BATS AND CAMELS: THE EMERGENCE OF
ZOONOTIC CORONAVIRUSES
In the
past decade, numerous novel coronaviruses have been discovered in a wide
variety of bat species and in Camels throughout Asia, Europe, Africa and
America. Within the coronavirus
genera Alphacoronavirus and Betacoronavirus, which mainly infect
mammals, 7 out of the 15 currently assigned viral species have only been found
in bats. Bats have been proposed as one of the major hosts for alphacoronaviruses and betacoronaviruses and play an important
role as the gene source in the evolution of these two corona- virus genera. The
coronaviruses harbored by bats have been found to be associated with two high
profile human disease outbreaks, Severe Acute Respiratory Syndrome (SARS) and
Middle East Respiratory Syndrome (MERS).
SARS
first emerged in late 2002 in Guangdong Province, southern China, as a novel
clinical severe disease (termed “atypical pneumonia”) marked by fever, head-
ache and subsequent onset of respiratory symptoms including cough, dyspnoea and
pneumonia. It is highly transmissible among humans and by July 2003, it had
caused 8096 confirmed cases of infection in 29 countries, 774 (9.6 %) of which
were fatal. The second outbreak in 2004 only caused 4 infections with no mortality
nor further transmission.
The MERS
epidemic emerged in the Kingdom of Saudi Arabia (KSA) in June 2012. It has a
similar clinical syndrome to SARS but seemingly less transmissible among humans.
In addition to respiratory illness, renal failure has also been identified in
some severe cases of MERS. Most human cases of MERS have occurred in clusters
and have been limited to countries in the Middle East. Limited cases have been
reported in African and European countries and the United States of America,
but exclusively in individuals traveling back from the Middle East. Some
patients may have a history of contact with camels.
The most recent MERS pandemic in the Republic
of Korea in 2015 was caused by a single person who returned from travel in the
Middle East. It was the second largest MERS epidemic with a total of 185 confirmed
cases and 36 deaths]. By 18 August 2015 a total of 1413 laboratory-confirmed
cases of MERS have been reported worldwide with a median age of 50 years,
including 502 related deaths. The mortality of MERS (approximately 35 %) is
much higher than that of SARS (around 10 %).
Taxonomic Classification
SARS-CoV
and MERS-CoV represent two novel distinct coronavirus species in the genus Betacoronavirus. Members of betacoronavirus
are separated into four lineages, A, B, C and D. SARS-CoV and MERS-CoV are
clustered in lineage B and C, respectively
Angiotensin-converting enzyme 2 (ACE2) is the
functional receptor of SARS-CoV and it binds using the SARS-CoV S protein.
Dipeptidyl peptidase 4 (DPP4, also known as CD26) is the functional receptor
for MERS-CoV and it is relatively conserved among mammalian species. MERS-CoV
can therefore infect and replicate in most cell lines derived from human,
non-human primate, bat, swine, goat, horse, rabbit, civet, and camel, but not
from mice, hamster, dog, ferret, and cat. DPP4 from camel, goat, cow and sheep
can be also recognized by MERS-CoV and can support MERS-CoV replication.
Civets
are the intermediate and transmission host of SARS-CoV. Molecular detection and
virus isolation studies have suggested that the pandemic-causing SARS-CoV
(2003/2004) originated from traded civets in wet markets.
Before the outbreak of SARS, two other
zoonotic viruses, Nipah virus and Hendra virus, emerged in Asia and Australia
and were both known to be originated from bats. These led scientists to
consider bats in the search of reservoirs of SARS-CoV.
In 2005,
the discovery of novel coronaviruses related to SARS-CoV in Horseshoe Bats (genus
Rhinolophus) was reported in China,
and they were termed SARS-like coronavirus (SL-CoV). SL-CoVs were also
discovered in rhinolophids from
Slovenia, Bulgaria and Italy in Europe. The European SL-CoVs exhibited
significant genetic variation from Chinese isolates. In Africa, novel
betacoronaviruses related to SARS-CoV have been detected in Hipposideros and Chaerophon species from Ghana, Kenya and Nigeria. These African viruses
of non-rhinolophid origin are
phylogenetically distant to SARS-CoV.
