Human Coronaviruses

By this time, it is likely that most everyone knows that COVID-19 is caused by a coronavirus. Some will actually be able to recall the specific name of the coronavirus that causes COVID-19 as SARS-CoV-2, an acronym for Severe Acute Respiratory Syndrome – Coronavirus – 2. A good number of people will quickly realize that if this virus is numbered “2,” there must have been a “1” attributed to the first coronavirus of its kind. That is correct.

Until SARS-CoV-2 emerged on the world stage in December of 2019 and got its name in January after this new (novel) virus was sequenced and its relationship to the first SARS virus was established, we had referred to the first coronavirus known to cause Severe Acute Respiratory Syndrome (SARS) as the SARS virus or SARS-CoV, because until January 2020, it was the only coronavirus that we were aware of that would cause this syndrome (most known coronaviruses that infect humans are considered to cause mild respiratory symptoms or “common colds.”). Once a second coronavirus was identified that could cause SARS in those it infects, the original SARS virus is now referred to as SARS-CoV-1 and the current strain is referred to as SARS-CoV-2. (However, as you will see below, this really is the third coronavirus that can cause severe acute respiratory syndrome in humans.)

So, let’s quickly review coronaviruses.

RNA vs. DNA viruses

All coronaviruses are RNA viruses (as opposed to DNA viruses). That means that the genetic material that they carry that is used when the virus takes over a cell it has infected to provide the blueprint to the cell’s machinery that normally serves as the factory line to produce proteins that are useful to normal cells, but now is hijacked to focus almost exclusively on making new coronaviruses, is comprised of RNA.

Why do we care whether a virus is a DNA virus or an RNA virus? Let’s look at the general differences (as in most all areas of science, there are exceptions to the rules, so before any virologists reading this get up in arms, let me just state that the following information is for non-virologists who are just trying to understand the major concepts) between DNA and RNA viruses.

I have already stated the obvious – a DNA virus carries its genetic material and instructions that it gives to the cells it infects as to how to make new virus in DNA, whereas an RNA virus carries those genetic instructions in RNA. As a general rule, a DNA virus must get into the nucleus of the cell it infects in order for its genetic material to be replicated, whereas, RNA viruses, like coronaviruses, need only get into the cytoplasm of the infected cell to have its genetic material replicated to form new viruses. (For non-biology majors, think of an egg you have cracked and then poured into a pan. We will use an analogy that the egg will represent a cell. The yolk will represent the nucleus – the innermost part of the cell where the cell’s own genetic material is stored. The white part of the egg surrounding the yolk is the equivalent of the cell’s cytoplasm – as soon as the virus gets through the shell of the egg (our analogy for the cell wall or membrane), the virus has made it to the cytoplasm. The RNA virus has arrived, whereas the DNA virus still needs to continue its journey on to the nucleus (keep in mind, there are also immune defenses inside cells that will potentially have more time to go after the DNA virus than the RNA virus that has already reached its target.

As a rule, because RNA viruses do not enter the nucleus where the cell’s genetic material is (think of this as our genes and chromosomes), and viral replication takes place in the cytoplasm, the genetic material of RNA viruses is not incorporated into the DNA of our cells (plus the fact that most RNA viruses do not contain an enzyme called reverse transcriptase that is needed to convert RNA to DNA – the major exception being retroviruses that have been demonstrated to translate their RNA to DNA and incorporate segments of DNA into human DNA). (This is why the disinformation being spread in order to try to scare people into not receiving the COVID vaccines, namely that the mRNA vaccines would alter our own DNA was completely false and baseless as the vaccine uses RNA and there is no reverse transcriptase in the vaccine). On the other hand, because DNA viruses do enter the nucleus to have the virus DNA copied, viral DNA can potentially be incorporated into our own DNA. In actual infections, it appears to occur infrequently, but it has been shown to occur.

