Virology tidbits

Virology tidbits

Saturday, 3 May 2014

Novel Coronavirus in dromedaries: not related to MERS-CoV so why bother?

Following the appearance of  a novel respiratory disease in 2003 and the subsequent identification of (then novel) Coronavirus, Severe Acute Respiratory Syndrome or SARS-CoV, a renewed interest in these viruses lead to the discovery of several new Coronaviruses, including HCoV-NL63 and HCoV-HKU1 in humans. In the search of the natural reservoir of SARS-CoV, a SARS-like Coronavirus was isolated from five different species of Chinese horseshoe bats (Rhinolopus spp.) and shown to utilize the same receptor, ACE2, thus suggesting that SARS-CoV is derived from a Coronavirus circulating in bats. Indeed, phylogenetic analysis of both human SARS-CoV and bat SARS-like Coronavirus suggests that the latter crossed into the human population relative recent and that SARS-CoV might be the result of a recombination between bat and human Coronaviruses. These results are reflected in the classification of both SARS-CoV and BCoV A1 within the Betacoronaviridae, albeit in different lineages (C and A respectively).
In 2012, a novel Coronavirus, Middle East Respiratory Syndrome (MERS-CoV), was identified to be the causative agent of severe respiratory infection associated with a high mortality. Molecular phylogenetic analysis revealed that MERS-CoV is closely related to BCoV-HKU4, which was isolated from Tyloncteris bats, as well as BCoV-HKU5 isolated from Pipistrellus spp. bats. Additionally, MERS-CoV neutralizing antibodies were shown to exist in dromedaries suggesting that camels might play a role in the dissemination of the virus but might not necessarily be a natural reservoir for MERS-CoV.
The analysis of fecal samples from dromedaries in Dubai led to the identification of novel Betacoronavirus -subsequently named Dromedary Camel Coronavirus (DcCoV) UAE HKU23. in 2013. Antibodies against the Nucleocapsid protein of DcCoV-UAE HKU23 were detected in the serum in 52% of samples tested. The analysis of the genome of three isolates identified DcCoV-UAE HKU23 to be a Betacoronavirus in lineage A1 -and such being in a different lineage than MERS-CoV which is a lineage C Betacoronavirus- related to bat and antelope derived Coronaviruses.
Genome organization of DcCoV-UAE HKU23 and BCoV A1 is different from SARS-CoV
In contrast to MERS-CoV or SARS-CoV but similar to HCoV-OC43, the genome of DcCoV-UAE HKU23 encodes an additional structural protein, Hemagglutinin Esterase (HE), which is not essential for virus replication but highly antigenic.

The hemagglutinin activity of HE allows the virus to bind to the Sialic Acid found on the cell surface and the Esterase activity cleave the Sialic Acid thus facilitating the release of the virus particle. Studies of the Mouse Hepatitis Virus (MHV) derived HE have shown that HE also contributes to the receptor specificity of the Coronavirus in question, thus extending the role of HE beyond the release of the mature viral particle. 
Prototype Betacoronavirus
Regarding DcCoV-UAE HKU23 and MERS-CoV, antibodies are not cross-reactive as expected from the genomic studies- which is rather good news given the high prevalence of the novel Coronavirus in dromedaries. Interestingly, DcCoV-UAE HKU23 is more common on dromedary calves than in adult dromedaries, suggesting that calves are more susceptible than adult dromedaries. Finally the question remains if DcCoV-UAE HKU23 causes any significant disease in dromedaries compared for instance to Infectious Bronchitis Virus (IBV) in the poultry industry. So far, DcCoV-UAE HKU23 was detected in multiple cases of diarrhea, but future research is needed to determine the pathology and the involvement in disease.

Given the proximity of camels and dromedaries continuous surveillance is warranted to understand and detect transmission of virus from animal to humans. Finally, the question remains how bat derived viruses are transmitted to dromedaries, other animals, and humans. The discovery of a novel Alphacoronavirus (Mystacina bat CoV) in guano from bats (Mystcina tuberculata) in New Zealand might provide an answer. Bats are known to transmit rabies to humans and be the reservoir for a number of zoonotic viruses and it has been speculated that the ancestor of modern Coronaviruses might be have been originally a bat Coronaviruses, a notion strengthened by the discovery of Mystacina tuberculata-CoV.

