key: cord-0895229-7hw23xae
authors: Du, Lin; Han, Guan-Zhu
title: Deciphering MERS-CoV Evolution in Dromedary Camels
date: 2016-01-08
journal: Trends Microbiol
DOI: 10.1016/j.tim.2015.12.013
sha: abc45f73d56cf8a1f86eca290ede1bd1a7989e55
doc_id: 895229
cord_uid: 7hw23xae

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.

detected in the saliva of humans with hemorrhagic CHIKV infection and in a macaque CHIKV hemorrhagic model [4] . The requirement for hemorrhagic disease is likely due to virus entering the oral cavity via gingival bleeding, and a similar pathway to infection is also plausible. It will be important to determine the relationship between hemorrhagic CHIKV infections and compromised immunity in salivabased transmission.

Gardner et al. [4] suggested the finding may not be broadly applicable to humans because transmission was observed only in highly immunodeficient mice and not in wild-type mice. Nonetheless, the study is potentially of great significance, particularly in the context of severe hemorrhagic disease and immunodeficiency. Many countries most affected by CHIKV have high numbers of immunocompromised patients, particularly due to HIV infection, but also due to other infections, other morbidities, intrinsic immunodeficiency, or even extreme age. In addition to increased susceptibility to CHIKV infection, many of these patients likely have oral lesions, which could also promote transmission and infection via saliva. The impact within this patient population could be highly significant. CHIKV infections can spread extremely rapidly through communities and we wonder whether transmission via saliva can contribute to this rapid spread. Further studies are required to rigorously test for CHIKV transmission via saliva, but this preliminary study suggests that we need to seriously consider this mode of transmission.

Numerous viruses are spread orally, most notably Epstein-Barr virus (EBV) and cytomegalovirus (CMV). EBV is highly infectious via the oral route, which is reflected in the common name given to EBV infectionsthe 'kissing disease'. In addition to kissing, other high risk activities for EBV transmission include sharing toothbrushes and eating utensils with an infected individual. The risk of transmission by saliva is particularly high among children and close family.

HIV and hepatitis B and C viruses are typically transmitted by blood or sexual contact but have also been detected in saliva. Hepatitis B transmission can occur through saliva [5] , but there are no established reports of transmission via saliva for HIV or hepatitis C [6] . Ebola virus is present in the saliva of infected individuals and although it seems likely that transmission via saliva does occur, the significance of this route of transmission is unclear, particularly as the virus is inactivated rapidly in saliva [7] . A number of viruses can be transmitted through open sores in the mouth, with saliva as the vehicle for transmission. Of course, many respiratory viruses can also be transmitted by saliva. Thus, the significance of viruses in saliva for transmission varies greatly from virus to virus, from highly transmissible to not at all.

There are few examples of non-vector based arbovirus transmission under natural conditions, with most cases being by intranasal or aerosol route of infection [8] . To our knowledge, this is the first report of likely arbovirus transmission via saliva. This mode of transmission has not been considered to date in models assessing CHIKV spread. Although it is unlikely that measuring CHIKV in saliva will have broad diagnostic value, its presence in the saliva may have prognostic value, particularly in relation to disease severity. The possibility of aerosol transmission also needs to be considered. It is intriguing to consider the possibility that CHIKV in the saliva could be related to the neurological complications reported in a minority of CHIKV cases [2] : could salivary CHIKV lead to central nervous system (CNS) infections via olfactory neurons, as has been described for a number of other viruses [9] ? More study is required to assess the significance of CHIKV in the saliva, particularly in immunocompromised patients. This needs urgent attention as it will have a major influence on efforts to counter the spread of this emerging virus. The possibility of saliva-mediated transmission of other arboviruses also needs to be reassessed. [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-tohuman, camel-to-camel, and human-tocamel ( 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 humanto-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.

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 ? 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. [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] 

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