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Coronavirus: phylogeny, smoking, mortality, and reducing the risk of getting sick



There is a feeling that about the epidemic COVID-19 is now broadcast from every iron. In this regard, Habr pleases with good posts with normal sources and constructive discussion. I also decided to share fresh preprints on the expression of ACE2 in smoked mice, features of the genetics and evolution of the virus, as well as recommendations for reducing the risk of getting sick. And since we are doing eye care in the laboratory, I just got questions that helps. In short - a packet on the head helps best.

UFO Care Minute


The pandemic COVID-19, a potentially severe acute respiratory infection caused by the SARS-CoV-2 coronavirus (2019-nCoV), has officially been announced in the world. There is a lot of information on Habré on this topic - always remember that it can be both reliable / useful, and vice versa.



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Evolution complete!


All populations of living organisms evolve. Not very lively either, if there is the pressure of natural selection and the ability to mutate. Viruses traditionally occupy a kind of intermediate niche between living and nonliving due to their primitiveness and inability to reproduce independently. In fact, this is an extremely minimalistic form of life (although they argue about it), which has saved on everything than is possible. There is no protein synthesis, no autonomous replication of genetic information. Only a small lump of protective proteins, protein mechanisms for penetration into the host cell and some DNA / RNA.

Plus, viruses have another important feature that allows them to evolve orders of magnitude faster than other species. Everything is bad with the repair mechanisms, which can be compared with the parity control systems in IT. Therefore, they are most often completely unimpressed if some not very necessary piece of code falls off during the process of reproduction or, on the contrary, a host DNA fragment is captured. Viruses multiply in such quantities that a certain percentage of defective virions usually does not affect the ability to reproduce.

It must be said that this instability of the genetic structure has both pros and cons for us. On the one hand, it increases the risks of circumventing our immunity, which, by searching for B-lymphocytes, picked up a successful combination of antibodies to suppress the past virus variant. Therefore, the change in neuraminidase and hemagglutinin, which HxNy in the designation of influenza strains, makes past antibodies useless. On the other hand, frequent mutations in combination with quarantine measures lead to the selection of strains in a lighter form.

For example, if the virus 24 hours after infection causes blood to flow from the ears and has a high mortality rate, then it will most likely be quickly unable to reproduce due to its visibility, the work of quarantine doctors and harsh people with flamethrowers. At the same time, mutants, which instead of terrifying symptoms are limited to continuous snot and sneezing, have a much greater chance of reproduction, since they will not try to close such people into protected quarantine zones.

In the case of COVID-19, doctors are trying to catch any visible forms as quickly as possible, including for selection towards the mild course of the disease. If you have had a mild, asymptomatic form of coronavirus, then a severe variety will most likely not be able to infect you. Yes, I am aware of reports of reinfection of SARS-CoV-2. But there are likely several options. Firstly, it can be false negative tests, which initially showed recovery, and then again gave a positive result. Secondly, there is a certain percentage of patients who do not form intense prolonged immunity. They can only rely on Herd immunity - the immunity of the crowd.


Phylogenetic tree SARS-CoV-2. On the horizontal axis, the number of different nucleotides. Source

If we talk about the phylogeny of SARS-CoV-2, then it does not differ in susceptibility to mutation. There are currently 48 registered variants of this virus, and the farthest orange branch of Wuhan-Hu-1/2019, the orange branch, has only 12 distinct nucleotides. This is a sample registered in Finland with an Italian ancestor.

Apparently, selection towards lighter forms can last for many years if the pandemic cannot be crushed.

Moving on to tips: smoking is bad, but it's too late to rock the boat


As already known, the virus uses the membrane receptor for the ACE2 protein (angiotensin-converting enzyme) for fixation and initial entry into the host cell. Most often, these receptors are found in the epithelium of the respiratory tract and are expressed in some quantities by the epithelial cells of the oral cavity. The more ACE2 is expressed, the easier it is for the virus to initially infect the body and multiply during the course of the disease. There are several factors.

Firstly, you should be “lucky” with the genotype. This protein is encoded by two variants of gene I and D. Accordingly, combinations of II, ID, DD are possible. If you have DD, then in addition to high risks in terms of cardiovascular disease, you get an additional vulnerability to SARS-CoV-2. Accordingly, mortality in different populations of mankind may differ due to differences in the ratio of genotypes.

Secondly, quit smoking. No, this will not help you for the current pandemic, but in any case, this is an aggravating factor. I found an interesting preprint that indicates an increase in ACE2 expression in smokers.


Relative ACE2 expression levels in volunteers with a different smoking history. GSE994 - expression in the lungs, GSE17913 - expression in the oral cavity.

Studies have shown that expression is significantly higher in smokers when compared to those who have never smoked or quit. Unfortunately, the study did not indicate how long the Former volunteers quit smoking, but most likely it is about 10+ years.
The primary gateway for infection is usually light, but with increased expression in the oral cavity there is a higher risk of receiving a life-giving dose of the virus by simply licking your fingers after the subway rail.


Expression of ACE2 in smoker mice

Similar results were obtained on the model of smoker mice, who were forced to breathe tobacco smoke with a certain frequency for up to five months. In this case, a direct correlation was observed between the length of smoking in mice and the degree of expression.

Summary: if you are an elderly smoker, then your mortality risks are extremely high.

About Umifenovir


There are several fairly well-known commercial preparations with umifenovir as an active substance. It is quite actively promoted in the domestic market for the treatment of all kinds of viral diseases.

