Mutation nsp6 L232F associated with MERS-CoV zoonotic transmission confers higher viral replication in human respiratory tract cultures ex-vivo.

Viral host adaptation plays an important role in zoonotic transmission of coronaviruses. For MERS-CoV that widely circulates in dromedary camels from Arabian Peninsula, camel-to human transmissions are ongoing, raising the possibility of human adaptive evolution for MERS-CoV. Here, we analysed MERS-CoV sequences and identified an amino acid mutation L232F in nsp6 to occur repeatedly in human MERS-CoV over the years since the first outbreak in 2012. We found the nsp6 L232F confers increase viral replication in-vitro, in ex-vivo upper human respiratory tract cultures and in mice, using a reverse genetics approach. Our results showed the nsp6 L232F may be advantageous for MERS-CoV to replicate in humans. This study highlighted a human adaptation of MERS-CoV and a need for continued surveillance of MERS-CoV to identify any further adaptations in humans, which may be relevant to the pandemic potential of MERS-CoV.