要性。
