Bacterial MgrB peptide activates chemoreceptor Fpr3 in mouse accessory olfactory system and drives avoidance behaviour

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.

The vomeronasal system of the newborn capybara: a morphological and immunohistochemical study

“…The vomeronasal organ (VNO) specialises in detecting pheromones for the purpose of reproductive behaviours such as maternal aggression and sexual attraction 5 . The VNS is also involved in the recognition of major histocompatibility complex (MHC) associated peptides 6 , kairomones 7 and aversive molecules 8 .…”

From immune to olfactory expression: neofunctionalization of formyl peptide receptors

“…The agonist potential of formylated peptides was extensively tested for the mouse FPR-rs1 in a heterologous expression assay, revealing that FPR-rs1 responds to some formylated bacterial signal peptides, but this vomeronasal receptor appears more narrowly tuned than immune FPRs. Recently, it was shown that HEK293T cells expressing FPR-rs1 respond to the formylated peptide motif f-MKKFRW (Bufe et al 2019 ), a signal peptide present in membrane proteins of a large family of Gram-negative bacteria, the Enterobacteriaceae (which include Escherichia , Salmonella , and Shigella , as well as a few Gram-positive bacteria). More specifically, the MKKFRW motif is highly conserved at the N-terminus of the virulence-regulating factor protein MgrB of these bacteria.…”

“…Mice lacking the FPR-rs1 receptor or components of the vomeronasal signaling cascade do not display any avoidance of the MgrB formylated peptide, clearly suggesting a critical role for FPR-rs1 as a chemoreceptor involved in the behavioral response to bacterial cues (Fig. 2 ) (Bufe et al 2019 ).…”

“…Because of the affinity of both immune and vomeronasal FPRs for pathogen- and immune-associated ligands, it has been speculated that vomeronasal FPRs might play a role in mediating sick conspecific avoidance behaviors (Boillat et al 2015 ; Dietschi et al 2017 ). It was shown that mice lacking Fpr-rs1 are still capable of discriminating between healthy and immune-challenged peers, thus excluding that FPR-rs1 alone is responsible for this behavior (Bufe et al 2019 ). Further studies with the deletion of the whole repertoire of vomeronasal FPRs will thus be necessary to define their potential role in the avoidance of sickness-related cues emitted by conspecifics.…”

Pathogens, odors, and disgust in rodents

“…In mice vomeronasal sensory neurons ((VSNrs) detect non-volatile chemostimuli that are indicative of infection and health status, immunological fitness, and genetic compatibility ( Boillat et al, 2015 ). The VSNrs include formyl peptide chemoreceptors that respond to specific bacterial cues as well as other receptors and mechanisms for detecting bacterial toxins, quorum-sensing molecules, and lipopolysaccharides ( Bufe et al, 2019 ; Chiu et al, 2013 ). Less is known regarding the detection of non-volatile viral associated cues.…”