New research suggests SARS-CoV-2 infects the throat, which makes important differences in how I will approach prevention.
Why This Matters
When I first wrote The Food and Supplement Guide for the Coronavirus, I took the position that SARS-CoV-2, the coronavirus that causes COVID-19, was most likely mainly infecting the lung without infecting parts of the upper respiratory tract such as the nose, mouth, or throat. However, I considered it open to further research and certain aspects of the protocol were meant as a hedge against the possibility that infection might begin in the upper respiratory tract.
For example, I focus on getting lots of oral zinc to raise systemic zinc status and get zinc into high concentrations of the lung. As a hedge against the possibility that the virus infects the nose, mouth, or throat, I put a small emphasis on getting some zinc in the form of zinc acetate lozenges, which are designed to disperse ionic zinc into those tissues.
As another example, I focus overwhelmingly on getting enough copper in the diet, mainly as food, to balance the zinc. As a hedge against the possibility that the virus infects the nose, mouth, or throat, I suggest the optional addition of a small amount of copper supplied in the form of a couple sprays of ionic copper into the mouth and throat.
Why Infection of the Nose, Mouth, and Throat Initially Seemed Unlikely
One of the reasons I found it unlikely the virus would infect the upper respiratory tract has to do with the location of ACE2, the protein on the cell surface that the virus uses to get into our cells.
A 2004 paper, published when SARS was the major concern (whose virus also uses ACE2 to get into the cell), used immunohistochemistry to determine the expression of the ACE2 protein in human tissues. This is a technique that uses a specific antibody to the ACE2 protein that can then be stained and visualized under a microscope. They found high expression on the surface of the lungs. Although they found ACE2 expressed in the oral and nasal mucosa, they found it all located on the basolateral side of the cell rather than the apical side of the cell. That's a fancy way of saying that the ACE2 is underneath the surface layer and faces away from the environment, so it wouldn't be available for an incoming virus to latch on to it.
On the other hand, a very recent paper in Nature showed that ACE2 is highly expressed in the oral cavity, with the highest expression on the tongue. But they found this by measuring RNA. Although that suggests the cells were making the ACE2 protein, it doesn't tell us whether it was on the environment-facing side of the cell or tucked underneath it.
Furthermore, early reports were suggesting that upper respiratory symptoms were rare. The common presence of a dry cough and rare addition of a runny nose or sore throat seemed consistent with a virus that infects the lungs but stays mostly clear of the nose, mouth, and throat.
Why the Case Remained Open
Still, without direct evidence measuring the live virus or signs of its replication in specific tissues, I considered the case open. Furthermore, in a recent discussion with Avi Bitton, MD, Avi pointed out to me that virions (virus particles) are small enough that they might be able to slip in between cells and access ACE2 underneath the environment-facing surface layer. This would allow them to get inside the cells of the nose, mouth, and throat, where they could hijack the cell's protein-producing machinery to start replicating.
New Information Shows the Virus Does Infect the Throat
A more recent German study, published as a preprint and not-yet peer reviewed, provides very direct evidence that SARS-CoV-2 infects and replicates in the throat.
Many cases of COVID-19 are identified based on symptoms first, and then testing to confirm. Since the testing is only done when the symptoms seem like a compelling case of COVID-19, the testing is biased toward the prevailing beliefs about the tell-tale symptoms. This makes the bias confirm itself: doctors only test when the symptoms cluster according to the early beliefs; therefore, cases where the symptoms differ from those beliefs are never tested and never confirmed.
For this paper, they identified people by testing individuals who had been in close association with already diagnosed cases, rather than individuals who had been identified by their symptoms. This allowed them to avoid that bias.
The patients were nine young to middle-aged professionals without underlying disease, and they all had mild self-resolving cases.
They tested for the viral RNA (which contains the virus's genetic information and suggests the presence of the virus) using either swabs of the nose and throat, or swabs of the mouth and throat. They also tested for viral RNA in sputum (phlegm), which mainly reflects what is coughed up from the lungs, and in stool.
They found no difference between the amount of viral RNA in nose-and-throat vs. mouth-and-throat swabs. In two cases, viral loads were higher in swabs than sputum; in two cases viral loads in sputum were higher than swab; in five they were similar.
The presence of viral RNA in a tissue does not show with any certainty that the virus is infecting the cells of that tissue. It is entirely possible that the virus is infecting the lung, and yet viruses are “shedding” and moving their way up the respiratory tract into the throat.
