Submitted by No Soap Radio

What is ACE2 and is it racially distributed?

Angiotensin-converting enzyme 2 is a protein on the surface of various cells that interacts with peptide hormones angiotensin I and II. Some viruses, such as coronaviruses, are able to bind to ACE2 so that they can enter the cell and begin replication. ACE2 can be found in many organs including the lungs, colon, and kidneys (1). Most important of these in terms of SARS-2 is the lungs, as they are the primary site of infection, and along with the oral cavity, that is where infection will begin. This is not to say other organs cannot become infected. They most definitely can and will as the disease progresses.

The immediate assumption to make is that the greater the expression of ACE2 in one’s lungs, the worse an infection will be and up to a certain point this will be true. So, the question that many are asking is what demographics are at risk? The simple answer is we don’t know, yet. In the last couple of weeks, at least three studies have appeared (all not yet peer reviewed), examining how the expression of ACE2 is distributed across various demographics. These studies looked at a combination of race, sex, age, and history of smoking. For simplicity sake, I will refer to the studies as Study 1 (2), Study 2 (3), and Study 3 (4).

Race

Of the three studies, only Study 1 found any relationship between ACE2 expression and race, finding that the Asian male sample had a much larger percentage of ACE2 expressing cells compared to that of the Caucasian and African American donors (2.5% of cells vs. 0.47%). However, there is a major issue with the study. With a sample size of 8, only one of whom was of Asian descent, it is not the type of analysis that conclusions should be drawn from. Rather, it is the type that should be used as a launching pad to direct further investigation. Of the remaining two studies, neither saw any relationship between expression and race. Interestingly, Study 2 found in one of their datasets that the Caucasian samples actually had higher ACE2 expression compared to the Asian samples, but this trend disappeared after other independent variables were accounted for.

Sex

Again Study 1 was the only one of the three to find a relationship between sex and ACE2 expression. It found that both the 2 male donors had a higher ACE2 expressing cell ration than all the other 6 female donors (1.66% vs. 0.41%). Once again, the small samples size is an issue here, but it certainly presents a relationship worth investigating.

Age

Of the three studies, only Study 3 found a strong indication that age and ACE2 expression may be weakly correlated. The other two found no relationship.

Smoking

Interestingly, while two of the studies found no relationship and Study 2 found a positive correlation between smoking and ACE2 expression, there are rat-model studies published in 2015 (5) and 2017 (6) that actually found the opposite. That is, in rats exposed to cigarette smoke they saw ACE2 expression was lower than in rats not exposed to cigarettesmoke.

To be entirely clear, this does not mean that there is no racial link, or any other link for that matter, to the expression of ACE2, only that there is not enough evidence to say one way or another. Whatever the case may be, thinking you are immune because of your 100% Bavarian phenotype is not a particularly wise belief to hold.

Why are all these random anti microbials being used instead of Influenza antivirals?

Much of the confusion here is due conflation of symptom and disease. Influenza antivirals such as oseltamivir and zanamivir are neuraminidase inhibitors. Neuraminidase is a protein found on the surface of influenza virus (among other microbes) and in this case is used to aid a virion in escaping the host cell. This protein is not found on coronavirus and so a neuraminidase inhibitor would have no effect.

The HIV-1 antivirals that are being trialed against SARS-2 are less specific. That is, they target mechanisms more common in a wide variety of viruses. Two of the drugs being trialed, lopinavir and ritonavir, being trialed are protease inhibitors. When HIV-1 translates its genetic code into proteins, like coronavirus and unlike humans, it does not make one discrete protein at a time. Instead, it makes polyproteins which are then cleaved by cellular or viral proteases at very specific spots so that the correct proteins are formed. Protease inhibitors prevent the protease from cleaving these polyproteins and so stop (or severely reduce) viral reproduction. The other antiviral commonly mentioned, redeliver, works as a nucleoside analogue which essentially mimics the building blocks of DNA and RNA causing replication of the virus’ genetic code to fail.

Chloroquine, a drug historically used in the treatment of malaria is another potential candidate. Studies examining its effect on Dengue showed that it may inhibit viral RNA replication, and this is likely why it was trialed.

Can SARS-CoV-2 reinfect you once you’re clear of the virus?

The answer to this is actually quite complicated but the short answer is, as you might expect, maybe. 