The
theory of bat origin of SARS-CoV lacked a powerful support due to the failure
of direct isolation of SL-CoV from bats, despite numerous trials. The isolation
of a bat SL- CoV genetically closely resembling SARS-CoV and having a
functional S protein capable of using the same ACE2 receptor as SARS-CoV
provided robust and conclusive evidence for the bat origin of SARS-CoV. This
also suggests a possible origin of SARS-CoV from recombination of different
SL-CoVs.
Most early MERS cases had contact history with
animals, e.g., dromedary camels. MERS-CoV RNA was detected in camels from Saudi
Arabia, Qatar and Egypt and showed high similarities (>99 %) to human MERS-CoV
in genomic sequences. Serological evidence further confirmed a high prevalence
of MERS-CoV infections in camels in the Middle East, Africa and Europe (Spain).
These results strongly suggest that MERS-CoV infection in humans were
transmitted through close contact with infected camels. By genomic analysis of
lineage C betacoronaviruses, MERS-CoV derived from camels show high
similarities to human MERS-CoV with >99.5 % nt identities, confirming that
the human and camel isolates belong to the same coronavirus species.
Bat viruses related to MERS-CoV
Based on
genomic sequence analysis, bat coronaviruses have been grouped into lineage C
of the genus Betacoronavirus. After
the outbreak of MERS, MERS-CoV related coronaviruses were found in more bat
species and countries. Among these viruses, full-length or near full-length genomes
of BtCoV-HKU4, BtCoV-HKU5, SC2013 and NeoCoV have been characterized. The bat
NeoCoV shares 85.6 % nt identities with MERS-CoV at genomic level and it can be
classified as the same MERS-CoV species. The most recent ancestor analysis
speculated that MERS-CoV may have jumped from bats to camels approximately 20
years ago in Africa, with camels then being imported into the Arabian Peninsula.
NeoCoV is closer to MERS-CoV than other bat coronaviruses at genomic level.
MERS-CoV has evolved to adapt to use human receptor and the DPP4-recognizing
bat coronaviruses like HKU4 may follow up, thereby posing a serious risk to
human health.
Comparison of Transmission of
MERS-CoV and SARS-CoV
Both SARS-CoV and MERS-CoV are emerging
zoonotic pathogens that have crossed the species barriers to infect humans. Bats
are the origin and natural reservoirs of both SARS-CoV and MERS-CoV. SARS-CoV
and MERS-CoV are then transmitted to humans via an intermediate host mainly
civets and camels, respectively.
Control and Prevention of
SARS-CoV
Human SARS-CoV infection originated from the
direct contact between humans and civets in markets or restaurants. Closing wet
markets and cleaning civet cut off the spread chain of SARS-CoV and effectively
ended the SARS epidemic.
In contrast, MERS-CoV is believed to have
existed in camels for a very long time and camels are widely distributed in
Middle East and African countries, serving as important transport vectors and
sources of meat and milk for the local population. A comprehensive control and
prevention approach involving the effective vaccination of camels against
MERS-CoV among other measures will be important in prevention of future
outbreaks.
HCoV-229E was found in the 1960s and causes
comparatively mild common colds worldwide. A bat coronavirus detected in Hipposideros cafferruber in Ghana is genetically related to HCoV-229E and were
predicted to share a most recent common ancestor (MRCA) only 200 years ago. These
hipposiderid bat coronaviruses are more diversified and form a single viral
species with HCoV- 229E. Interestingly, phylogenetic analysis revealed the
intermediate position of a 229E-related alpaca virus between bat and human
viruses. These findings suggested the ancestral origin of HCoV-229E in
hipposiderid bats and the role of camelids as potential intermediate hosts.
HCoV-NL63 was first isolated from babies suffering of pneumonia and bronchiolitis
in 2004.
In 2010, a bat coronavirus termed ARCoV.2
(Appalachian Ridge CoV) detected in North American tricolored bat (Perimyotis subflavus) in the US showed close relationship with HCoV-NL63. Further analysis indicated that HCoV-NL63 can
replicate in cell lines derived from the lungs of tricolored bats. These
results suggest that prototypes of HCoV- NL63 may also exist in bats and there
may also be a bat origin of this human coronavirus.
Dr.
Moses Bwana
