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The impact of clade B lineage 5 MERS coronaviruses spike mutations from 2015 to 2023 on virus entry and replication
Ray T Y So1, Kenrie P Y Hui1,2, John C W Ho2
1School of Public Health, LKS Faculty of Medicine, The University of Hong Kong, Hong Kong SAR, China.
Abstract:
Middle East respiratory syndrome coronavirus (MERS-CoV) is an emerging coronavirus that can cause zoonotic disease in humans with lethal severe viral pneumonia. Dromedary camels are the source of zoonotic infection. As of November 2025, MERS-CoV has resulted in a total of 2630 reported cases, 37% of these being fatal. The number of reported human cases has been on a decreasing trend since 2016 and reached a nadir during the COVID-19 pandemic. The reason for the reduction of cases is unclear and may be multifactorial. We hypothesized that mutations accumulating in the virus spike protein may have reduced zoonotic potential. Here, we investigate the impact of recently emerged virus spike-protein mutations on virus replication competence using pseudoviruses and replication-competent recombinant viruses. We found that virus spike variants detected in 2019 and some from 2023 show a reduced cell entry, lower viral replication and reduced fitness in human primary alveolar epithelial cells and multiple cell lines. All the MERS-CoV spikes tested showed a cell-entry pathway preference via the cell-surface TMPRSS2 route. Mechanistically, we showed the V530A mutation in the 2019 spike sequence had a reduced human DPP4 binding phenotype. Our data highlighted MERS-CoV spike mutations can modulate viral fitness in human cells and provide new insights to understand recent MERS epidemiology.
Insights
Mutations in the Middle East respiratory syndrome coronavirus (MERS-CoV) spike protein may explain its declining human cases. Recent MERS-CoV variants show reduced cell entry and replication in human cells.
Area of Science:
- Virology
- Epidemiology
- Molecular Biology
Background:
- Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic virus causing severe pneumonia in humans, with dromedary camels as the primary source.
- MERS-CoV has seen a decreasing trend in reported human cases since 2016, reaching a low during the COVID-19 pandemic, with the reasons remaining unclear.
Purpose of the Study:
- To investigate the impact of MERS-CoV spike protein mutations on viral fitness and replication competence.
- To understand if accumulated mutations in the spike protein could explain the reduced zoonotic potential and declining epidemiology of MERS-CoV.
Main Methods:
- Utilized pseudoviruses and replication-competent recombinant viruses to assess MERS-CoV spike variants.
- Examined virus replication, cell entry, and binding affinity to human DPP4.
- Tested MERS-CoV spike variants detected in 2019 and 2023 in human primary alveolar epithelial cells and various cell lines.
Main Results:
- MERS-CoV spike variants from 2019 and some from 2023 exhibited reduced cell entry, lower viral replication, and decreased fitness in human cells.
- All tested MERS-CoV spikes demonstrated a preference for cell entry via the TMPRSS2 pathway.
- A specific mutation (V530A) in the 2019 spike sequence was associated with reduced binding to human DPP4.
Conclusions:
- Mutations in the MERS-CoV spike protein can significantly modulate viral fitness in human cells.
- These findings offer insights into the potential mechanisms behind the recent decline in MERS-CoV epidemiology and reduced zoonotic potential.
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