Origin and Evolution of Coronaviruses

Coronavirus, SARS, MERS, SADS, 2019-nCoV, Wuhan, Bats

With the province Wuhan in China shut and isolated due to 2019-nCoV, sadly, Coronavirus is the news of the New Year. The truth is that Coronavirus has been in news since the onset of the 21st century. Let’s all be clear with one thing at the very outset and that is that there is no single coronavirus. There are coronaviruses, instead. Moreover, due to frequent and multiple genetic recombinations in some of their strains, they keep mutating. And, this event causes all the havoc.

Update on the Wuhan Coronavirus 2019-nCoV

In the 21st century, so far three zoonotic coronaviruses have caused pandemic outbreaks – SARS (2003), MERS (2012) and SADS (2017) the first two claiming thousands of human lives worldwide. They originated from bats and two of them had outbreaks in China. There was thus high probability of the next coronavirus outbreaks being originating from bats and occurring in China. Unfortunately, both the Chinese authority and the world medical research community couldn’t rise to the occasion. The result is the ongoing outbreak of 2019-nCoV in Wuhan, China.

Coronaviruses (CoVs) have primarily been enzootic causative agents. The term enzootic qualifies a particularly locational and or seasonal disease regularly affecting birds and animals. However, in the last few decades, CoVs have developed the capability of infecting humans as well. Unfortunately, the infections have high level of lethality.

OUTBREAKS

SARS or the Severe acute respiratory syndrome broke out in 2003 to be followed by more recent MERS or the Middle-East Respiratory Syndrome. And, now the still un-managed Wuhan 2019-nCoV outbreak – these have all demonstrated the lethality of CoVs when they cross the species barrier and infect humans.

So, these viruses were initially limited only to their natural animal hosts. However, recently some of the CoVs have crossed the animal-human species barrier and caused zoonotic diseases in humans. Of note, they had already crossed the species barrier as they were not restricted to a particular species. Only now, we humans are also at danger especially from the cross-species barrier jumpers like the SARS-CoV and the MERS-CoV since they have manifested as virulent human viruses.

Such outbreaks at frequent intervals have renewed interest in coronaviral research, which in turn has led to the discovery of several novel human CoVs. Much progress has also been made in understanding the CoV life cycle. Let’s start with phylogenetic positioning.

TAXONOMY

As per the International Committee on Taxonomy of Viruses, CoVs belong to the subfamily Coronavirinae in the family Coronaviridae and the order Nidovirales. On the basis of their phylogenetic relationships and genomic structures, this subfamily consists of following four genera:

  • α-coronavirus (Alpha)
  • β-coronavirus (Beta)
  • γ-coronavirus (Gamma) and
  • δcoronavirus (Delta)

The Alpha and Beta infect only mammals. They cause respiratory illness in humans and gastroenteritis in animals. They can pose a heavy disease burden on livestock. These viruses include the recently emerged Swine Acute Diarrhoea Syndrome coronavirus (SADS-CoV). Gamma and Delta infect birds, but some of them can also infect mammals. Apart from SARS and MERS there are at least four other human coronaviruses and all these are found to have animal origins – apparently, mammalian:

  • Bats – SARS, MERS, HCoV-NL63, HCoV-229E.
  • Rodents – HcoV-OC43, HKU1.

INSERT PICTURE HERE

In the accompanying figure taken from Nature, solid arrows indicate confirmed data. Broken arrows indicate potential interspecies transmission. Black arrows indicate infection in the intermediate animals, yellow arrows indicate a mild infection in humans, and red arrows indicate a severe infection in humans or animals.

SARS

SARS had broken out in the Guangdong province of China. The direct progenitor of SARS-CoV was evidently produced by recombination within bats and then transmitted to farmed civets – cat like strongly scented animals – or another mammal, which then transmitted the virus to civets by faecal-oral transmission. When the virus-infected civets were transported to the market, the virus spread in market civets and acquired further mutations before spillover to humans.

Over the two decades, numerous SARS-related (SARSr-CoV) strains have been identified from bats. These bat SARSr-CoVs are the likely progenitors of SARS-CoV that infected humans and civets, and hence understanding their interactions with human or civet ACE2 is critical for tracing the origins of SARS-CoV and for preventing and controlling future SARS-CoV outbreaks among us.

COURSE

The research so far on genetic evolution, receptor binding and pathogenesis demonstrates the following course:

  1. SARS-CoV most likely originated in bats through sequential recombination of bat SARSr-CoVs.
  2. Genetic recombination likely occurred in bats before SARS-CoV was introduced into Guangdong province through infected civets or other infected mammals from Yunnan.
  3. The SARS-CoV introduced into the civets underwent rapid mutations in S and ORF8 and successfully spread in market civets.
  4. After several independent spillovers to humans, some of the strains underwent further mutations in S and became epidemic during the SARS outbreak in 2002–2003.

MERS

As the name suggests, MERS outbreak was in the Middle East. Most of the early MERS index cases had contact with dromedary camels. Dromedary camels form an Arabian camel-breed, light, swift and trained for riding or racing. MERS-CoV strains isolated from camels were found to be almost identical to those isolated from humans. Also, MERS-CoV-specific antibodies have been highly prevalent in the camels from the Middle East, Africa and Asia. MERS-CoV infections were detected in camel serum samples collected in 1983, suggesting that MERS-CoV was present in camels at least 30 years ago.

