“If you know the enemy and know yourself, you need not fear the result of a hundred battles.” (Sun Tzu, The Art of War)

Did you know there are seven human coronaviruses?

Humans Coronaviruses discovered in the 1960s
Human coronaviruses (CoVs) were unknown to science until the 1960s, when they were detected in the nasal discharge of patients with the common cold. They have been named ‘coronavirus’ because, when observed by electron microscopy, the spike projections from the CoV virions resemble a crown, or corona in Latin.

SARS-CoV
For the next 40 years, CoVs were considered fairly harmless to humans, typically causing only mild upper respiratory disease in otherwise healthy people. This all changed in 2002 with the outbreak of severe acute respiratory syndrome (SARS) that began in Guangdong Province, China. The SARS-CoV was identified as the causative agent of this outbreak. This 2002–2003 outbreak resulted in a total of just over 8000 confirmed cases and 774 deaths (9% mortality rate). The elderly fared worse, with a mortality rate of close to 50% among those > 60 years old. Fortunately, the transmission of SARS-CoV was relatively inefficient, as it only spread through direct contact with infected individuals after the onset of illness. Thus, the outbreak was largely contained within households and healthcare settings, and could be controlled through quarantining.

MERS-CoV
A decade later, another highly pathogenic CoV emerged in Middle Eastern countries, which was named Middle East respiratory syndrome coronavirus (MERS-CoV). MERS has killed around 34% of the roughly 2500 confirmed cases since it was first reported in 2012 in Saudi Arabia. An outbreak in South Korea in 2015 from a patient returning from the Middle East reminded us that the risk is far from over.

COVID-19 (SARS-CoV2)
In late 2019, the emergence of a novel coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), caused an outbreak of viral pneumonia (COVID-19) in Wuhan, China. At the time of writing (27 March 2020), SARS-CoV-2 has spread to more than 177 countries, more than 600,000 cases have been confirmed, with at least 28,000 deaths. The entire world is experiencing an unprecedented lockdown, and it is very likely that this virus is going to permanently impact our lifestyle and our perception of infectious diseases. While highly transmissible, the COVID-19 case-fatality rate seems to be somewhere between 1% and 3.4%. Although the fatality rate for COVID-19 is less than that of the 2002–2003 SARS outbreak, even at the lower estimate of ~1% COVID-19 is around 10-times more deadly than a bad flu season (0.1%).

Excluding the SARS, MERS, and COVID-19 CoVs, four other human coronaviruses have been described: HCoV-NL63, HCoV-229E, HCoV-OC43, and HKU1. These are still circulating and contribute to between 15-30% of cases of common cold.

You likely haven’t heard as much about these non-deadly CoVs, but that doesn’t mean they can’t be useful to us – remember “know the enemy”. More on this below.

Where did these viruses originate?
All coronaviruses circulating in humans are believed to have evolved from bat coronaviruses, although some reports suggest that CoV-OC43 and HKU1 may have originated in rodents. It has been estimated that CoV-OC43 was transmitted to humans about 120 years ago, CoV-229E transmitted from bats about 200 years ago, and CoV-NL63 transmitted from bats 500–800 years ago. Although the time of transmission of SARS-CoV and MERS-CoV to humans remains unclear, both viruses are at least phylogenetically linked to bat coronaviruses. The common ancestor of all known coronaviruses likely existed millions of years ago.

How fast do human coronaviruses mutate?
Relative to other single-stranded RNA viruses, CoVs have a moderate to high mutation rates, which is mostly introduced through mutations and recombination during viral replication. Point mutation alone are insufficient to create a novel virus, such as SARS-CoV-2, and CoVs can gain a genomic fragments (of 100s or 1000s bases) from other co-infecting CoVs. This process is known as recombination, and is thought to be more important than point mutations for enabling viruses to expand or switch ecological niches. While coronaviruses can acquire fragments of the new genome through the process of recombination, they are less able to acquire large chunks of genome relative to influenza viruses. This is because influenza viruses have segmented genomes that allow the exchange of the whole genome, whereas the CoV genomes tend to have overlapping reading frames that makes recombination less likely.

The non-deadly human CoVs as important research tools
The non-deadly human CoVs (229E, OC43, NL63, and HKU1) seem well adapted to humans, circulating widely and mostly causing only mild disease in immunocompetent adults. The other three coronaviruses (SARS-CoV, MERS-CoV, and SARS-CoV-2) are new to humans and, while they are believed to have originated from animal species, the exact route of transmission to humans remains unclear.

These non-deadly CoVs can be incredibly useful research tools. First, because they do not cause severe disease, researchers can handle these viruses under less stringent conditions than their more deadly cousins. Live 229E, OC43, NL63, and HKU1 viruses can be handled in bio-safety level (BSL) 2 labs, whereas non-clinical SARS-CoV-2 requires at least BSL 3 (BSL 4 is the maximum). Also, a major barrier to understanding the SARS and MERS viruses is that their outbreaks were – thankfully – short and constrained. For example, there were 2500 confirmed cases of MERS, leaving little opportunity to study this virus’ interactions with its human hosts.

The research addressing 229E, OC43, NL63, and HKU1 has already generated many interesting and potentially useful insights. For example, these viruses have been shown to vary in their tolerance to genetic variability. 229E isolates from around the world have only minimal sequence divergence, while OC43 isolates gathered from a single location but isolated in different years show significant genetic variability.

This likely explains why HCoV-229E cannot cross the species barrier to infect mice, while HCoV-OC43 (and the closely related bovine CoV) can infect mice and several ruminant species. Luckily, the more deadly SARS-CoV and MERS-CoV have not adapted well enough to humans to spread globally and are mainly transmitted via zoonotic reservoirs, with occasional spillover into humans, possibly via an intermediate host species. It is easy to imagine how findings related to the adaptedness of 229E, OC43, NL63, and HKU1 to human hosts could translate to the more dangerous CoV strains.

Also, antivirals identified against the more-safely-handled 229E, OC43, NL63, and HKU1 could then be prioritized for testing against COVID-19. Not only that: inhibitors able to block multiple coronaviruses may also have the ability to inhibit future emerging coronaviruses.
It is likely that we are going to need them again.