Are Multiple Chemosensory Systems Accountable for COVID-19 Outcome?

Chemosensory systems (olfaction, taste, trigeminus nerve, solitary chemoreceptor cells, neuroendocrine pulmonary cells, and carotid body, etc.) detect molecules outside or inside our body and may share common molecular markers. In addition to the impairment of taste and olfaction, the detection of the internal chemical environment may also be incapacitated by COVID-19. If this is the case, different consequences can be expected. (1) In some patients, hypoxia does not trigger distressing dyspnea (“silent” hypoxia): Long-term follow-up may determine whether silent hypoxia is related to malfunctioning of carotid body chemoreceptors. Moreover, taste/olfaction and oxygen chemoreceptors may be hit simultaneously: Testing olfaction, taste, and oxygen chemoreceptor functions in the early stages of COVID-19 allows one to unravel their connections and trace the recovery path. (2) Solitary chemosensory cells are also involved in the regulation of the innate mucosal immune response: If these cells are affected in some COVID-19 patients, the mucosal innate immune response would be dysregulated, opening one up to massive infection, thus explaining why COVID-19 has lethal consequences in some patients. Similar to taste and olfaction, oxygen chemosensory function can be easily tested with a non-invasive procedure in humans, while functional tests for solitary chemosensory or pulmonary neuroendocrine cells are not available, and autoptic investigation is required to ascertain their involvement.

The Microvillar and Solitary Chemosensory Cells as the Novel Targets of Infection of SARS-CoV-2 in Syrian Golden Hamsters

Patients infected with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of coronavirus disease 2019, suffer from respiratory and non-respiratory symptoms. Among these symptoms, the loss of smell has attracted considerable attention. The objectives of this study were to determine which cells are infected, what happens in the olfactory system after viral infection, and how these pathologic changes contribute to olfactory loss. For this purpose, Syrian golden hamsters were used. First, we verified the olfactory structures in the nasal cavity of Syrian golden hamsters, namely the main olfactory epithelium, the vomeronasal organ, and their cellular components. Second, we found angiotensin-converting enzyme 2 expression, a receptor protein of SARS-CoV-2, in both structures and infections of supporting, microvillar, and solitary chemosensory cells. Third, we observed pathological changes in the infected epithelium, including reduced thickness of the mucus layer, detached epithelia, indistinct layers of epithelia, infiltration of inflammatory cells, and apoptotic cells in the overall layers. We concluded that a structurally and functionally altered microenvironment influences olfactory function. We observed the regeneration of the damaged epithelium, and found multilayers of basal cells, indicating that they were activated and proliferating to reconstitute the injured epithelium.

Transcriptional profiling reveals potential involvement of microvillous TRPM5-expressing cells in viral infection of the olfactory epithelium

BackgroundUnderstanding viral infection of the olfactory epithelium is essential because the olfactory nerve is an important route of entry for viruses to the central nervous system. Specialized chemosensory epithelial cells that express the transient receptor potential cation channel subfamily M member 5 (TRPM5) are found throughout the airways and intestinal epithelium and are involved in responses to viral infection.ResultsHerein we performed deep transcriptional profiling of olfactory epithelial cells sorted by flow cytometry based on the expression of mCherry as a marker for olfactory sensory neurons and for eGFP in OMP-H2B::mCherry/TRPM5-eGFP transgenic mice (Mus musculus). We find profuse expression of transcripts involved in inflammation, immunity and viral infection in TRPM5-expressing microvillous cells.ConclusionOur study provides new insights into a potential role for TRPM5-expressing microvillous cells in viral infection of the olfactory epithelium. We find that, as found for solitary chemosensory cells (SCCs) and brush cells in the airway epithelium, and for tuft cells in the intestine, the transcriptome of TRPM5-expressing microvillous cells indicates that they are likely involved in the inflammatory response elicited by viral infection of the olfactory epithelium.

Gingival solitary chemosensory cells are immune sentinels for periodontitis

Solitary chemosensory cells (SCCs) are epithelial sentinels that utilize bitter Tas2r receptors and coupled taste transduction elements to detect pathogenic bacterial metabolites, triggering host defenses to control the infection. Here we report that SCCs are present in mouse gingival junctional epithelium, where they express several Tas2rs and the taste signaling components α-gustducin (Gnat3), TrpM5, and Plcβ2. Gnat3−/− mice have altered commensal oral microbiota and accelerated naturally occurring alveolar bone loss. In ligature-induced periodontitis, knockout of taste signaling molecules or genetic absence of gingival SCCs (gSCCs) increases the bacterial load, reduces bacterial diversity, and renders the microbiota more pathogenic, leading to greater alveolar bone loss. Topical treatment with bitter denatonium to activate gSCCs upregulates the expression of antimicrobial peptides and ameliorates ligature-induced periodontitis in wild-type but not in Gnat3−/− mice. We conclude that gSCCs may provide a promising target for treating periodontitis by harnessing innate immunity to regulate the oral microbiome.

Development of solitary chemosensory cells in the distal lung after severe influenza injury

H1N1 influenza virus infection induces dramatic and permanent alveolar remodeling mediated by p63+ progenitor cell expansion in both mice and some patients with acute respiratory distress syndrome. This persistent lung epithelial dysplasia is accompanied by chronic inflammation, but the driver(s) of this pathology are unknown. This work identified de novo appearance of solitary chemosensory cells (SCCs), as defined by the tuft cell marker doublecortin-like kinase 1, in post-influenza lungs, arising in close proximity with the dysplastic epithelium, whereas uninjured lungs are devoid of SCCs. Interestingly, fate mapping demonstrated that these cells are derived from p63-expressing lineage-negative progenitors, the same cell of origin as the dysplastic epithelium. Direct activation of SCCs with denatonium + succinate increased plasma extravasation specifically in post-influenza virus-injured lungs. Thus we demonstrate the previously unrecognized development and activity of SCCs in the lung following influenza virus infection, implicating SCCs as a central feature of dysplastic remodeling.

Tuft Cells—Systemically Dispersed Sensory Epithelia Integrating Immune and Neural Circuitry

Tuft cells—rare solitary chemosensory cells in mucosal epithelia—are undergoing intense scientific scrutiny fueled by recent discovery of unsuspected connections to type 2 immunity. These cells constitute a conduit by which ligands from the external space are sensed via taste-like signaling pathways to generate outputs unique among epithelial cells: the cytokine IL-25, eicosanoids associated with allergic immunity, and the neurotransmitter acetylcholine. The classic type II taste cell transcription factor POU2F3 is lineage defining, suggesting a conceptualization of these cells as widely distributed environmental sensors with effector functions interfacing type 2 immunity and neural circuits. Increasingly refined single-cell analytics have revealed diversity among tuft cells that extends from nasal epithelia and type II taste cells to ex- Aire-expressing medullary thymic cells and small-intestine cells that mediate tissue remodeling in response to colonizing helminths and protists.