Molecular Evolution of MERS Coronavirus: Dromedaries as a Recent Intermediate Host or Long-Time Animal Reservoir?

Lau, Susanna K. P.; Wong, Antonio C. P.; Lau, Terrence C. K.; Woo, Patrick C. Y.

While there is evidence suggesting that MERS-CoV may have infected camels for at least a few decades, it is intriguing that the present molecular clock analysis using available dated MERS-CoV genome sequences suggests a relatively recent common ancestor dated to approximately 2010. Based on existing evidence, there are two possibilities in the evolutionary pathway of MERS-CoV. The first possibility is that MERS-CoV has resided in camels for long time before infecting humans to cause the epidemic in 2012. The alternative hypothesis is that MERS-CoV has only emerged in camels recently from an unknown animal reservoir, and was spilled over to humans because of efficient receptor binding to human dipeptidyl peptidase 4 when a sufficient proportion of camel population was infected. The first hypothesis is supported by two previous serological studies showing that MERS-CoV neutralizing antibodies in archived sera samples of dromedaries in Eastern Africa and Kenya can be detected as early as 1980s and 1990s [19, 20] . Moreover, the lack of positive selection at the receptor binding domain of spike protein of MERS-CoV may suggest the virus has been well adapted in camels and humans for a period of time. However, several questions were not readily answered by this hypothesis. First, since genomes of MERS-CoVs from humans and camels were intermingled and closely related without major adaptation before transmission to humans, one would expect similar camel-to-human transmission efficiency before the epidemic in 2012. However, no human cases before 2012 were reported so far, and more importantly, MERS-CoV has not been detected in any archived human or camel samples before 2012. Nevertheless, there is a possibility that early human cases may have been missed if they were not investigated for coronaviruses. Yet, if MERS-CoV has been circulating in camels for long time, one would expect a much earlier estimated tMRCA by molecular clock analysis using available MERS-CoV genome sequences. Although the present study may be limited by the lack of "historical" strains of MERS-CoV for analysis, the diverse circulating strains detected since 2012 should have reflected the history of evolution of MERS-CoV and allow a fair estimation of tMRCA. Nevertheless, isolation of MERS-CoV or detection of viral RNA from archived samples will be important to confirm if camels are indeed long-time reservoir of MERS-CoV.