Immunity system complexity: innate immunity at work (Introduction)

by David Turell , Saturday, January 28, 2023, 17:49 (665 days ago) @ David Turell

It picks up foreign protein signals:

https://www.sciencemagazinedigital.org/sciencemagazine/library/item/27_january_2023/407...

"Within multicellular organisms, innate immune pattern recognition receptors (PRRs) control host defenses to infection. These receptors are activated by microbes, which facilitate their own demise by producing PRR ligands called pathogen-associated molecular patterns (PAMPs). Notably, the mechanisms of PRR-mediated microbial detection are inconsistent with the sensing of successful pathogens. I propose that PRRs do not detect pathogenic agents per se. Rather, PRRs detect PAMPs that are released from microbes as a result of biochemical infidelities, or mistakes, that occur during infection. These mistakes render individuals within an otherwise infectious population noninfectious but immunostimulatory. Microbes could evolve strategies that increase the fidelity of their infectious strategies to evade PRRs. However, imperfect activities enable biochemical innovations that ensure the survival of the species. By detecting PAMPs that are released as a result of low-fidelity biochemical activities, PRRs may, in effect, be targeting the very process that microbes need for long-term survival—evolvability.

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"The specific nucleic acids detected by TLRs suggest preferential detection of dead microbes. Free guanosines and uridines represent cofactors that, along with single-stranded RNA (ssRNA), activate TLR7 and TLR8, respectively (1). Similarly, trinucleotides containing cytosines synergize with CpG-containing ssDNA to activate TLR9. The requirement of short nucleotide sequences (or free nucleosides) to activate several TLRs supports the idea that lysed microbial cells or degraded virions are detected after their genomes have been hydrolyzed.

[Many specific reactions are presented as examples of the battle.]

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"Like all areas of biology, exceptions to suggested biological rules exist. For example, PRRs that detect bacterial LPS molecules and lipoproteins may represent examples of pathogen detection systems. These molecules are displayed on the surface of bacteria and are detected by specific TLRs in their intact forms. Similarly, the PRRs dectin-1 and dectin-2 recognize b-glucans and a-mannans, respectively, whose positioning on the fungal cell wall facilitates detection. However, there are possible explanations for these exceptions. The mammalian LPS detection systems are not as ancient as other PRR networks, such as the endosomal TLRs, RLRs, cGAS, and STING. These ancient PRR systems detect the most definitive example of PAMPs that are released as a result of infection infidelity—nucleic acids. Outside of mammals, few examples of immunostimulatory LPS activities (or LPS receptors) exist. Indeed, the genes encoding the mammalian LPS receptors CD14, TLR4, and MD2 are absent from the genomes of fish and invertebrates (which constitute >90% of metazoan life). Thus, exceptions to the error-centric theme of pattern recognition may be a recent evolutionary innovation.

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"Even if low-fidelity biochemical reactions were rarely detected by PRRs during infection, the rarity would need to approach zero for host defenses to be avoided. The very nature of the mammalian inflammatory and plant hypersensitive responses induced by PRRs enables tissue (and likely systemic) defenses to be executed against the entire microbial community. Studies of infection at the single-cell level could reveal the generality of these concepts and how they affect defense. Additional work is also needed to understand how inflammatory activities that drive tissue repair after infection resolution may be affected by residual PAMPs derived from dead microbes.

"An implication of the infection infidelity concept is that it provides the opportunity to develop anti-infective drugs that are also immunotherapies. It is possible that drugs that disrupt viral life cycles would, in immunocompetent cells, result in the release of PAMPs to the host immune system. Similarly, antibiotics that target bacterial cell walls may cause the release of cell wall components or cyclic dinucleotides that stimulate PRRs. Integrating PRR assays in anti-infective clinical pipelines may therefore offer opportunities for drug development."

Comment: I presented this article to show the complexity of the innate immune system in detecting foreign protein that is, fighting infections.