Infection infidelities drive innate immunity

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.