We believe that the reason viral DNA is not commonly found integrated into human DNA is that this is not necessary, and perhaps not efficient, for DNA viral replication. When viral DNA is incorporated into the cell’s DNA, it may result in disruption of the cell, or may play a role in either viral persistence (latency) (in latency, the full viral genome is retained within the host cell, but replication is dramatically slowed such that there may still be persistent viral antigens, but whole viruses are not being produced and released from the cells) or potentially could play a role in disordered replication of the cell that could potentially lead to tumor cells (adenovirus has been shown to do this in hamsters), however, viral integration into human DNA does not appear to be the common mechanism in which DNA viruses may become latent or oncogenic.

Examples of latent viruses are herpes simplex virus, varicella-zoster virus (chickenpox virus, which when reactivated later in life can cause shingles), Epstein-Barr virus (in most people who become ill causes an infectious mononucleosis illness, but later in life can cause multiple sclerosis and a number of uncommon malignancies), cytomegalovirus, and human immunodeficiency virus (which can cause AIDS). These are all DNA viruses, except for HIV, which is an RNA virus.

Finally, as we have discussed many times before, DNA viruses tend to be fairly stable, while RNA viruses mutate frequently and may acquire mutations (errors in translating the genetic material during replication) or recombinations (swapping pieces of genetic material with another virus or variant) that increase or decrease their transmissibility, their virulence and the degree of immune evasion relative to prior forms of the virus.

Types of human coronaviruses and their history

Until the outbreak with the first SARS virus, there were two human coronaviruses that had been identified that caused disease in humans and two more would be identified within a year of the SARS outbreak:

Alphacoronaviruses

• Human coronavirus 229E (HCoV-229E)
• Human coronavirus NL63 (HCoV-NL63

Betacoronaviruses

• Human coronavirus OC43 (HCoV-OC43)
• Human coronavirus HKU1 (HCoV-HKU1)

The difference in whether a coronavirus falls in the alpha group or beta group is related to structure of the virus.

We have known about coronaviruses since the 1930s when they were first detected in birds and then mice, then cows and subsequently in cats. There are now a large host of animals that certain coronaviruses can infect (e.g., delta- and gamma-coronaviruses (not to be confused with the delta and gamma variants of SARS-CoV-2) infect birds, but not humans).

The first coronavirus identified to cause disease in humans was HCoV-229E from studying respiratory illnesses in medical students in Chicago. Student #229E was ill in 1962 and the investigators published their results identifying this new coronavirus in 1966.

In 1965, HCoV-OC43 was identified while studying and sampling subjects with the common cold.

But, between 2002 and 2003, an outbreak with a novel coronavirus occurred in Guangdong in the southern portion of China causing severe acute respiratory syndrome, as opposed to just a common cold, warning us that coronaviruses could vary widely in their virulence (severity of illness) and pathogenicity (the manner in which disease is caused and manifests). SARS spread to more than two dozen countries in North America, South America, Europe and Asia before the outbreak could be contained. SARS-CoV-1 infected 8,098 people worldwide and killed 774 of those infected (case fatality rate of just over 9.5%). Only eight Americans were known to have been infected, and each had traveled internationally near the beginning of the outbreak.

Key to containing the SARS outbreak so that it did not spread further to more people and more countries was the willing embrace of masking and other mitigation measures (no doubt in part due to the fact that almost 1 in 10 persons with SARS died), especially by those in Asian countries and the fact that once infected, people tended to be so severely ill that they did not go to work, school or social events to further spread the disease. It appears that SARS-CoV-1 may have been eliminated from the world, in part due to the rapid and effective containment before the virus spread to many more people and developed new variants, but also because there does not appear to be an animal reservoir (i.e, an animal species in which the virus continues to circulate to serve as a potential source for reverse zoonosis, i.e., human –> animal –> human).

Since that time, our surveillance for coronaviruses has significantly increased and the other two human coronaviruses listed above (HCoV-NL63 and HCoV-HKU1) were detected in 2003. Of note, HCoV-HKU1 was first detected in a 71-year-old man with pneumonia, again reminding us that human coronaviruses can cause more severe disease than just a common cold, especially in infants (HCoV-NL63 was first detected in an infant with bronchiolitis (a potentially serious lung infection) and conjunctivitis) and the elderly.

