The mammalian olfactory system does more than just detect food odours and pheromones. The discovery of a novel class of olfactory receptor provides evidence that mammals can also sniff out cell damage and disease.
The mammalian olfactory system recognizes diverse chemical stimuli conveying information about such things as food quality, the genetic identity or sexual status of potential mates, and even stress1,2. An exciting paper by Rivière et al.3 (page 574 of this issue) describes the identification of a previously unrecognized type of chemosensory neuron in the rodent nose that responds to stimuli associated with cell damage, disease and inflammation. These results should help us to understand how animals identify pathogens or assess the health status of potential partners.
Not so long ago, it was believed that the olfactory system of most mammals had only two divisions: a main olfactory system that detects environmental odours, for instance those emitted by food or predators, and an accessory (vomeronasal) olfactory system that detects pheromones — intraspecies chemical signals that elicit a stereotyped behavioural or hormonal change. It is now clear that the sense of smell is much more complex. Indeed, the main and accessory olfactory systems each respond to both general odours and pheromones4,5,6. Furthermore, each olfactory division contains several types of sensory cell identified by the receptors and other proteins they express, the connections they make in the olfactory part of the brain, and the chemical stimuli to which they respond2. This diversity of sensory cells in the nose has given rise to the concept of olfactory subsystems, each dedicated to a particular chemosensory role2.
There is a growing literature indicating that animals use olfaction to assess whether other organisms may be dangerous, or even to judge the health status of potential partners. For example, mice use olfactory cues to avoid potential mates that are infected with parasites7, whereas nematode worms develop aversions to odours given off by harmful bacteria, thereby avoiding toxic food8. However, although such olfactory-based aversion behaviours have been documented, no olfactory subsystem that is dedicated to the assessment of health status or disease has been identified in mammals. The findings of Rivière and colleagues3 may provide this missing link.
In mammals, most olfactory receptors are members of the G-protein-coupled receptor (GPCR) superfamily, which signal the presence of stimuli by initiating a cascade of biochemical changes within chemosensory cells2,9. Reasoning that novel vomeronasal receptors would similarly belong to this group of proteins, Rivière and colleagues screened mouse vomeronasal tissue for the expression of about 100 known and candidate GPCRs. They found that rodent vomeronasal sensory neurons (VSNs) express five formyl peptide receptor (FPR)-like genes (Fpr-rs1, Fpr-rs3, Fpr-rs4, Fpr-rs6 and Fpr-rs7)10. These genes are expressed in subsets of VSNs that do not express other known vomeronasal receptors, indicating that Fpr-rs-expressing VSNs are a novel group of chemosensory neurons.
FPR and FPR-like receptors are also found in immune cells, where they mediate cellular responses to cell damage, disease and inflammation10. Rivière and colleagues3 engineered cells to express the VSN-specific FPR-rs proteins on their surface and found that they responded to several of the same activators (agonists) that stimulate the immune-cell FPR and FPR-like proteins. These agonists included peptides and lipids derived from microorganisms, or involved in the inflammatory response. Each type of FPR-rs responded to a distinct, but overlapping, panel of agonists (Fig. 1a).
But do these diverse FPR-rs agonists actually activate VSNs? Rivière and colleagues addressed this question by exposing isolated VSNs and VSNs in intact vomeronasal epithelium to several of the FPR-rs agonists. They measured cellular activation by imaging changes in calcium levels within the VSNs. Responses to FPR-rs agonists were concentration dependent and were observed at nanomolar concentrations, reminiscent of the exquisite sensitivity of other VSN subpopulations to volatile and peptide stimuli5. Agonist selectivity also varied among individual VSNs, a finding consistent with the pattern of FPR-rs expression across the vomeronasal epithelium. This arrangement would ensure that VSNs can discriminate between different FPR-rs agonists, while at the same time allowing for the detection of diverse chemical stimuli. A similar strategy is seen in the retina, which uses several related GPCRs called opsins to detect light. The different opsins have overlapping spectral tuning curves that permit the detection of light across the visual spectrum. Furthermore, the non-overlapping expression of these different opsins in subsets of retinal photoreceptors, each with distinct connections to the brain, contributes to our ability to discriminate colour.
Rivière et al.3 provide compelling evidence for a class of olfactory receptor that is expressed in a unique subpopulation of VSNs and that is responsive to novel chemosensory stimuli. However, it will be essential to show that behavioural or physiological responses to the presence of pathogens, spoiled food or diseased animals depend on activation of this group of VSNs before we can firmly conclude that they are part of an olfactory subsystem dedicated to discerning pathogenicity or health status.
Intriguingly, there are already clues that some FPR-rs-expressing VSNs may have disparate chemosensory roles. Four FPR-rs proteins are restricted to VSNs found in the apical zone of the vomeronasal epithelium, whereas one (FPR-rs1) is instead found only in VSNs of the basal zone (Fig. 1b). The segregation of these two VSN populations, which can be identified by the G-protein subunits they express, is maintained in the olfactory part of the brain (Fig. 1b), suggesting that the apical and basal VSNs encode different types of chemosensory information5,6. Thus, stimuli that can activate both FPR-rs1 and at least one other FPR-rs protein could evoke two distinct perceptions, behavioural responses or physiological changes. There is evidence in the main olfactory system that the sensory information extracted from the same odour compound differs depending on which cells detect it11. Similar strategies may be at work in the accessory olfactory system.
The nose is a busy place for researchers right now, with the discovery of several families of olfactory receptors and a multitude of distinct sensory cell types. As the biological roles of individual olfactory subsystems are elucidated, we can begin to truly understand how animals detect and dissect their complex chemosensory worlds.