Deciphering MERS-CoV Evolution in Dromedary Camels.

The emergence of the Middle East respiratory syndrome coronavirus (MERS-CoV) poses a potential threat to global public health. Many aspects of the evolution and transmission of MERS-CoV in its animal reservoir remain unclear. A recent study provides new insights into the evolution and transmission of MERS-CoV in dromedary camels.

The initial case of the Middle East respiratory syndrome coronavirus (MERS-CoV) was reported in 2012. Since then, MERS-CoV has been thought to represent a potential threat to global public health. As of December 22, 2015, a total of 1621 MERS cases from 26 countries have been reported, resulting in 584 (36.0%) deaths (http://www.who.int/emergencies/mers-cov/en/). Accumulating evidence suggests that dromedary camels serve as an intermediate reservoir for human MERS-CoV infections. However, much remains unclear about the prevalence and evolution of MERS-CoV in dromedary camels, as well as the routes of MERS-CoV transmission. A recent study in Science by Sabir et al. [1] reports an extensive surveillance for MERS-CoV in dromedary camels and provides new insights into the evolution and transmission of MERS-CoV.

Coronaviruses (CoVs) are classified into four genera, that is, Alphacoronavirus, Betacoronavirus (further into four clades A–D), Gammacoronavirus, and Deltacoronavirus. MERS-CoV belongs to the clade C of Betacoronavirus. Sabir et al. [1] provide a snapshot of the CoV diversity in dromedary camels. They found that 25.3% of camels were positive for CoVs and identified three different CoV species, including MERS-CoV, β1-HKU23-CoV (Betacoronavirus clade A), and camelid α-CoV (Alphacoronavirus). The co-infection of MERS-CoV and camelid α-CoV appears to be frequent. The high prevalence of these CoVs (12.1% and 19.8% for MERS-CoV and camelid α-CoV, respectively) indicates that they are enzoonotic in dromedary camels.

Sabir et al. [1] found at least five lineages of MERS-CoV in Saudi Arabian camels, though there might be some problems in defining viral lineages (some of the viral lineages they defined are not phylogenetically monophyletic). This result suggests multiple lineages have been co-circulating, a prerequisite for recombination to occur. As with other positive-sense RNA viruses, recombination did occur among MERS-CoV strains. Sabir et al. [1] identified at least six recombination events, indicating recombination is frequent in MERS-CoV. Most surprisingly, one lineage (designated lineage 5 by Sabir et al.), which is associated with the recent Riyadh outbreak and the human infections in South Korea and China, has a recombinant origin. This recombinant lineage originated between December 2013 and June 2014, but has quickly become predominant in Saudi Arabian camels since November 2014. It raises a potential link between recombination and increased pathogenicity, which merits further investigation.

Phylogenetic approaches have been extensively used as a tool for tracing the origin, evolution, and epidemiology of MERS-CoV. Because different genome regions of recombinants have different evolutionary histories, ignoring recombination could seriously compromise phylogenetic analysis [2]. Therefore, recombination analysis should be performed before phylogenetic analysis of MERS-CoV

There are four possible routes of MERS-CoV transmission in humans and camels, namely camel-to-human, human-to-human, camel-to-camel, and human-to-camel (Figure 1 ). The former three routes have been well accepted 3, 4. In the Sabir et al. study [1], the high prevalence again suggests that MERS-CoV is enzootic in dromedary camels and could be transmitted among camels. However, the human-to-camel transmission is theoretically possible but largely ignored [5], because of the obsession of animals as sources of human viruses. Recent studies reveal influenza A virus can be transmitted from human to a range of animal species (especially swine), a phenomenon known as reverse zoonosis [6]. For another CoV, severe acute respiratory syndrome-associated coronavirus (SARS-CoV), reverse zoonosis has been reported in cats and pigs [7]. When inspecting Sabir et al.’s phylogenetic trees of MERS-CoV (Figures 1, S2, and S3 in [1]), we found many viruses of camel origin fell within the diversity of human viruses. There are two possible explanations for this phylogenetic pattern: (i) It is artifact due to sampling bias, if many camel viral strains are not sampled. If this is the case, we must miss substantial diversity of MERS-CoV and should expand our surveillance in camels to fully capture the MERS-CoV diversity. (ii) MERS-CoV could be transmitted from humans to camels, which means that humans serve as a source of MERS-CoV for camels. The role of camels in generating and maintaining MERS-CoV diversity has been repeatedly emphasized [1]. If human-to-camel transmission occurs, it requires us to refine our concept of the definition of a ‘breeding ground’ for MERS-CoV, which has important practical implications for developing vaccination strategies and control measures.

Figure 1

Four Possible Routes for MERS-CoV Transmission. The well accepted human-to-human, human-to-camel, and camel-to-camel are labeled in solid arrows. The possible and ignored human-to-camel transmission is labeled in a dashed arrow. The camel and human images courtesy of Steven Traver and T. Michael Keesey.

Both MERS-CoV and SARS-CoV belong to the Betacoronavirus genus, but they belong to different clades, and it will be interesting to compare the transmission pattern between SARS-CoV and MERS-CoV. Phylogenetic analysis of SARS-CoV indicates two independent transmission events occurred from animals to humans [8]. In contrast, the phylogenetic tree of MERS-CoV from Sabir et al. [1] suggests tens of independent transmission events (Figures 1, S2, and S3 in [1]). It follows that the barrier of human-animal transmission is relatively lower for MERS-CoV. It is of great importance to understand the mechanisms underlying the difference of transmission pattern between SARS-CoV and MERS-CoV, with the implications for assessing the emergence risk of other CoVs.

Although the study of Sabir et al. provides important insights into the evolution and transmission of MERS-CoV in dromedary camels, several outstanding questions arise: (i) What is the evolutionary and pathogenic significance of recombination in MERS-CoV? Comparing the pathogenicity of parental and recombinant strains might help resolve this question. (ii) Does human-to-camel transmission occurs in MERS-CoV? The phylogenetic analysis of Sabir et al. suggests this possibility. Also, there are some other clues for this type of transmission [5], but rigorous experimental evidence is still needed. (iii) Are there other intermediate hosts for MERS-CoV? To date, other than camels, sheep, cows, and chickens have been detected for MERS-CoV infections. But none of them show serological evidence of MERS-CoV infection [9]. Nevertheless, more animal species should be sampled. (iv) What is the mechanisms underlying the difference of interspecies transmission between SARS-CoV and MERS-CoV? Both ecological and molecular mechanisms [e.g., the usage of different receptors, angiotensin converting enzyme 2 (ACE2) for SARS-CoV and dipeptidyl peptidase 4 (DPP4) for MERS-CoV] might contribute to this difference.

In summary, Sabir et al.’s study reveals the extensive diversity of MERS-CoV in dromedary camels. Further studies and surveillance, as conducted by Sabir et al. [1], will help improve our understanding of the evolution, ecology, and human-animal interface of MERS-CoV.