This is a summary/explanation of Pathogenesis of COVID-19 from a cell biology perspective by Robert J. Mason.

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We live in a society. The disease of covid-19, caused by the virus SARS-CoV-2, is so dangerous that our society is now in a pandemic. At the time of writing, we didn’t know much about the infectiousness or mortality of the disease, which is startling since it is killing thousands daily, but we know even less about its microbiology, which is tragic, because understanding of how this virus targets our respiratory system can help us explain its symptoms and progression from the root cause. To try to ameliorate this problem, this article looks the cellular biological route of SARS-CoV, a similar virus, to explain how covid-19 operates. Based on which part of the body it is infecting, we can divide the disease progression into 3 stages:

Stage 1: Asymptomatic state (initial 1–2 days of infection)

When you’re in close contact with someone who carries the virus, you may breathe in their virus-containing spit. The virus attaches to the inner skin cells of your nose/nasal cavity. Coronaviruses have these angry red triangles on them, which attach to a part of your cell membrane called ACE2 receptor. ACE2 receptors are the main attachment points for both SARS-CoV and SARS-Cov-2.



<figcaption class="caption">SARS-CoV 2 with its angry red spike proteins.</figcaption>



<figcaption class="caption">Virus entering a cell by binding its spike protein to an ACE2 receptor.</figcaption>

Once attached, the virus can get free passage into your cell ☹. It hijacks your cell to making more viruses with angry red triangles, then these new viruses go on to infect new cells, etc. Some experiments with SARS-CoV in petri dishes or test tubes indicate that the main cells the virus likes to hijack are cells lining your trachea and other windpipes that have cilia on them, little hairs that wiggle up and down that are responsible for bringing mucus up your windpipes.

However, this might not be reflective of what viruses do in our bodies, because there is indication of low amounts of ACE2 receptors on windpipe-lining-cells, and RNA from the virus does not have any sign of cell type preference.

At this stage, the virus can be detected with nasal swabs. You have no symptoms, but you are still able to give this virus to other people, because your spit will contain the virus. Tragic. The virus will spread around some limited local areas but your immune system is still too asleep to fight back.

RT-PCR tests reverse-transcript covid-19’s genetic material RNA into DNA, duplicates the DNA in “cycles” (the more duplication cycles the more DNA) and can quantify how much viruses you have, based on how many cycles it took to find a trace of the virus. Your RT-PCR cycle threshold value can predict how many viruses are in your body, and thus, when compared to other people’s test results, it’ll predict how much crap you’ll have to endure in the following days of your disease. We might even be able to detect if you have a virus that’ll spread crazy-fast. For you to trust this measurement, however, you have to trust the integrity of our healthcare system to have used a standardized test for everyone, as throat swabs are more sensitive than nasal swabs. If different patients had different tests, your results would be skewed, and you will be screwed.

Stage 2: Upper airway and conducting airway response (next few days)

At this stage, the virus goes down the respiratory tract, and your immune system will begin fighting harder. At this stage, a nasal swab or mucus coughed up from the respiratory tract will contain traces of the virus as well as the immune response. At this stage, symptoms will show up. Cytokines, molecules released by immune cells to signal the presence of a virus telling immune cells to do their jobs, may also be found. Usually the cytokine found with innate immune responses, where certain most awake white blood cells first ounce on pathogens, is CXCL10. CXCL10 is also used as the signal for the SARS disease. 



<figcaption class="caption">CXCL10 is released by your immune system at the site of a viral infection, or any other infection.</figcaption>

CXCL10 is awesome because it has an awesome signal to noise ratio when signalling the presence of both SARS-CoV and the flu, which means that its presence is an accurate sign that a virus exists. The skin cells in contact with the virus produce beta and lambda “interferons”, which are chemicals that play a major role in helping fight off viral infections by signalling to other skin cells to start activating their virus-fighting-military. If you were infected with covid-19, seeing how your immune system reacts to it can predict how bad the disease will get subsequently, which signals whether you need to be more closely monitored.

