27 April 2020 – Monday – #43

It was a spectacular day in Barcelona yesterday, first day warm enough to wear a camiseta. I stayed inside, but not everyone did.

La Barceloneta, 26 Apil 2020 (unatrributed)

Two months ago, I would have wondered why everyone was so spread out. Now it looks like a scene from a horror film where a deadly virus is lurking in someone’s nose, but we don’t know whose. This photo presents us with our current conundrum: what do we have to do to enjoy life outside once again?

Unfortunately, I’m not going to answer that today. Or tomorrow. Or next week. No one is.

Yesterday I went on a whirlwind tour of Covid-19 science and technology, mostly looking at what’s going on with testing. We’re entering the phase of the pandemic where testing is our best bet to keep Covid-19 at bay as we spend more time outdoors.

One of the testing technologies I wrote about was Paul Buchheit’s effort to create a Covid-19 test platform using Surface Plasmon Resonance (SPR). I’m a little less optimistic about this effort after an email from my friend Dennis.

… SPR was the technique Liz Holmes et al were using for their blood sampling at Theranos.  And we all know where that landed. SPR is wildly famous for being hypersensitive to the conditions of the optics in the sensor.  Down to the angstrom level for parallelness and completely free of contamination on surfaces to the level of an atom or two per square millimeter or so.  You have to deal with those issues to have a successful sensor based on SPR.

Email from Dennis Hancock

SPR sounds great in a controlled lab environment, not so great for deploying a network of millions of test stations. Still, it’s good someone talented is doing the SPR experiment.

Today, I’m continuing on from yesterday to look at some Covid-19 basic science. I’ll try to make this enjoyable enough that you won’t need a hit from your bong or a quarantini to make it through. I want to warn you that most of my knowledge of the immune system comes from high school biology and from studying developments made during the AIDS crisis when scientists were figuring out the role of T-cells.

Shane forwarded this morning a few articles on Covid-19 pathogenesis. I know “pathogenesis” is a fancy scientific word because WordPress spellcheck flags it. “Pathogenesis” means the way a disease or, more specifically, a pathogen develops. There’s still a lot to work out with Covid-19 pathogenesis, but it’s becoming clear that Covid-19, or the SARS-Cov-2 virus, hijacks the body’s immune system in a clever way, a way completely different from HIV.

In addition to pathogenesis, I want to introduce two additional terms, ACE2 (Angiotensin Converting Enzyme 2) and Interferon. The same way it was worth getting to know about T-cells during HIV / AIDS, it’s worth getting to know about ACE2 and interferon because you’ll be hearing about them more and more.

ACE2 is an enzyme commonly known for its role in modulating blood pressure. I’m simplifying here, but enzymes are kind of like scissors for proteins. You already may know something about ACE2 because one class of hypertension (high blood pressure) therapeutics is called ACE-inhibitors. ACE2 is found throughout the human body and plays other roles in addition to blood pressure modulation.

Interferons are proteins that our immune systems use to send signals. A cell that detects a pathogen, for instance, emits interferon to signal for help. Interferons are one part of a general class of proteins called cytokines that modulate immune system response. I’ve written about Covid-19 induced “cytokine storms” in previous entries.

Now that we’ve got definitions out of the way, what do ACE2 and Interferon have to do with Covid-19? In a pre-proof of an article with the simple title SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues (Ordovas-Montanes, Shalek, et al.), the authors make some interesting and hard to understand claims.

Strikingly, we discover that ACE2 is a human interferon stimulated gene (ISG) in vitro using airway epithelial cells, and extend our findings to in vivo viral infections. Our data suggest that SARS-CoV-2 could exploit species-specific interferon-driven upregulation of ACE2, a tissue-protective mediator during lung injury, to enhance infection

From summary of SARS-CoV-2 receptor ACE2 is an interferon-stimulated gene in human airway epithelial cells and is detected in specific cell subsets across tissues pre-proof.

Put down your bong or your quarantini. Not yet. Luckily we have an article that helps explain what this summary means. What the researchers have discovered this year is that SARS-CoV-2 (I’m going to use that term for the Covid-19 virus here) uses ACE2 to gain entry to human cells and replicate itself. It turns out the virus needs help not just from ACE2, but also from another enzyme, a protease called TMPRSS2.

The next thing the researchers asked was, where does SARS-CoV-2 find the ACE2 and TMPRSS2 it needs to hijack human cells? It turns out there are only a few places that human cells produce both ACE2 and TMPRSS2. “Those cells fall in three types: goblet cells in the nose that secrete mucus; lung cells known as type II pneumocytes that help maintain the alveoli (the sacs where oxygen is taken in); and one type of so-called enterocytes that line the small intestine and are involved in nutrient absorption.”

Now we have a clue about why Covid-19 is transmitted via the nose and why it so often develops into a lung disease. The nose and lungs areas of the body are rich in ACE2 and TMPRSS2 as well as easily accessible by airborne Covid-19.

There’s one other important thing Ordovas-Montanes, Shalek, et al. seem to have figured out. It has to do with our friend interferon. Remember, that’s the protein that cells emit when they detect a virus and signal for help. It turns out that one effect of interferon is to increase ACE2 production. So, when cells detect SARS-CoV-2 and they yell for help with interferon, they end up increasing levels of the ACE2 that SARS-CoV-2 needs to enter cells. It’s kind of like the infected cells emitting interferon are inadvertently pouring gas on the SARS-CoV-2 fire burning all around them.

This is pretty exciting stuff! Covid-19 tricks our immune systems to produce more of the enzymes it needs to attack us. There is a ton more for scientists to figure out, like whether administration of interferon helps or hurts Covid-19 patients and whether hypertension patients should stop using ACE-inhibitors.

The good news is that this kind of basic research also is leading to new potential therapies. One example is the use of X-ray crystallography to discover the structure of the main protease in SARS-CoV-2 called Mpro. Simplifying again, this is like figuring out what kind of scissors SARS-CoV-2 use. Scientists are developing an Mpro inhibitor to gum up the inner workings of Covid-19 and believe they can deliver it with an inhaler.

I realized after talking with some of my younger gay friends that they don’t have a good working knowledge of the human immune system. During the AIDS crisis, I was a sponge for immune system information. During that era, researchers were figuring out how T-cells worked and how the immune system signaled its various components to manage the HIV pathogen.

My cousin Nancy posted this interview about Covid-19 vaccine development with Dr. Jerome Kim, the Director General of the International Vaccine Institute. It’s about 45 minutes long and a good explainer on Covid-19 vaccine development that includes a quick tour of the human immune system. This is highly relevant, easily digested information about all aspects of Covid-19 from a top world expert. Well worth the time.

Dr. Jerome Kim, the Director General of the International Vaccine Institute, discusses Covid-19 and HIV vaccines as well as the human immune system.

Sorry if it got a little science-y today. You can pick up your bongs and quarantinis now. I’ve got just the thing to relax you: Celeste Barber on Day 8 of Quaranine.

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