In the study, he was compared with placebo. As a result, the placebo group gave negative PCR for coronavirus in 71.8% of cases, and umifenovir in 82.6% of cases. So, tablets without an active substance did not have statistically significant differences from umifenovir in terms of their effect on the rate of recovery.

Mortality and human experience


A topic that annoys everyone and causes the most controversy. As has been said many times, it is incorrect to measure mortality before the end of the epidemic, but it can be determined with one error or another based on epidemic models. This is exactly the situation where selection bias rises to its full height: patients with severe symptoms do not go to the doctor, but simply cough slightly and infect everyone else.


Plague Ship - Diamond Princess

For a correct experiment, you need to lock a crowd of people in a limited space, wait until everyone gets sick and count the number of survivors. Of course, such methods are not very humane, but such an experiment turned out quite by accident in the incident with Diamond Princess, when 3,600 people were quarantined. As a result, despite the precautions and regular transfer of the infected to the hospital, more and more new passengers and staff became infected. The result was a good estimate for the lower mortality limit - 1%. Given that the passengers on the cruise ship were mostly elderly, it can be assumed that in the general population the mortality rate will be at least 0.4-0.5%. The basic reproductive number is R0, in the case of the liner is 2.8, which is comparable to the flu. It should be notedthat this coefficient is applicable to hard quarantine conditions. In a large city without special events, it can be significantly higher.
The upper limit is now estimated at around 4%. The main risk group is elderly patients ( source , data as of February 17):

Age



Mortality



80+ years



14.8%



70-79 years old



8.0%



60-69 years old



3.6%



50-59 years old



1.3%



40-49 years old



0.4%



30-39 years old



0.2%



20-29 years old



0.2%



10-19 years old



0.2%



0-9 years old



0



Do not lick your hands



The biggest problem in spreading the virus is the hands. If you remember, the entrance gates are the cells of the oral cavity and pulmonary tract expressing ACE2.

FFP3 / N99 class respirators provide some protection against viral aerosol. Moreover, it is very unfortunate to get under a cloud of viral particles in droplets of saliva and mucus after a sneezed person. On average, such a cloud indoors hangs in the air for no more than five minutes, after which it is deposited on surrounding objects. It’s quite fun when the patient coughs or sneezes in the palm of his hand, after which he touches all the handrails and handles in a row. Therefore, the banal recommendation to regularly process door handles and constantly wash your hands is more than effective, provided that you are not in the immediate vicinity of sneezing people.

Masks and respirators, by the way, have another important effect - they do not allow you to touch your lips and nose with infected hands.


There is a gorgeous series of Legionbreakers dedicated to contamination. It shows very clearly how the "infected" Adam very quickly covers with an ultraviolet marker everything around, including the faces of his colleagues.


Men, get rid of the irresistible desire to touch each other's hand.

In short, wash my hands, wipe the keyboard with the mouse with alcohol and wean the way to say hello. Many times I saw this strange ritual in open space, when a crowd of people spends five minutes to touch each other. Naturally, no one washes hands after the subway rail.

What should you do if you have relatively protected your lungs from a viral aerosol with a respirator, but in the metro you suspiciously coughed up a suspicious Italian with Asian roots talking on the phone in Farsi? To begin with, it is not at all necessary to wrap yourself in a white sheet and immediately crawl towards the cemetery. But this also does not mean that you need to walk all day covered with droplets of alien saliva and mucus from the nasopharynx. Yes, you did not inhale the viral aerosol, but some particles got on the mucous membranes of the eyes. The mucous membranes of the eyes themselves, apparently, are not the gateway to infection, but the nasolacrimal canals wash away everything into the nasopharynx, where the virus can eventually become fixed. In fact, in the absence of sealed glasses, the eyes become an additional entry gate for infection.

You have several ways to solve the problem: if you were coughed up right in the entrance of your house, it will be optimal to wash well, washing your eyes thoroughly. For washing, our laboratory has a blepharolotion . The first part of the questions that got me is about him. No, even if you clean your eyelids according to the instructions, this will not help from the virus. More precisely, it will help in the same way as washing with water. But blepharolotion was developed for the eyelids, so when washing it less injures these same eyelids. It is better to wash with special equipment and walk clean than not to wash at all. But it is better to wash with water than to go dirty.

Worse, if there is no way to fully wash with soap. The most important thing - do not pour aggressive sanitizers in your eyes - you will get a chemical burn. Almost all medical protocols for contact with biologically contaminated fluids in the eyes involve washing with neutral solutions. The cornea is an extremely delicate structure and is easily irreversibly damaged by unsuitable drugs. In the case of processing with neutral things, part of the virions will be washed off the surface. A little later, already fully wash your eyes when you can find the sink. It is also convenient to use sterile blepharosafewe have developed to treat the skin around the eyes. We did them for resuscitation and for another, but in the end they are in almost every pharmacy in individual packages "for wiping the eyes" (actually a century). It works very well. No, she’s not fighting makeup. No, the virus does not destroy, but it allows you to slightly reduce the risks. Like water.



Therefore, the general principle is that eye protection is needed either completely (a spacesuit), or wash yourself on time, or don’t walk in public places where they can sneeze in your face. Judging by the conclusion of Chinese epidemiologists , a distance of at least 4.5 meters can be considered safe. You will not go anywhere in the subway, but there are already special people standing there who measure the temperature with a thermal imager, so, logically, everything should be relatively good.

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