Bullfighting Covid
Teaching my immune system how to ignore Covid’s red cape and go for the matador
Today’s story begins with an incident that haunts the nightmares of molecular virologists. In the late 90s, Ronald Jackson and Ian Ramshaw attempted to develop a humane approach to the mouse overpopulation problem in Australia. The idea was to elicit an immune response that would effectively sterilize female mice. The team’s initial attempt used a mousepox engineered to express mouse egg proteins. The approach didn’t work, so Jackson and Ramshaw reasoned that adding an immune signaling flag, in the form of mouse interleuken 4 (IL-4), might improve the immune response against the egg proteins. Since mousepox can’t infect people and mouse IL-4 doesn’t engage human IL-4 receptors, there was no reason to imagine the experiment could be in any way dangerous. However, the results turned out to be surprisingly disturbing. The virus engineered to express IL-4 rapidly killed mouse strains that are ordinarily resistant to mousepox infection. An even scarier observation was that the IL-4 mousepox even killed mice that had previously been vaccinated against the virus.
Bioethicists have spent a lot of time and energy wringing their hands over the question of whether Jackson and Ramshaw should have published their results. I find the question inane. Of course they should have published! While it’s valid to wonder whether a psychopath might see the results as an instruction manual for how to weaponize human poxviruses, the mousepox study is far from the only clue in published literature hinting that IL-4 might make some viruses more dangerous. It was better for Jackson and Ramshaw to tell us what things a terrorist might conceivably dream up so we can start thinking about how to defend ourselves in case of such an attack. More importantly, it’s not just terrorists we have to worry about - evolution is independently cooking up these types of horror stories all the time. One example is Kaposi’s sarcoma herpesvirus, which carries its own natural immune-flummoxing version of IL-6. In the classic wisdom of Laurence Fishburne’s character in Contagion, “Someone doesn't have to weaponize the bird flu. The birds are doing that.”1
Which grimly brings us back to my first Covid infection (see: “The Original Meaning of Quarantine Was Forty Days”). While the Moderna boost I got two weeks before catching Covid obviously didn’t give me magical Wonder Woman bracelets of sterilizing immunity, my vaccination history does appear to have empowered my immune system to keep the infection bottled up only in my sinuses. The question at hand is why my apparently sinus-restricted infection rebounded twice over the course of more than three weeks before I finally cleared the damn thing (assuming there’s not a third rebound still in store for me).
My emerging model for what happened to me starts with the mousepox and KSHV story. What if Covid is promoting an IL-4 or IL-6 dominated response that made it harder for me to mount an effective immune response that can quickly clear the infection. Natural history studies already offer some support for this concept - Covid infection triggers increased IL-4 and IL-6 levels that can last for many months after clearance of the initial acute infection. Also, treating Covid patients with a therapeutic anti-IL-4 antibody called dupilumab results in less severe disease.
It’s important to be aware that the immune system uses different types of responses to fight different types of pathogens. It’s a bit of an oversimplification, but at a very broad level T cell responses can be thought of as divided into T-helper-1 (Th1) and Th2 categories. In general, the two types of helper T cell responses seem to have a see-saw relationship - meaning you generally either mount a Th1 response or a Th2 response against a new infection. Th2 responses, which are coordinated by IL-4 and IL-6 signaling, are thought to have evolved primarily as a defense against parasitic worms2. Classic Th2 responses often involve a type of white blood cell called a mast cell that’s involved in allergic reactions. A signaling chemical called histamine is a hallmark of mast cell activation - and a broad class of drugs called antihistamines are a familiar way to fight this type of response.
We traditionally think of antihistamines as only treating the symptoms of a cold, but the the IL-4 mousepox result makes me wonder: what if sniffling and sneezing are actually just an outward sign that a virus is attempting to flummox the immune system by directing the response toward a worm-fighting Th2 response that’s not very effective for fighting viruses. In that case, suppressing the IL-4/IL-6/allergic/mast cell/histamine response wouldn’t just alleviate symptoms - it could also shift the immune see-saw away from Th2 response and toward a Th1 response that’s more effective for eradicating the underlying viral infection. The idea is that it’s incorrect to simply think about “anti-inflammatory” treatments - you have to instead think about the kinds of inflammation you’re inhibiting or promoting.
