Immunity system complexity: detecting infections (Introduction)

by David Turell , Sunday, February 05, 2023, 22:28 (789 days ago) @ David Turell

Either from surface molecules or from leaks (a late finding):

https://www.agnosticweb.com/index.php?mode=posting&id=43247&back=entry

"Kagan asserts that the pattern recognition receptors (PRRs) that induce an immune response are not activated by the pathogens themselves. Instead, they respond to pathogen-associated molecular patterns (PAMPs), which are ligands such as short strands of genetic material or degraded cell wall proteins that are only released when the infectious agent has made an error, such as performing a low-fidelity genomic replication or dying as a result of a maladaptive or untidy mutation.

***

"...research in the late 1990s and early 2000s when these so-called windows, these pattern recognition receptors, started being identified. And these days, we know that there are a few dozen of them and their job is exactly what Janeway predicted, which was to sense molecules produced by infectious agents. there was a very simple if-then statement that if the infectious agent is producing these molecules and causing disease, then we sense the infectious agent that’s causing disease. And it’s for this reason that we call these molecules that our innate immune system senses pathogen-associated molecular patterns.

***

"And there’s no living organism that displays its nucleic acids on its surface: A bacterium hides its DNA and RNA inside of itself. Viruses do the same thing; our cells do the same thing. And so, it was kind of odd that the sensors of infection would detect molecules that were hidden from those sensors by the infectious agent itself.

***

"Intellectual disconnect number two came from the discovery, over many labs over the years, that many of these DNA and RNA sensory proteins can be found in lysosomes. And so, if they’re inside of lysosomes, that means then that not only are these molecules sensing nucleic acids, but they’re sensing nucleic acids in an organelle that’s designed to destroy the bacteria and the viruses that we see. Successful pathogens would have avoided being killed, and [therefore] avoided being sensed. And so, you have this very odd disconnect number two: You have sensors of infection that are placed in regions of the cell that are only inhabited by infectious agents that made a mistake; infectious agents that tried to infect their cells but got themselves killed.

***

"... years of research showing that not all infectious agents are capable of actually causing infection. So, for example, if you take 100 bacteria, or 100 viruses, and you add them to cells, some of them—I’ll make up the numbers, let’s say 80 percent of them—will be able to successfully infect a cell, but two out of ten will actually fail in their infectious attempts and be killed by the host. Sometimes the host wins, and sometimes the pathogen wins. And once the pathogen makes a mistake, that is when, I would argue, your immune system is able to dispense the entire infection.

***

"...what that means, then, is that pathogens are always allowing themselves to make mistakes for the long-term survivability of the species. But because it’s a mistake that’s being made, it’s very difficult for the pathogen to control it. By waiting for a pathogen to make a mistake, which always happens during an infection, you, by definition, will be able to detect the infection itself. A successful pathogen, which may have infected the cell right next to you, is still going to be eliminated because all of our immune responses and the immune responses of plants are systemic. A chain is only as strong as its weakest link; if you have a chain of 100 pathogens, and one out of that makes a mistake, that one is the one that’s detected by the immune system. And now you have inflammation and defense against the entire population of infectious agents.

***

"...if you want to say that it is true that pathogens exist and they cause infection, and it’s also true that the PAMPs that we know of are the real ones, there must be a way to accommodate both of those statements. And the way to accommodate both those things is to propose that there are indeed mistakes made during an infection. And we call these mistakes, for scientific reasons, infectious infidelities, which means that if it was a higher-fidelity infection, all the pathogens would be able to succeed. If it’s a low-fidelity infection, sometimes they’re going to make a mistake.

***

"...many examples that are in the literature, which really counter the idea that the pathogen is the entity that pattern recognition receptors sense... there is a sister of the pattern recognition receptors, and these proteins are called Guards [or GarDs]. And guard proteins are almost certainly capable of directly sensing the pathogenic entity.

***

"So, now we know that your innate immune system needs to respond to the dying cancer cells in order to protect you from the cancer itself. The same exact logic applies here. Perhaps the most effective antibiotics already on the market today are so effective not because only they kill the bug, but because they kill the bug in a way that releases a PAMP."

Comment: this interview with a scientist reveals he expects automatic actions from the immune system. Contrary to dhw's distortions of this mechanism, it is nothing like evolution. The cells do the same operations automatically for their lifetime while creating a library of defenses to deploy as neeeded.