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UNLABELLED: Middle East respiratory syndrome coronavirus (MERS-CoV) causes zoonotic disease. Dromedary camels are the source of zoonotic infection. We identified a mutation of amino acid leucine to phenylalanine in the codon 232 position of the non-structural protein 6 (nsp6) (nsp6 L232F) that is repeatedly associated with zoonotic transmission. We generated a pair of isogenic recombinant MERS-CoV with nsp6 232L and 232F residues, respectively, and showed that the nsp6 L232F mutation confers higher replication competence in ex-vivo culture of human nasal and bronchial tissues and in lungs of mice experimentally infected in-vivo. Mechanistically, the nsp6 L232F mutation appeared to modulate autophagy and was associated with higher exocytic virus egress, while innate immune responses and zippering activity of the endoplasmic reticulum remained unaffected. Our study suggests that MERS-CoV nsp6 may contribute to viral adaptation to humans. This highlights the importance of continued surveillance of MERS-CoV in both camels and humans. IMPORTANCE: 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.

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