Virology
The virus MERS-CoV is a new member of the beta group of coronavirus,
Betacoronavirus, lineage C. MERS-CoV genomes are phylogenetically classified into two
clades,
clade A and B. The earliest cases of MERS were of clade A clusters
(EMC/2012 and Jordan-N3/2012), and new cases are genetically distinct
(clade B).
[5]
MERS-CoV is distinct from
SARS and distinct from the common-cold coronavirus and known endemic human betacoronaviruses HCoV-OC43 and HCoV-HKU1.
[6] Until 23 May 2013, MERS-CoV had frequently been referred to as a SARS-like virus,
[7] or simply the novel coronavirus, and early it was referred to colloquially on messageboards as the "Saudi SARS".
Origin
The first confirmed cases were reported in an Amman, Jordan hospital
among health care workers and nursing staff in April 2012, where the
cases were determined to be H2H transmission. Later a 60-year-old male
patient with acute
pneumonia and acute
renal failure, who passed away in
Jeddah,
Saudi Arabia on 24 June 2012.
[6] Egyptian virologist Dr. Ali Mohamed Zaki isolated and identified a previously unknown coronavirus from the man's
lungs.
[8][9][10] Dr. Zaki then posted his findings on 24 September 2012 on
ProMED-mail.
[9][11][11] The isolated cells showed
cytopathic effects (CPE), in the form of rounding and
syncetia formation.
[11]
A second case was found in September 2012. A 49-year-old male living
in Qatar presented similar flu symptoms, and a sequence of the virus was
nearly identical to that of the first case.
[6]
In November 2012, similar cases appeared in Qatar and Saudi Arabia.
Additional cases were noted, with deaths associated, and rapid research
and monitoring of this novel coronavirus began.
It is not certain whether the infections are the result of a single
zoonotic
event with subsequent human-to-human transmission, or if the multiple
geographic sites of infection represent multiple zoonotic events from a
common unknown source.
A study by Ziad Memish of Riyadh University and colleagues suggests
that the virus arose sometime between July 2007 and June 2012, with
perhaps as many as 7 separate zoonotic transmissions. Among animal
reservoirs, CoV has a large genetic diversity yet the samples from
patients suggest a similar genome, and therefore common source, though
the data are limited. It has been determined through molecular clock
analysis, that viruses from the EMC/2012 and England/Qatar/2012 date to
early 2011 suggesting that these cases are descended from a single
zoonotic event. It would appear the MERS-CoV has been circulating in the
human population for greater than one year without detection and
suggests independent transmission from an unknown source.
[12][13]
Tropism
In humans, the virus has a strong
tropism
for nonciliated bronchial epithelial cells, and it has been shown to
effectively evade the innate immune responses and antagonize
interferon (IFN) production in these cells. This tropism is unique in that most respiratory viruses target ciliated cells.
[14][15]
Due to the clinical similarity between MERS-CoV and
SARS-CoV, it was proposed that they may use the same cellular receptor; the exopeptidase, angiotensin converting enzyme 2 (
ACE2).
[16] However, it was later discovered that neutralization of ACE2 by recombinant antibodies does not prevent MERS-CoV infection.
[17] Further research identified dipeptyl peptidase 4 (
DPP4; also known as
CD26) as a functional cellular receptor for MERS-CoV.
[15] Unlike other known coronavirus receptors, the
enzymatic activity
of DPP4 is not required for infection. As would be expected, the amino
acid sequence of DPP4 is highly conserved across species and is
expressed in the human bronchial epithelium and kidneys.
[15][18]
Bat DPP4 genes appear to have been subject to a high degree of adaptive
evolution as a response to coronavirus infections, so the lineage
leading to MERS-CoV may have circulated in bat populations for a long
period of time before being transmitted to people.
[19]
Transmission
On 13 February 2013, the
World Health Organization stated "the risk of sustained person-to-person transmission appears to be very low."