Overall, all the MERSr-CoVs isolated from bats support the hypothesis that MERS-CoV originated from bats. However, given the phylogenetic gap between the bat MERSr-CoVs and human and camel MERS-CoVs, there should be other yet-to-be-identified viruses that are circulating in nature and directly contributed to the emergence of MERS-CoV in humans and camels. Hopefully, such viruses will be found in bats in the future.

Numerous recombinations imply that MERS-CoV originated from the exchange of genetic elements between different viral ancestors, including those isolated from camels and the assumed natural host bats. The full-length genomic sequences of MERS-CoVs isolated from humans and camels are almost identical (>99% identity). To date, bat MERSr-CoVs and human and camel MERS-CoVs share the same genomic structures but differ substantially in their genomic sequences.

Researchers have so far discovered MERSr-CoVs and related viruses (HKU4 and HKU5) in different bat species in five continents. Given the massive number of coronaviruses carried by different bat species, the high plasticity in receptor usage and other features such as adaptive mutation and recombination, frequent interspecies transmission from bats to animals and humans is expected.

SARS vs. MERS

Particulars

SARS

MERS

Receptor

angiotensin-converting enzyme 2 (ACE2)

dipeptidyl peptidase 4 (DPP4 or CD26)

Infects

ciliated bronchial epithelial cells

unciliated bronchial epithelial cells

Intermediate

Civets

Camels

Natural hosts

Bats

Bats

SADS-CoV

Between October 2016 and May 2017, swine acute diarrhoea syndrome (SADS) broke out in four pig breeding farms in Guangdong province, again in China, with a mortality up to 90% for piglets 5 days or younger. This added new dimensions to the CoVs threat.

Domestic animals are the important links as intermediate hosts between natural hosts to humans. In the process, domestic animals themselves suffer the bat-borne disease. Bats appear to be the major natural reservoirs of α-coronaviruses and β-coronaviruses. At the time of the SARS epidemic, almost all early index patients had been reported to have animal exposure before developing disease. The data indicate that SARSr-CoVs (SARS related CoVs) have wide intercontinental spread over Asia, Africa and Europe, and might have been prevalent in bats for a very long time.

STATUS

Public health authorities ironically regarded Coronaviruses (CoVs) in the pre-SARS era as relatively harmless respiratory pathogens to humans. However, now the Coronaviruses have emerged as highly transmissible agents with high pathogenicity and mortality rates in human populations. At this juncture, global action is geared towards containment of the infectious pathogens at international borders of China and other affected Asian nations.

The world still lacks effective licensed medicines towards combating the coronavirus outbreaks. It being a viral threat, molecular biology only kindles some hope. Clearly, the seriousness of these infections and the lack of effective, licensed treatments for CoV infections underpin the need for a more detailed and comprehensive understanding of coronaviral molecular biology, with a specific focus on both their structural proteins as well as their accessory proteins. Live, attenuated vaccines and fusion inhibitors may in due course be developed.

On the face of it, it is obvious now that SARS, MERS, SADS and the related strains can all be traced back to the bats, a mammal. There are phylogenetic gaps still to be filled. It means, there should be other yet-to-be-identified viruses that are circulating in nature and directly contributing to the emergence of Coronaviruses in humans. Hopefully, to find such viruses scientists will not have to look beyond the bats. Once these all viruses are isolated and their molecular biology understood, the menace will be conquered forever.

RECOMMENDATIONS

The State and the (United) States should fund more researches to fully elucidate the pathogenic mechanism of these viruses, to construct reproducible animal models, and ultimately develop countermeasures to conquer not only SARS-CoV, MERS-CoV, SADS-CoV and the newly emergent Wuhan-CoV (not an official name) but also future-emerging coronaviral diseases.

Currently, no clinical treatments or prevention strategies are available for any human coronavirus. In addition, little information is available on HKU3-related strains that have much wider geographical distribution and bear truncations in their RBD. Furthermore, little is known about the replication and pathogenesis of these bat viruses. Research should focus on the biological properties of these viruses using virus isolation, reverse genetics and in vitro and in vivo infection assays. Hopefully, these researches would culminate in preventing and controlling the emerging SARS or MERS or Wuhan-like diseases in the future. Research on the structure and function of the S (for Spike) and E (for Envelope) proteins on the surfaces of different Coronaviruses is expected to throw interesting light on our understanding of the coronavirus microbiology.

A recent serological investigation has found antibodies against the SARSr-CoV nucleocapsid in humans living around a bat cave. Interestingly, they had not shown clinical signs of disease. This suggests that the virus can infect humans through frequent contact. Perhaps the researchers can use those antibodies in the future to contain the spread of coronaviruses in human population.

It is widely accepted that many viruses have existed in their natural reservoirs for a very long time. The constant spillover of viruses from natural hosts to humans and other animals is largely due to human activities, including modern agricultural practices and urbanization. Therefore, the most effective way to prevent viral zoonosis is to maintain the barriers between natural reservoirs and human society, in line with the ‘one health’ concept.

ABSTRACT

  • SARS broke out in 2003 with about 10% fatality-rate. MERS in 2012-18 had 35.5% fatality. CoVs generally cause respiratory illness in humans and gastroenteritis in animals.
  • The origin of Coronaviruses can be traced to bats. Domestic animals play the role of intermediate host. They suffer as well.
  • CoVs belong to the subfamily Coronavirinae, family Coronaviridae and the order Nidovirales.
  • Antibodies against the SARSr-CoV have been found in humans living around a bat cave but unaffected by the disease.
  • No effective clinical treatments or prevention strategies are available for any human coronavirus including 2019-nCoV. Maintaining barriers between natural reservoirs and human society is the only natural and long-lasting solution to the frequent outbreaks.

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