Why Does COVID-19 Have So Many Symptoms?

Why Does COVID-19 Have So Many Symptoms?

For a respiratory disease, COVID-19 sure seems to affect more than just the respiratory system. Scientists think the receptor ACE2 is to blame.

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At first, we were told to watch out for coughing,fever, and trouble breathing. That is still true. But COVID-19 has a /lot/ of possible symptoms,not all of which scream “respiratory disease” -- even though the virus SARS-CoV-2 infectsour airways, and is thought to spread primarily through droplets we breathe out. COVID-19 patients have experienced some unexpected symptoms that affect more than just their lungs -- like GI problems, skin rashes, anda loss of smell and taste. Some of this is due to our immune response to the virus. But today we’re going to focus on the moleculethe virus uses to infect our cells: the angiotensin-converting enzyme 2 receptor, or ACE2 for short. This molecule lets certain coronaviruses,including SARS-CoV-2, affect us in a /ton/ of different ways. All cells have various surface receptors embeddedin their outer membrane. As their name suggests, they receivesignals and stuff from outside the cell -- stuff like hormones, neurotransmitters, nutrients,and immune molecules.

ACE2 is a surface receptor with a bunch of important jobs throughout our bodies, not just our lungs. Unluckily for us, that also means SARS-CoV-2has the potential to infect a variety of cell types. It still only causes the one disease -- COVID-19-- but this helps explain some of its broader effects. One of ACE2’s major functions is workingwith another protein, angiotensin II, to keep blood pressure in balance. Angiotensin II raises blood pressure, andwhen it gets too high, ACE2 breaks it down to lower blood pressure again. ACE2 does lots of other things, too, like accelerating tissue repair and modulating the microbes in our guts. And while there are lots of other kinds of surface receptors that viruses can use to get into cells and hold them hostage, ACE2just happens to be the one that SARS-CoV-2 uses to get in. Scientists think the infection most often starts when the virus is introduced to someone’s nasal passages. The nasal cavity has tons of ACE2 receptors,so it’s fertile ground for the virus, which can invade those cells to replicate. At this point, the newly-infected host mightnot have any symptoms, or they may develop a fever, sore throat, dry cough, or loss ofsmell and taste That loss of taste and smell might seem likethe odd one out, but it has ACE2’s fingerprints all over it.

One study in mice from May of 2020 found that ACE2 is expressed in cells of the nose that help transfer odors from the air to neurons,so the infection could block those signals. The researchers also found that older micetend to have more ACE2 in nasal cells than younger ones. If this is true in humans, it could help explainwhy older people are more susceptible to COVID-19. Upon infection, the virus can make itsway to our lungs. When the virus binds to ACE2 in the lungs,scientists think that it disrupts the normal breakdown of angiotensin II. Which means angiotensin II is free to runamok, leading to a vicious cycle of inflammation, cell death, and even blood clots that keepthe lungs from getting oxygen to the body.

So it’s no wonder that many patients needhelp breathing. And that’s not where it ends. Because, like we said, ACE2 is expressed inall /sorts/ of cell types. Like the circulatory system. A series of case reports in the journal theLancet looked at three patients with severe inflammation and cell death in their endothelialcells — the cells that line the inside of blood vessels. Researchers are pretty sure that the viruscan directly infect these cells using their ACE2 receptors -- though the significanceof that isn’t totally clear yet. And if that wasn’t enough, there’s theheart.

In severe cases of COVID-19, doctors haveobserved cardiac injuries. And COVID-19 patients with severe heart injuriesalso had relatively high amounts of ACE2 in their heart cells. For example, one patient in Italy presentedat the ER with all of the symptoms of a heart attack, but doctors couldn’t find evidenceof a blockage in the coronary arteries that would normally cause such symptoms. The patient tested positive for COVID-19. And while researchers don't yet fully understand the cause it's possible that SARS-CoV-2's relationship with ACE2 is contributing tocardiac symptoms. Then there’s the gut. The lining of the lower digestive tract is rich in ACE2 receptors, which could explain why up to half of people with COVID-19 havediarrhea. A study in the journal Science Immunology showed that the virus can directly infect human and mouse intestinal cells in culture. This study also suggested that the virus breaksdown before it exits the colon, making transmission by that route less likely -- but research is still ongoing there. Researchers are still trying to get a clear picture of COVID-19 and all its symptoms. This has just been the short list of thingswe’re pretty sure can be traced to ACE2. We’ve barely touched on the more indirect effects that seem to be a result of our immune system going into overdrive. The good news, though, is that it also makesACE2 a potential target for therapies -- which opens up another potential treatment path for COVID-19. It takes incredibly smart humans to diagnose diseases and come up with treatments.

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