[20]
The cells MERS-CoV infects in the lungs only account for 20% of
respiratory epithelial cells, so a large number of virions are likely
needed to be inhaled to cause infection.
[18]
As of 29 May 2013, the WHO is now warning that the MERS-CoV virus is a "threat to entire world."
[21] However, Dr.
Anthony S. Fauci of the
National Institutes of Health
in Bethesda, Maryland, stated that as of now MERS-CoV "does not spread
in a sustained person to person way at all." Dr. Fauci stated that there
is potential danger in that it is possible for the virus to mutate into
a strain that does transmit from person to person.
[22]
The infection of healthcare workers (HCW) leads to concerns of human to human transmission.
[23]
The
Centers for Disease Control and Prevention (CDC) list MERS as
transmissible from human-to-human.
From their FAQ, in answer to the question "Does MERS-CoV spread from
person to person?", they answer "MERS-CoV has been shown to spread
between people who are in close contact. Transmission from infected
patients to healthcare personnel has also been observed. Clusters of
cases in several countries are being investigated.".
[24] There is also a
New York Times article which provides some correlative context for this.
[25]
Natural reservoir
Early research suggested the virus is related to one found in the
Egyptian tomb bat. In September 2012 Ron Fouchier speculated that the virus might have originated in bats.
[26] Work by epidemiologist Ian Lipkin of
Columbia University in New York showed that the virus isolated from a bat looked to be a match to the virus found in humans.
[27][28] [29] 2c betacoronaviruses were detected in
Nycteris bats in Ghana and
Pipistrellus bats in Europe that are phylogenetically related to the MERS-CoV virus.
[30]
Recent work links
camels to the virus. An ahead-of-print dispatch for the journal
Emerging Infectious Diseases records research showing the coronavirus infection in
dromedary camel calves and adults, 99.9% matching to the genomes of human clade B MERS-CoV.
[31]
At least one person who has fallen sick with MERS was known to have come into contact with camels or recently drank
camel milk.
[32]
On 9 August 2013, a report in the journal
The Lancet Infectious Diseases showed that 50 out of 50 (100%)
blood serum from
Omani camels and
15 of 105
(14%) from Spanish camels had protein-specific antibodies against the
MERS-CoV spike protein. Blood serum from European sheep, goats, cattle,
and other camelids had no such antibodies.
[33] Countries like
Saudi Arabia and the
United Arab Emirates produce and consume large amounts of
camel meat. The possibility exists that African or Australian
bats harbor the virus and transmit it to camels. Imported camels from these regions might have carried the virus to the Middle East.
[34]
In 2013 MERS-CoV was identified in three members of a dromedary camel
herd held in a Qatar barn, which was linked to two confirmed human
cases who have since recovered. The presence of MERS-CoV in the camels
was confirmed by the
National Institute of Public Health and Environment (RIVM) of the Ministry of Health and the
Erasmus Medical Center
(WHO Collaborating Center), the Netherlands. None of the camels showed
any sign of disease when the samples were collected. The Qatar Supreme
Council of Health advised in November 2013 that people with underlying
health conditions, such as heart disease, diabetes, kidney disease,
respiratory disease, the immunosuppressed, and the elderly, avoid any
close animal contacts when visiting farms and markets, and to practice
good hygiene, such as washing hands.
[35]
A further study on dromedary camels from Saudi Arabia published in
December 2013 revealed the presence of MERS-CoV in 90% of the evaluated
dromedary camels (310), suggesting that dromedary camels not only could
be the main reservoir of MERS-CoV, but also the animal source of MERS.
[36]
According to the 27 March 2014 MERS-CoV summary update, recent
studies support that camels serve as the primary source of the MERS-CoV
infecting humans, while bats may be the ultimate reservoir of the virus.
Evidence includes the frequency with which the virus has been found in
camels to which human cases have been exposed, seriological data which
shows widespread transmission in camels, and the similarity of the camel
CoV to the human CoV.
[37]