To rule that out, the researchers measured viral subgenomic messenger RNAs (sgRNAs), which are only transcribed in infected host cells and not packaged into virions. The presence of sgRNAs in a tissue provides very compelling evidence that the virus is infecting the cells of that tissue.
In throat swabs, sgRNAs were present for the first five days after symptoms started, but then disappeared. They persisted in sputum, by contrast, through at least day 9 of symptoms.
This suggests that the throat is infected early in the disease but clears relatively quickly, while infection in the lungs is stronger and persists for longer.
They were also able to isolate live viruses, usually from sputum, but often from the throat swabs.
In one patient, the viral genome in her throat swab developed a mutation. On the first day the mutation was detected, the viral genome in her sputum still contained the original gene. This strongly supported the interpretation that the virus was independently replicating in her throat.
It seems likely to me now that the infection starts in the nose, mouth, and throat. This is where the virus first enters, and where the virus must pass through to get to the lungs.
This study found that viral loads were already declining in throat swabs when symptoms started. In some of the patients, viral loads were also declining in sputum, but they declined more slowly and lasted longer. In a few patients, viral loads were increasing in sputum after symptoms started. The two patients whose viral loads peaked in sputum in the second week of symptoms were the same two patients who developed some initial signs of pneumonia.
All in all, it seems like the infection starts in the nose, mouth, or throat, and travels into the lung. In the lung, it is stronger and lasts longer. The stronger it gets in the lung and the longer it lasts there, the more likely someone is to have the severe symptoms associated with the pneumonia.
Key Differences From SARS
SARS-CoV, which caused the SARS outbreak of 2003, has a set of proteins that are on average 87% identical to SARS-CoV-2, which causes COVID-19. It therefore makes sense to compare and contrast the two.
In SARS, upper respiratory symptoms were rare, throat swabs were most often negative, and the live virus could never be isolated from throat swabs. That's quite different from COVID-19, where throat swabs are good at identifying cases and the live virus can be isolated from throat swabs many times.
COVID-19 seems to differ from SARS in that the virus replicates more quickly and initially does so in the upper respiratory tract. This allows it to achieve high viral loads in the upper respiratory tract that are easily spread from one person to another. As a result, it spreads much more easily than SARS. Later on in the infection, the viral load peaks in the lungs and COVID-19 begins to resemble SARS in its potential to cause serious damage to the lungs.
Why this difference? The authors suggest that it is because of a difference in the spike protein of the two viruses. The spike protein is the protein the virus uses to bind to ACE2 and enter into the cell. While both viruses bind to ACE2, SARS-CoV-2 cleaves its spike protein into two parts, and SARS-CoV does not. This appears to give SARS-CoV-2 better ability to bind to ACE2 and fuse with the cell membrane. They suggest that in tissues where ACE2 is expressed in a lower amount (or, I would add, perhaps where the ACE2 is harder to reach because of its location in the cell surface), SARS-CoV-2 has a better ability to infect than SARS-CoV. In this case, that means that SARS-CoV-2 can infect tissues of the nose, mouth, and throat much more effectively than SARS-CoV.
Still, the fact that this is mostly a lung disease and the most serious consequences are all in the lungs reflects the fact that the higher ACE2 expression in the lung drives a much more significant infection rate in that tissue. ACE2 still winds up being a key determinant of what tissue gets infected, and individual differences in its expression are almost certainly key determinants of differing susceptibility to disease.
A Quick Note on the Gut
The other tissue where ACE2 is highly expressed besides the lung is the gut. This is why both SARS and COVID-19 can cause diarrhea.
Still, the diarrhea is an uncommon feature.
In this study, viral RNA was found in high amounts in stool, and it tended to correlate with the amount of viral RNA in sputum. However, they were never able to isolate live virus or sgRNA from the stool. They suggested that something about the gut environment might neutralize the virus and render it incapable of infection.
What This Changes
As a result of this research, I will soon be updating The Food and Supplement Guide for the Coronavirus to put a greater emphasis on increasing zinc and copper concentrations in the mouth and throat through lozenges and sprays, I'll be considering copper-based nasal sprays, and I'll be researching whether it makes sense to use certain herbal or food components in the form of lozenges.
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I am not a medical doctor and this is not medical advice. I have a PhD in Nutritional Sciences and my expertise is in conducting and interpreting research related to my field. Please consult your physician before doing anything for prevention or treatment of COVID-19, and please seek the help of a physician immediately if you believe you may have COVID-19.
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