Spread of Mutant Middle East Respiratory Syndrome Coronavirus with Reduced Affinity to Human CD26 during the South Korean Outbreak

Abstract

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 isolated 13 new viral genomes from 14 infected patients treated at a hospital and found that 12 of these genomes possess a point mutation in the receptor-binding domain (RBD) of viral spike (S) protein. Specifically, 11 of these genomes have an I529T mutation in RBD, and 1 has 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 virus bearing an I529T mutation in S protein showed reduced entry into host cells compared to virus with wild-type S protein. 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.

Analysis of intrapatient heterogeneity uncovers the microevolution of Middle East respiratory syndrome coronavirus

“…3). Recently, both D510G and I529T mutations in RBD were shown to reduce its affinity for human CD26 compared with the wild-type RBD (Kim et al 2016c). Although the previous study did not test the binding affinity of the double mutant, in our data the two mutations are mutually exclusive, suggesting that the double mutant severely impairs viral fitness.…”

“…Thus, we questioned whether the selection pressure was exerted by a host immune response such as neutralizing antibodies, as previously suggested (Kim et al 2016c). In such cases, a reduction in host immune pressure might increase the frequency of the wild type.…”

“…Recently, in an analysis of 13 MERS-CoV genomes associated with the 2015 outbreak in South Korea, Kim et al (2016c) reported that 11 of those genomes had an I529T mutation in RBD, and one had a D510G mutation. The study showed that D510G and I529T mutations resulted in reduced affinity of RBD for the human CD26 receptor compared with the wild-type RBD.…”

“…The study showed that D510G and I529T mutations resulted in reduced affinity of RBD for the human CD26 receptor compared with the wild-type RBD. Based on the spread of a mutant MERS-CoV with reduced affinity for the receptor, the authors suggested that MERS-CoV adaptation during human-to-human spread might be driven by host immunological pressure such as neutralizing antibodies (Kim et al 2016c). Consistent with the previous analysis, our data showed that the I529T and D510G mutations were observed in the consensus sequences from 29 and 4 of 35 samples, respectively.…”

Characterization of novel monoclonal antibodies against MERS-coronavirus spike protein

“…Since the MERS outbreak in South Korea, 13 new viral genomes from 14 infected Korean patients were isolated, and 12 of these genomes were identified to possess a point mutation in the receptor-binding domain (RBD) of the S glycoprotein (Kim et al, 2016a, b;Min et al, 2016). Specifically, 11 of these genomes showed an I529 T mutation in RBD, and 1 showed a D510 G mutation, which exhibits reduced affinity of RBD to its cellular receptor, human dipeptidyl peptidase 4 (DPP4; also known as CD26), compared with the wild type RBD, suggesting that MERS-CoV adaptation during human-to-human spread may be driven to escape from neutralizing antibodies, rather than to evolve for a stronger affinity to DPP4 (Kim et al, 2016b;Park et al, 2016). Therefore, several mAbs against different epitopes within S might be used as a prophylactic or therapeutic agent to avoid the immune escape of the virus.…”