Further reading

Woo PC, Lau SK, Wernery U, Wong EY, Tsang AK, Johnson B, Yip CC, Lau CC, Sivakumar S, Cai JP, Fan RY, Chan KH, Mareena R, & Yuen KY (2014). Novel betacoronavirus in dromedaries of the middle East, 2013. Emerging infectious diseases, 20 (4), 560-72 PMID: 24655427 

Zaki AM, van Boheemen S, Bestebroer TM, Osterhaus AD, & Fouchier RA (2012). Isolation of a novel coronavirus from a man with pneumonia in Saudi Arabia. The New England journal of medicine, 367 (19), 1814-20 PMID: 23075143

Lau SK, Li KS, Tsang AK, Lam CS, Ahmed S, Chen H, Chan KH, Woo PC, & Yuen KY (2013). Genetic characterization of Betacoronavirus lineage C viruses in bats reveals marked sequence divergence in the spike protein of pipistrellus bat coronavirus HKU5 in Japanese pipistrelle: implications for the origin of the novel Middle East respiratory syndrome coronavirus. Journal of virology, 87 (15), 8638-50 PMID: 23720729 

Reusken CB, Haagmans BL, Müller MA, Gutierrez C, Godeke GJ, Meyer B, Muth D, Raj VS, Smits-De Vries L, Corman VM, Drexler JF, Smits SL, El Tahir YE, De Sousa R, van Beek J, Nowotny N, van Maanen K, Hidalgo-Hermoso E, Bosch BJ, Rottier P, Osterhaus A, Gortázar-Schmidt C, Drosten C, & Koopmans MP (2013). Middle East respiratory syndrome coronavirus neutralising serum antibodies in dromedary camels: a comparative serological study. The Lancet infectious diseases, 13 (10), 859-66 PMID: 23933067 

Spaan, W., Cavanagh, D., & Horzinek, M. (1988). Coronaviruses: Structure and Genome Expression Journal of General Virology, 69 (12), 2939-2952 DOI: 10.1099/0022-1317-69-12-2939

Langereis, M., Zeng, Q., Heesters, B., Huizinga, E., & de Groot, R. (2012). The Murine Coronavirus Hemagglutinin-esterase Receptor-binding Site: A Major Shift in Ligand Specificity through Modest Changes in Architecture PLoS Pathogens, 8 (1) DOI: 10.1371/journal.ppat.1002492 

Gorbalenya AE, Snijder EJ, & Spaan WJ (2004). Severe acute respiratory syndrome coronavirus phylogeny: toward consensus. Journal of virology, 78 (15), 7863-6 PMID: 15254158 

Ren W, Li W, Yu M, Hao P, Zhang Y, Zhou P, Zhang S, Zhao G, Zhong Y, Wang S, Wang LF, & Shi Z (2006). Full-length genome sequences of two SARS-like coronaviruses in horseshoe bats and genetic variation analysis. The Journal of general virology, 87 (Pt 11), 3355-9 PMID: 17030870 

Lau SK, Li KS, Tsang AK, Shek CT, Wang M, Choi GK, Guo R, Wong BH, Poon RW, Lam CS, Wang SY, Fan RY, Chan KH, Zheng BJ, Woo PC, & Yuen KY (2012). Recent transmission of a novel alphacoronavirus, bat coronavirus HKU10, from Leschenault's rousettes to pomona leaf-nosed bats: first evidence of interspecies transmission of coronavirus between bats of different suborders. Journal of virology, 86 (21), 11906-18 PMID: 22933277 

Hall RJ, Wang J, Peacey M, Moore NE, McInnes K, & Tompkins DM (2014). New Alphacoronavirus in Mystacina tuberculata Bats, New Zealand. Emerging infectious diseases, 20 (4) PMID: 24656060 

Chan JF, To KK, Tse H, Jin DY, & Yuen KY (2013). Interspecies transmission and emergence of novel viruses: lessons from bats and birds. Trends in microbiology, 21 (10), 544-55 PMID: 23770275

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