Emergence and spread of mutant MERS CoV with reduced affinity to CD26 during the south Korean outbreak Uni Park, Abdimadiyeva Aigerim, Yuri Kim, and Myung-Sik Choi, and Nam-Hyuk Cho Department of Microbiology and Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine
The newly emerging Middle East respiratory syndrome coronavirus (MERS-CoV) causes a severe respiratory infection with a high mortality rate (~35%). MERS-CoV has been a global threat due to continuous outbreaks in the Arabian peninsula and international spread by infected travelers since 2012. From May to July 2015, a large outbreak initiated by an infected traveler from the Arabian peninsula swept South Korea and resulted in 186 confirmed cases with 38 deaths (case fatality rate, 20.4%). Here, we show the rapid emergence and spread of a mutant MERS-CoV with reduced affinity to the human CD26 receptor during the South Korean outbreak. We found that majority of viral genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, more than 80% of spike sequences identified from Korean patients have an I529T mutation in RBD, and approximately 15% have a D510G mutation. Strikingly, both mutations result in reduced affinity of RBD to human CD26 compared to wild-type RBD, as measured by surface plasmon resonance analysis and cellular binding assay. Additionally, pseudotyped lentivirus bearing an I529T mutation in S protein showed reduced entry into host cells compared to wild type virus and in vitro viral plaque of I529T mutant MERS-CoV is significantly reduced than that of wild type virus. These unexpected findings suggest that MERS-CoV adaptation during human-to-human spread may be driven by host immunological pressure such as neutralizing antibodies, resulting in reduced affinity to host receptor, and thereby impairs viral fitness and virulence, rather than positive selection for a better affinity to CD26. Systemic analysis of viral spike genotypes and epidemiological features of Korean outbreak also suggests a potential association of superspreading events with the emergence of spike mutations in our recent study.
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