To be or not to be a pathogen, that is the question

Coevolution has created an "immunological paradox", forcing the host to combine tolerance of the commensal microbiota with rapid recognition of pathogenic microbes. This raises an essential question: how does the host discriminate between a pathogen and a symbiont? The question is made all the more complex by the fact that the molecules responsible for innate recognition of microbes essentially recognize motifs (PAMPs) that are common to the prokaryotic world (pathogenic or not), compared with the eukaryotic world. It is now clear that, beyond recognition of the prokaryotic nature of the cell encountered (first signal or priming), the host recognizes a second signal, or "danger signal", which is the mark of the pathogen's aggressive attitude. This "danger signal" is highly variable: massive release of ATP into the extracellular environment by cells engaged by the pathogen, perception of alterations in the plasma membrane of the infected cell induced by contact with the pathogen or a membranolytic toxin, perception of the presence of bacteria or bacterial molecules such as peptidoglycan in the cell cytoplasm. Many of these alterations converge on a single signaling pathway, the inflammasome, whose activation leads to the activation of caspase-1, the maturation of IL-1 beta, a potently pro-inflammatory cytokine, and its secretion into the extracellular environment. In turn, these danger signals, which warn of the pathogenic nature of the microorganism concerned, also help to orient and activate the adaptive immune response (adjuvant effect).