To explain why maybe, I will need to provide some background on how the body defends itself against infection. Once you are infected by a virus (or other any pathogen) your body is able to “see” the antigen (antigen means something that produces an immune response, in this case a virus or fragments of the virus) and in response to “seeing” the antigenproduces a series of antibodies that are designed to rapidly neutralise the pathogen or to signal to other parts of the immune system to attack the thing it is attached to (or both!). When antibodies are created, they are specific for a single epitope (a region on the antigen). This means unless two antigens are very closely related, the antibodies produced to fight one will not affect the other.

Once the infection has been cleared, these antibodies remain as a sort of early warning system to activate the adaptive immune system once it encounters the pathogen again. These antibodies, also called immunoglobulins, are grouped intoisotypes that are expressed differently. Some are embedded into the surface of cells other float loose through plasma.Some are present during the first few days of infection and others only appear weeks into an illness. The amount of these various antibodies decline overtime, some over the course of days, others weeks, and the longest lived over months or evenyears. The presence of these antibodies does not mean you are immune to reinfection, only that your body is able to clear the pathogen much faster than it would without, often even before symptoms appear.

With that out of the way, there are broadly three possibilities explaining the reinfection we see in the media that I find reasonable.

The first, and least likely in my opinion, is that of a new infection by a different strain of SARS-2. I am very much oversimplifying here but if there are two populations of SARS-2 that look different to our immune systems then it would stand to reason that you could be infected more than once. This line of thinking has some major technical problems, such as the lack of any sequence data that could imply this. The simplest and most obvious issue the theory has is the extremely low number of cases of re-infection relative to the total infected. The SARS-CoV-2 outbreak by the official numbers has infected close to 100 thousand people at the time of writing, yet we see maybe 2 dozen cases of re-infection being reported total. While one research article does propose splitting SARS-2 into two groups (L and S), and there are some small differences between the two groups, they are still extremely similar and would almost certainly elicit the same immune response.

The second possibility is that some mechanism is causing either less antibody to be produced, or only producing certain isotypes. The ability of some viruses to influence the adaptive immune system so that it can escape detection or destruction is well known. However, the mechanisms are numerous and not well known so I not comment further.

The final and, in my opinion, most likely possibility is that the virus entered a latent phase. Many pathogens, not just viruses, can hide in various tissues to remerge at a later date. Herpes viruses are well known for this. Varicella-zoster virus infects infants causing chicken pox before hiding away to emerge years later as shingles. Similarly, herpes simplex virus also has periods of latency and re-emergence. Yellow fever virus, a flavivirus, also has two phases. The toxic phase can emerge up to 24 hours after the first phase has passed and the patient can appear to be fully recovered. 

If the third option is correct, this has significant implications on how we treat patient recovery. At the very least a quarantine period would need to be extended weeks or even months after convalescence.

Wash your hands

In my first article, I mentioned some simple things to do to help slow the spread of the disease and help keep you and your family safe. Given the now widespread international occurrence of SARS-2 it is appropriate to follow up with some more pointers. Most of these you likely have heard before but it’s worth reiterating.

1) Stop shaking hands. 

2) Wash your hands. Again, both soap and 70% alcohol-based hand sanitizer work. Not a quick once over, 10-20 seconds minimum.

3) Avoid crowded places.

4) If you have children, pay extra care of their hygiene and make sure their hands are washed often.

5) Open push doors with a hip or closed fist, use paper towel to open pull doors where possible.

6) Use disposable sanitary options, that is don’t use handkerchiefs to open doors or lift fuel pumps, use paper towel or tissue that you throw away after.

7) Use your knuckles to press buttons or light switches.

8) A good habit to get into is to wash your hands as soon as you get home, every time you get home. Having something to wash your hands at the entrance is something to consider.

Good luck.

References1. https://www.nature.com/articles/s41368-020-0074-x/figures/12. https://www.biorxiv.org/content/10.1101/2020.01.26.919985v1.full.pdf3. https://www.preprints.org/manuscript/202002.0051/v14. https://www.preprints.org/manuscript/202002.0258/v15. https://www.researchgate.net/publication/273833068_Activation_of_renin-angiotensin-aldosterone_system_RAAS_in_the_lung_of_smoking-induced_pulmonary_arterial_hypertension_PAH_rats#pf46. https://www.atsjournals.org/doi/abs/10.1513/AnnalsATS.201706-464MG