If you are lucky, like 80% of people who get covid-19, your disease will only reach your nose, nasal cavity, throat, trachea, bronchi, and bronchioles, basically – the sections of your respiratory system that don’t deal with gas exchange. If this is the case, you’ll likely not be hospitalized, but you will be trapped to your bed for a few days while taking some medications that improve your symptoms/make you feel better. As you’ll see in the next section, when covid-19 infects alveoli (the part of the lungs that do deal with gas exchange) is where the real sticky slimy stuff happens.



<figcaption class="caption">Conducting airways vs. gas exchange airways</figcaption>

Stage 3: Hypoxia, ground glass infiltrates, and progression to ARDS

~20% of people with covid-19 will reach this severe stage where a fluid such as pus or blood fills the area of the lungs that contain alveoli. 2% people who reach this stage die, but your exact chances depends on how old you are, and this number will become more accurate once we better understand the amount of mild/asymptomatic cases. Notably, the virus now affects alveolus cells known as alveolar type II cells that are responsible for a fluid that reduces surface tension (known as a surfactant) at the boundary between air and liquid of the lungs. 



<figcaption class="caption">Alveolus lined with surfactant layer. Note how the type II cell manufactures the surfactant that other cells need.</figcaption>

Both the coronavirus SARS-CoV and the flu virus prefer to infect type II alveolar cells on the area between the lung and the 2-layered-membrane that covers each lung, known as the pleura, that cushions the lung against the rib cage. With a large enough viral load, these cells will die through programmed cell death, which leads to the effect of lung-cell-killing-toxins self-propagating down to infect type II cells. In some areas of the lung, the majority of type-II cells will die, which is especially harmful because type I cells form from type II cells. This above sequence of events has been proven to play out when you contract flu pneumonia. The events cause diffuse alveolar damage, a fatal condition where dead membranes made up of dead cells, surfactant, and protein (known as hyaline membranes) are deposited against the wall of alveoli, making gas exchange difficult.



<figcaption class="caption">Normal alveolus vs. injured alveolus. RIP alveoli, we will forever remember your sacrifice ;( We will always remember how all other cells would be nothing if not for you working tirelessly day after day to take in our beloved life juice of O2. </figcaption>

The wounds will not heal properly, which can cause more severe scarring and fibrosis (fibrous connective tissue developing on injuries that can increase risks of lung cancer) than other acute respiratory diseases. To recover from this disease, a rigorous immune response and regrowth of dead epithelial cells is required. But this isn’t very easy, because giving epithelial growth factors (ex. KGF) might increase the number of viruses in your body because they might create more cells that contain ACE-2, the coronavirus’s receptor, allowing coronavirus to bind to more of our cells and make more copies of themselves. This is why older people are more likely to die from covid-19: they have a smaller response from their immune system as well as being slower to replace dead epithelium. The elderly also are slower at removing deposited particles (such as viruses) from the mucus of their respiratory tract, which gives more opportunity for the virus to spread to the alveoli of the lungs, to hinder gas exchange.

This article was based on the assumption that SARS-CoV-2 infiltrates the respiratory system in a similar fashion as SARS-CoV. This may not be completely the case, as for instance, we don’t’ know if SARS-CoV-2 can bind to any receptors other than ACE2 to enter our cells. SARS-CoV can use the CD209L receptor as well as ACE2. The author of the article is eager to see research about the innate immune responses of different types of respiratory cells. The cilia on the top of cells lining your airways and the non-moving finger-like protrusions that increase cell surface area/absorption, called microvilli, on the top of type II cells may help the virus enter!

If you ever find yourself with Covid-19, here’s a rule of thumb: if your disease is confined to the conducting airways, consider yourself lucky and stay at home with Tylenol. If there are viruses in your alveoli, you should go to a hospital, and make sure you’re monitored closely by doctors. So you don’t like, you know, die.

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