Two off-the-beaten-path research papers on the coronavirus, with interesting results

There have been a flood of research papers released in the last few days related to coronavirus as the world’s researchers try to understand where this virus came from and what it does.  Much of the work is either clinical to understand how to properly diagnose and treat patients, or epidemiological to understand (and hopefully control) how it spreads.  But there are many other research teams exploring other aspects of the coronavirus; here are two such examples, with interesting results. One looks at whether there is reason to believe that at least some COVID patients lose their sense of smell; and the other tryin to clarify which animal (or animals) were the original source for this virus.

The first paper, done by a team at the Harvard Medical School, looks at the claim by many COVID patients that when they became infected they lost their sense of smell to see if there is a plausible mechanism for that to be an actual symptom of the coronavirus.

The medical community knows a fair amount about how viruses work: they sneak in through the cell wall and insert themselves into the RNA of the cell such that the protein-manufacturing machinery in the cell is tricked into making copies of the virus. In the case of this particular coronavirus (and many other coronavirus strains), it gets through the cell wall via a molecule on the cell surface known as TMPRSS2, and it attaches itself through the protein called ACE2. But a human body has a lot of different kinds of cells, not all of which have TMPRSS2 on the surface or manufacture ACE2. So the coronavirus has a particular affinity for the cells that do. It’s been established that the human respiratory tract has many such cells, which is why COVID is mainly a respiratory disease — the symptoms we experience are mainly our own immune system trying to fight off the virus in infected respiratory cells.

Knowing this, the research team asked: are there any known cells in the nose that have TMPRSS2 and ACE2?  And the answer is “yes, but.” There are two main parts to the inside of our noses: the respiratory epithelium (RE), which humidifies air as it enters the nose; and the olfactory epithelium (OE), which is where our sense of smell is located. The RE has many cells with TMPRSS2 and ACE2, and it is believed that those cells are a “reservoir” for COVID infection. Less is known about the OE cells. But our intrepid research team scoured the research journals and found some interesting and relevant data on mouse olfactory cells.

There are four main types of cells in the olfactory system: the olfactory sensory neurons that detect scents and transmit information to the brain; support cells that act as structural supports, detoxify damaging substances, and maintain salt and water balance; mucus-secreting cells; and stem cells that regenerate the other cells as necessary. The researchers found evidence that while the sensory neurons in mice don’t seem to have ACE2 and TMPRSS2, the sustaining cells, mucus-producing cells, and stem cells do. They then found similar reported patterns in the same cells in the human olfactory system. Those cells could potentially be infected by the coronavirus, and if it interferes enough with the functioning of the support cells, that could cause a loss of the sense of smell. More worrisome: the researchers hypothesize that if the virus does enough damage to the stem cells, then it could inhibit the olfactory system from regenerating and cause a permanent loss of smell.

It’s also possible that the coronavirus makes it up into the brain and infects the part of the cortex that processes signals from olfactory neurons; that has been documented with other viruses.

So yes, it is entirely possible that COVID-19 patients could lose their sense of smell, though experimental and clinical research would need to be done to confirm that with hard evidence.

The paper ends by throwing out one last super interesting point: the RE cells in juvenile mice produce less TMPRSS2 and ACE2 than old mice. If that holds true for younger humans as well, and the RE cells are indeed a “reservoir” for the virus inside the body, then it not only suggests that younger people might not lose their sense of smell as frequently as adults, but it also hints at a possible reason why younger people seem to have milder cases of COVID-19. As with all good research, this paper raises more excellent research questions than it answers.

The second paper looks at the zoonotic origins of this coronavirus (SARS-CoV-2), i.e. which animal(s) it inhabited before it made the jump to humans.  Two weeks ago a paper suggested that the gene sequence for the virus was very similar not only to coronaviruses seen in bats (which was expected) but also to those seen in pangolins (which was not). Now this paper takes the pangolin hypothesis one step further and does a deep dive into the coronaviruses that pangolins carry.

Pangolins are highly endangered, and despite government protections are heavily trafficked as an exotic food and for use in traditional Chinese medicine.

The research team obtained several tissue samples from pangolins confiscated by the Chinese government in anti-smuggling operations in 2017, 2018 and 2019. They isolated several coronavirus strains from those samples and sequenced their genomes. They found several strains that were “sisters” to SARS-Cov-2: not direct ancestors, but sharing a common parent strain (see the red dots in figure 1 in the paper). But there is also a strain of bat coronavirus that is very closely related — and in fact are more closely related to SARS-CoV-2 than the pangolin coronaviruses.

Further analysis revealed that there seems to be recombination of mutations across bat coronavirus, pangolin coronavirus, and SARS-CoV-2. Either that, or “convergent evolution” happening in parallel across the species’ viruses.

The research falls short of identifying what the species was that incubated SARS-CoV-2 before it jumped to humans, though it lends more credence to the hypothesis that it was either a bat or a pangolin — both of which have been present in Chinese “wet” markets.  But it does show that there is clearly zoonotic transfer happening for coronaviruses, and pangolins seem to be a fertile breeding ground for it. The researchers make a strong argument that pangolins should be handled with extreme caution and should be strictly banned from sale in wet markets.

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