Abstract: Innate immune chemoreceptors of the formyl peptide receptor (Fpr) family are expressed by vomeronasal sensory neurons (VSNs) in the accessory olfactory system. Their biological function and coding mechanisms remain unknown. We show that mouse Fpr3 (Fpr-rs1) recognizes the core peptide motif f-MKKFRW that is predominantly present in the signal sequence of the bacterial protein MgrB, a highly conserved regulator of virulence and antibiotic resistance in Enterobacteriaceae. MgrB peptide can be produced and secreted by bacteria, and is selectively recognized by a subset of VSNs. Exposure to the peptide also stimulates VSNs in freely behaving mice and drives innate avoidance. Our data shows that Fpr3 is required for neuronal detection and avoidance of peptides derived from a conserved master virulence regulator of enteric bacteria.
Introduction
A diversity of defence mechanisms have evolved to reduce the burden of infectious disease and to enable survival and reproduction in the face of tremendous pathogen challenges. These mechanisms are generally categorised into three basic strategies: avoidance of exposure to the pathogen (A), resistance to infection (R), and tolerance to the presence of the pathogen (T)1,2. Avoidance is likely to be the most cost-effective way of defence1, yet investigations into the role of the nervous system in mediating this function have only recently begun, and the cellular and molecular mechanisms for infection-avoidance behaviour remain largely unknown. Avoidance mechanisms are based on the remote sensing of pathogen-associated metabolites1 that activate the olfactory and/or other chemosensory systems in the body. In fact, there is now increasing evidence from nematodes3 and fruitflies4 to fishes5, rodents6,7 and humans8,9 that chemosensory cues associated with harmful microbes or inflammation and reduced fitness can be detected and avoided by conspecifics. In the mouse, interest has focused on the vomeronasal organ (VNO), a chemosensory organ that provides sensory input to the accessory olfactory bulb (AOB) in the olfactory forebrain10,11,12. Vomeronasal sensory neurons (VSNs) detect chemostimuli that result in instinctive decisions causing an individual either to be attracted to another individual, to avoid it, or even to attack and kill it11,12,13,14,15. VSNs are also implicated in social identification processes involved in the neural recognition of health status, immunological fitness and genetic compatibility11,16. The vomeronasal system mediates the detection and innate avoidance of sick conspecifics17.
Formyl peptide receptors (Fprs) are innate immune chemoreceptors of the seven transmembrane domain superfamily that recognise bacterial and mitochondrial formylated peptides as well as some other ligands18,19,20,21. In the immune system, Fprs play important roles in the initial sensing of infection through the detection of pathogen- and danger-associated molecular patterns that signal the presence of bacteria18,19. Subsets of mouse VSNs express several distinct immune-related molecules22,23,24 including five Fprs25,26,27,28,29. In analogy to their role in innate immunity, a chemosensory function associated with the identification of pathogens26 or an assessment of the bacterial flora of conspecifics25 has been hypothesised for vomeronasal Fprs as well. However, their precise function in olfaction has remained elusive; no Fpr knockout mice have been analysed in this regard; and there is no causal relationship between Fpr activation and odour-guided behaviour.
Here, we explore the role of Fpr3 (also known as Fpr-rs1, Fprl1, Lxa4r, or LXA4-R; see MGI gene ID 1194495) in olfaction. We find that Fpr3 functions as a pattern recognition receptor for a distinct subset of N-formyl methionine-containing (fMet) peptides that are predominantly present in the signal sequence of the bacterial protein MgrB, a highly conserved regulator of virulence and antibiotic resistance in Enterobacteriaceae. Native mouse VSNs detect such peptides with exquisite selectivity, and peptide-evoked cellular responses are abolished in a novel gene-targeted mouse strain carrying a knockout mutation in the Fpr3 locus. MgrB peptide stimulates VSNs of freely behaving mice and drives a form of innate avoidance that requires Fpr3, the G protein Gαo, and the ion channel Trpc2. We conclude that the chemoreceptor Fpr3 is required in the accessory olfactory system for sensing specific MgrB and MgrB-like peptides and for enabling behavioural avoidance to these bacterial cues.
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