Covid Rings a Bell

How Covid causes such intense inflammatory reactions, via Toll receptors.

Those who have gotten a Covid vaccine might have an appreciation of our adaptive immune system. This comprises the B and T cells that learn about detailed features on pathogens that invade us, and then form, through an amazing feat of genetic reprogramming, novel proteins (such as antibodies) that can precisely zero in on those pathogens and call in lethal powers such as killer cells, phagocytes, neutrophils, etc. But there is another part, called the innate immune system, which is not adaptive, is evolutionarily older, and plays key roles in our day-to-day defense as well as in the beginning phases of the adaptive response. For how, after all, are pathogens recognized in the first place so that the adaptive response can even get started?

The innate immune system has many layers and actors, being very ancient. But one of its themes is that it recognizes "patterns", rather than the ultra-specific "epitopes" that the adaptive immune system gears itself up against. These patterns come in a two general forms, called pathogen-associated molecular patterns (PAMPs), which as the name implies come from outside, and damage-associated molecular patterns (DAMPs), which are typically cellular debris of various kinds that give notice that an injury has occurred. (There are also MAMPs and XAMPs for microbial and xenobiotic patterns, respectively.) PAMPs can include bacterial cell wall components like lipopolysaccharides and peptidoglycans, flagellin, fungal chitin, and a variety of nucleic acids such as double-stranded RNA characteristic of viruses, single stranded RNA, and DNA without special host markings.

What detects these patterns? Well, there are cell surface receptors for that, called the Toll-like receptors, or TLRs. Toll is a fly gene that was originally found to play important roles in development, (in German, it means "fantastic"), helping (together with its developmental ligand, Spätzle) embryos figure out their up/down, or dorsal/ventral polarity, and express the appropriate cell types to those locations. It was later found that fly adults use Toll for a totally different purpose- the activation of their innate immune systems, even though what pathogens it recognizes in that setting is still not known. All animals have TLRs, and plants have related systems, so this kind of thing is very ancient. Humans have at least 13 TLRs, so several bases are covered, making it difficult for a pathogen to completely escape this method of relatively crude detection.

The TLRs mediate immune responses against four general types of molecular patterns comprising damage/danger-associated molecular patterns (DAMPs), microbial/microbe-associated molecular patterns (MAMPs), pathogen-associated molecular patterns (PAMPs), and xenobiotic-associated molecular patterns (XAMPs). They do this by directly binding them. For instance, long double-stranded RNA, which is a common viral component, is detected by human TLR3. The TLR proteins form little hooks facing out from the cell. It takes two of them to fully bind one of the pattern molecules they detect, and when such a pair of TLRs forms, then their internal domains dimerize and set off a cascade of signaling inside the cell that serves as a danger alert. In this case, the antiviral program of interferon production, among many other genes, is activated. 

A structural model of a pair of TLR receptors, binding in this case a double stranded RNA. One TLR is blue, the other purple. One RNA strand is green, the other red. Binding the pathogenic pattern molecule drives dimerization of the receptor, which then causes its cell-internal domains to pair up and drive an activating signaling cascade.

Among the genes activated are signaling molecules called cytokines that alert and attract cells of the adaptive immune system ( T-cells and antigen presenting cells). Further genes are activated that process and present pieces of the pathogen pieces to those adaptive immunce cells. So the innate immune system, which has many other components, is a critical stage of our defensive system, both in its own right and as an initiator of the adaptive system.

This gets us back to Covid, where the SARS CoV2 virus causes extraordinary immune system activation in some people, a condition that is far worse than the original infection. A recent paper (review) suggested that the spike protein- the very same protein that is the first to dock to our respiratory epithelial cells, and the one that all the vaccines are made against, also binds in combinations of TLR2, TLR1, and TLR6. They do not show direct binding, but show that the spike protein by itself generates high TLR activity, and that this activity is composed of dimers of either TLR2+TLR6 or TLR2+TLR1. These receptors are known for the following activities:

• TLR2: Binds glycolipids from bacteria and also zymosan from fungi.
• TLR1: Binds lipopeptides, components of bacterial cell walls.
• TLR6: Binds diacyl lipopeptides, components of bacterial cell walls.

This is somewhat odd, since a pathogen would normally try to avoid triggering these sorts of receptors and responses. And a virus would particularly have little business activating a series of bacterial-specific TLR receptors. Covid may yet evolve towards evasion rather than activation, as it evolves to become endemic in humans and trade virulence for transmissibility. But for now, it is a here-and-gone kind of pathogen which seems to value immune activation and the associated respiratory expectoration that goes along with it. The authors also suggest that this activation may be a diversionary tactic, setting off the anti-bacterial alarms, and thus quieting the antiviral alarms, which the virus has more reason to fear. SARS CoV-2 is a wily antagonist, apparently purposefully activating some front-line immune defenses and landing many victims in a form of immune system over-activation called the cytokine storm.

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