The next pandemic? Establishing an experimental framework for assessing virus zoonotic potential using coronaviruses of rodents and humans

COVID-19大流行已成为人畜共患病毒传播可能对人类构成风险的严峻提醒。尽管SARS-CoV-2和致病性前体SARS-CoV和MERS-CoV被认为起源于蝙蝠，但其他医学上重要的人类冠状病毒（CoV），即OC 43和HKU 1，被广泛认为起源于啮齿动物。因此，虽然最近的重要研究集中在蝙蝠中冠状病毒的起源和人畜共患潜力上，但啮齿动物中的冠状病毒仍然知之甚少。为此，尽管自2015年以来已经在不同的啮齿动物物种中发现了数十种冠状病毒，但我们对这些病毒的了解几乎完全是基于计算机（基于序列）。因此，迫切需要进行实验研究，以更好地了解啮齿动物中冠状病毒的大流行潜力，特别是考虑到它们的近家庭/近城市性质。此外，这种人类和啮齿动物共享空间的倾向也突出了同样迫切需要了解啮齿动物是否可能作为人类CoV的储存库。因此，这里提出的工作将调查啮齿动物和人类之间CoV传播的潜力和决定因素，使用4个主要目标：1。评估啮齿动物冠状病毒向人类传播的能力2。确定人类冠状病毒在啮齿动物中建立储库的能力3。确定控制冠状病毒在人类和啮齿动物之间传播的特定分子屏障4。计算预测人类和啮齿动物之间的冠状病毒传播风险为了实现这些目标，该研究金将采用多样化和雄心勃勃的分子和计算方法，并在体外和体内实验中建立桥梁。最终，这不仅将阐明CoV跨物种传播的风险，而且还将建立一个更广泛地评估病毒人畜共患和大流行潜力的实验框架。

The COVID-19 pandemic has been a stark reminder of the risks that zoonotic virus transmission can pose to humans. Although SARS- CoV-2 and pathogenic predecessors SARS-CoV and MERS-CoV are believed to have origins in bats, other medically important human coronaviruses (CoVs), namely OC43 and HKU1, are widely believed to have rodent origins. Thus, while significant recent research has focused on the origins and zoonotic potential of CoVs in bats, those in rodents remain more poorly understood. To this end, although dozens of CoVs have been identified in diverse rodent species since 2015, our knowledge of these viruses is almost entirely in silico (sequence-based). There is therefore an urgent need to undertake experimental investigations that will provide a better understanding of the pandemic potential of CoVs in rodents, particularly in light of their peri-domestic/peri-urban nature. Moreover, this propensity for humans and rodents to share space also highlights the equally urgent need to understand whether rodents might serve as reservoirs for human CoVs.The work proposed here will thus investigate the potential for, and determinants of, CoV transmission between rodents and humans, using 4 primary objectives:1. Evaluate the capacity for zoonotic transmission of rodent CoVs to humans2. Determine the capacity of human CoVs to establish reservoirs in rodents3. Identify specific molecular barriers that govern transmission of CoVs between humans and rodents 4. Generate computational predictions of CoV transmission risks between humans and rodentsTo achieve these aims, the fellowship will incorporate diverse and ambitious molecular and computational approaches and bridge in vitro and in vivo experimentation. Ultimately this will not only elucidate CoV cross-species transmission risks but establish an experimental framework for more broadly evaluating virus zoonotic and pandemic potential.