Day 91: Snakes and Smokers

Massachusetts is up another "plateauing" 3% today. The governor, perhaps getting a bit annoyed at all the tin-pot mayors making up their own I-know-better-than-the-MDPH mask guidelines, has turned his CDC-based recommendation into a requirement, with fines. It's otherwise unchanged, though: you still don't need to wear a mask outdoors if you're able to socially distance, because the coronavirus is not some misunderstood medieval miasma. It's just a virus.

Believe it or not, today's title refers to a single, prepress paper at the open access journal Toxicology Reports: Editorial: Nicotine and SARS-CoV-2: COVID-19 may be a disease of the nicotinic cholinergic system. There's a lot of stuff going on in this paper (though no actual experiments), and to understand the relationship between snakes, smokers, and COVID-19, we need to back up a bit.

Back in the day when only East Asian men seemed to be catching the new coronavirus, there was a theory out there that their smoking habit (as well as their over-expression of ACE2) was part of the problem. (Smoking is known to increase susceptibility to other respiratory ailments.) But the numbers disagreed, as they so often do. Some authors of the current paper published several reports showing that smoking instead seemed to be protective, as did others including the CDC (although the CDC wasn't explicit about it, so you need to read the tea leaves of the linked table). The number of smokers hospitalized for COVID-19 has fallen far short of expectations, though it has been observed that once hospitalized (and thus, PlagueBlog postulates, deprived of their smokes), outcomes for smokers are poorer than average.

Why? you may ask. The paper posits the activity of nicotine as "an important inhibitor of pro-inflammatory cytokines acting through the cholinergic anti-inflammatory pathway". Moreover, because "the cholinergic anti-inflammatory system provides better control and modulation of the cytokine response compared to blocking a single [cytokine]," nicotine may actually be a better drug for the condition than several cytokine blockers currently being tested.

The paper also considers the ACE2 question. There have been conflicting studies over whether smoking and nicotine down-regulate or up-regulate ACE2, the later results being for up-regulation. While extra ACE2 was, like smoking, once thought to be a free ride for the virus into cells, more recent theories give extra ACE2 a positive role in continuing to perform its own functions after much ACE2 has been disabled by the virus. The paper also notes that up-regulated ACE2 is an advantage of estrogen and youth, and women and young people are known to have milder courses of disease.

There's a lot of (theoretical) mechanism of action in this paper, if you've been looking for some gory details of what SARS-CoV-2 is doing differently in the body than your average respiratory disease. The authors note that anosmia and its less-reported brother, ageusia (lack of the sense of taste) are signs of the virus attacking brain cells that happen to express ACE2, including, they postulate, the vagus nerve. The exact mechanism by which swelling of the vagus nerve affects the cholinergic pathway is not so clear from the paper, but apparently nicotine can still get through and do its anti-inflammatory magic.

And then, there were snakes. Why snakes?

As more studies presented the clinical manifestations, laboratory findings and disease progression in COVID-19 patients, it became apparent that the nicotinic cholinergic system could explain most (if not all) of the disease characteristics. It would be unlikely for a single “defence system” to ameliorate all the diverse and complex manifestations of COVID-19, unless that “defence mechanism” was the target of the viral host. Could that be possible?

[...] Taking into consideration that snake venom toxins are competitive antagonists of acetylcholine on α7-nACh receptor with high affinity, we decided to explore the hypothesis that SARS-CoV-2 may have acquired sequences by any of the potential, and not defined yet, intermediates through genomic recombination [on its way through a snake]. We compared the protein sequences between SARS-CoV-2 and snake venom neurotoxins. We were able to identify regions with four or five amino acids homology between the coronavirus and several neurotoxin molecules.

Though they're not very explicit about it, the authors do cite a paper that mentions snakes as a likely intermediate species that was also for sale at the Huanan Seafood Wholesale Market.

P.S. A redditor has collected vast quantities of SARS and COVID-19 smoking statistics.