To drill down on this idea, let’s geek out on the literature for a specific over-the-counter antihistamine called azelastine (brand name Astepro). Early in the pandemic, surveys of medical records detected an intriguing correlational trend in which people with prescriptions for many common allergy medicines were found to be less likely to test positive for Covid. People with azelastine prescriptions seemed particularly unlikely to have positive Covid test results on file. The observation led to a number of randomized controlled trials, all of which found that people given antihistamines show faster resolution of Covid symptoms compared to people given a placebo.
In one study, azelastine promoted faster disappearance of Covid symptoms while also promoting faster disappearance of virus in nasal swabs. A recent paper offers a possible explanation for this result by showing that SARS-CoV-2 can use azelastine’s target, a cell surface protein called histamine receptor H1 (HRH1), as an infectious entry receptor. Azelastine prevents SARS-CoV-2 from using HRH1 to infect cells. At face value, this appears to tie a tidy bow on the story of how azelastine promotes faster clearance of the virus, but there’s a hidden problem with the inference. The concentration of azelastine required to suppress SARS-CoV-2 infection in cell culture is a thousand times higher than the peak concentration of azelastine in circulation. Since azelastine never approaches the concentrations required for direct inhibition of viral replication in vivo, there must be something else going on behind the scenes. My bet is that SARS-CoV-2 Spike is directly triggering HRH1 signaling and azelastine is effective in vivo because it counteracts the false histamine signal. If we imagine SARS-CoV-2 as a matador then azelastine is effectively removing one of the virus’s Th2 red capes - in a way that helps the immune system mount a proper Th1 response that can clear the virus more quickly.
Another example to drill down on is famotidine - a familiar antacid that goes by the brand name Pepcid. Famotidine targets histamine receptor H2 (HRH2). Unlike HRH1, which is abundant in the nasal mucosa, HRH2 is abundant in the gut. Famotidine was one of the first “repurposed” drugs to show clinical efficacy against Covid, including efficacy against neurological symptoms. Famotidine, like azelastine, reduces SARS-CoV-2 viral load in Covid patients. In contrast to azelastine, a series of papers have ruled out the possibility that famotidine exerts direct antiviral effects in cell culture systems. It again seems that the most likely explanation is that famotidine is working by removing the red cape of Th2 flummoxing.
A number of supplement products have crossed my radar as having convincing Covid-fighting effects in clinical trials. Now that I’m looking through the Th2 lens, I realize that curcumin, melatonin, and quercetin have all been implicated in suppressing things like mast cell activity. Another promising Covid treatment, metformin, has a dizzyingly wide range of metabolic effects, but one of its known activities is suppression of mast cell activation. If you drill down on the C19early.org summary of the diverse range of interventions with evidence of efficacy for treating Covid, a large majority of them suppress IL-4/IL-6 signaling. It’s very suspicious.
In summary, the idea that has been swimming up through the murk in my mind is that we may have been missing a unified field theory of Covid drug repurposing. Anything we can get our hands on that inhibits IL-4-related pathways suddenly seems like an interesting candidate for fighting Covid because drugs and supplements in this category could help shift the immune response in a more productive direction that doesn’t merely clear the virus faster, but could also help lay down a better immune memory that protects people against repeat Covid infection in the future. And it’s not just Covid - it’s conceivable that other pathogens are using IL-4/IL-6 pathways as a red cape too.
There are a bewilderingly large number of drugs and supplements to consider in the Th2-antagonist category, and it’s very frustrating to realize that the effects I’m invoking won’t be detectable in standard lab assays aimed at measuring direct antiviral activity in cell culture. The theory suggests we’re doomed to investigate this kind of thing in the real world in actual humans. Consumer Reports for Medicine! Now!
Song of the day: “The Birds Are Doing That” by Cliff Martinez. Bonus song: I also love Martinez’s super-shiny work on the Solaris Soundtrack.
Another interesting connection here is that the controversial early-pandemic Covid treatment ivermectin - which is used for treating parasitic worm infections in horses - may have been successful for treating Covid in lower and middle income countries because it inadvertently eradicated underlying worm infections. Under that hypothesis, the underlying worm infection may have been putting an additional thumb on the scale toward the type of IL4-dominated responses that I suspect are ineffective for clearing Covid.