Self and Non-self Discrimination of Intracellular Membranes by the Innate Immune System

To discriminate self from non-self, the innate immune system evolved a large repertoire of germline-encoded receptors that detect molecular patterns associated with infections [1]. As originally proposed by the late Charles Janeway, such pattern recognition receptors (PRRs) [2] detect three broadly defined categories of patterns that can best be described as ‘‘microbial non-self,’’ ‘‘inducedor aberrant-self,’’ and ‘‘missing-self’’ [3]. The minimal definition of each pattern consists of two terms: 1) the nature of the PRR ligand(s) and 2) its cellular context, especially its precise location within the infected organism [4]. For example, the bacterial non-self molecule lipopolysaccharide is immunostimulatory in the intestinal crypts but typically not in the gut lumen [5]. Similarly, a number of intracellular self molecules including ATP or DNA-binding proteins activate PRRs and elicit immune responses exclusively when released from infected or injured cells into the extracellular milieu [6,7]. Therefore, in order to detect molecular patterns, the expression of PRRs must be and indeed is spatially compartmentalized [1]. Accordingly, PRRs are traditionally defined by the location of their cognate ligands and placed into two separates groups: PRRs for extracellular-derived ligands and PRRs for soluble, cytosolic ligands [1,4]. Here, I propose the classification of a third group of PRRs that act as intracellular ‘‘membrane sensors’’ by sampling and recognizing properties of intracellular membranes and microbial surfaces that are found inside infected host cells. Although the principles of immune recognition by ‘‘membrane-sensing’’ PRRs as outlined here are most likely widely applicable to intracellular infections with various classes of pathogens, for the sake of simplicity, I will focus on bacterial infections in this PLOS Pearls article.