Then, in 2012, another novel human coronavirus was detected that was again causing SARS. This came to be identified as Middle East Respiratory Syndrome (MERS) and the virus was named MERS-CoV. This virus was first detected in a 60-year-old man in Saudi Arabia with pneumonia, respiratory distress, and kidney failure who subsequently died from the infection. This outbreak, too, was fortunately contained, as the case fatality rate for this infection was 35% (2600 confirmed cases and 935 deaths). Unfortunately, we were not so fortunate as with SARS-CoV-1 to be able to eliminate MERS-CoV. In fact, we continue to see periodic infections, primarily in the Middle East, due to the fact that dromedary camels are a reservoir for this virus. Camels can, but generally don’t become severely ill with infection from MERS-CoV, in fact, they are usually not visibly ill at all. They tend to be infected in their upper respiratory airways, and they shed very high levels of infectious virus from their noses for at least a week after infection, promoting the spread of infection among camels, but also creating the risk of transmission to humans. Camels from 34 countries have been demonstrated to have been infected either by seroprevalence testing (checking for antibodies to the virus) or by molecular testing (similar to our PCR tests from nasal swabs for COVID).  This testing also suggests that llama and alpaca can be infected, though at this time, there is not evidence that they are a risk for transmitting the virus to humans.

And, then, the latest novel coronavirus, with which we are all too familiar, was identified in early January 2020 following an outbreak in the Wuhan province of China in December 2019.

So, now, I can complete our list of known coronaviruses that cause disease in humans:

Alphacoronaviruses  

• Human coronavirus 229E (HCoV-229E)   1962
• Human coronavirus NL63 (HCoV-NL63)   2003

Betacoronaviruses

• Human coronavirus OC43 (HCoV-OC43)   1965
• Human coronavirus HKU1 (HCoV-HKU1)   2003
• Severe acute respiratory syndrome coronavirus (SARS-CoV-1)   2003
• Middle East respiratory syndrome-related coronavirus (MERS-CoV)   2012
• Severe acute respiratory syndrome coronavirus – 2 (SARS-CoV-2)    2019

We believe that all coronaviruses entered the human population through zoonotic transmissions (animal –> human). Below is a summary of what we currently believe to be the natural host for the virus is (the normal animal that the virus infects and resides in before being transmitted on to another species), the intermediate host (the species of animal(s), if any, that are incidentally infected from the natural host and then humans interact with to subsequently become infected).

Coronavirus	Natural Host	Intermediate Host
HCoV-229E	bats	?
HCoV-NL63	bats	palm civets
HCoV-OC43	bats	cattle
HCoV-HKU1	bats	mice
SARS-CoV-1	bats	palm civets
MERS-CoV	bats	camels
SARS-CoV-2	bats	?

Unfortunately, the world did not respond to SARS-CoV-2 in the manner that we did to SARS-CoV-1 and MERS-CoV. Given the fact that SARS-CoV-2 can produce more asymptomatic or pauci-symptomatic (few and mild symptoms) disease than SARS-CoV-1 and MERS-CoV, perhaps we had no chance to contain this outbreak, but as we discuss in our book, Preparing for the Next Global Outbreak, we certainly could have responded better, but missed any chance that we might have had to contain this outbreak. Now, due to uncontrolled transmission of the virus, we have many subsequent generations of variants with increased transmissibility and immune evasion capabilities. Further, we likely have huge numbers of immunocompromised persons with chronic infections greatly increasing the potential for significant and sudden antigenic shift (a sudden big jump to a different form of the virus), and unlike SARS-CoV-1 that was contained within a year and doesn’t appear to be retained in an animal reservoir, SARS-CoV-2 has been detected in numerous animal species:

Binturong

Cats

Dogs

Ferrets

Fishing cats

Gorillas

Hamsters

Hippopotamus

Lions

Lynx

Mink

Otters

Pumas

Snow leopards

South American coati

Spotted hyenas

Tigers

White-tailed deer

Thus, it seems inconceivable that we can ever eliminate SARS-CoV-2. Further, I hope that we learn that some coronaviruses have significant pandemic potential. Given that we had deadly novel coronavirus outbreaks emerge every 7 – 9 years over the past two decades, we must prepare now (we are already more than 3 years out from the last novel coronavirus outbreak). And, of course, I haven’t even discussed other viruses with pandemic potential!