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Trends in Neurosciences Jan 2023The mechanisms of olfactory dysfunction in COVID-19 are still unclear. In this review, we examine potential mechanisms that may explain why the sense of smell is lost or... (Review)
Review
The mechanisms of olfactory dysfunction in COVID-19 are still unclear. In this review, we examine potential mechanisms that may explain why the sense of smell is lost or altered. Among the current hypotheses, the most plausible is that death of infected support cells in the olfactory epithelium causes, besides altered composition of the mucus, retraction of the cilia on olfactory receptor neurons, possibly because of the lack of support cell-derived glucose in the mucus, which powers olfactory signal transduction within the cilia. This mechanism is consistent with the rapid loss of smell with COVID-19, and its rapid recovery after the regeneration of support cells. Host immune responses that cause downregulation of genes involved in olfactory signal transduction occur too late to trigger anosmia, but may contribute to the duration of the olfactory dysfunction.
Topics: Humans; COVID-19; Smell; SARS-CoV-2; Olfaction Disorders; Olfactory Mucosa
PubMed: 36470705
DOI: 10.1016/j.tins.2022.11.003 -
Neuroscience Letters Mar 2021Patients with COVID-19 often complain of smell and taste disorders (STD). STD emerge early in the course of the disease, seem to be more common in SARS-CoV-2 infection... (Review)
Review
Patients with COVID-19 often complain of smell and taste disorders (STD). STD emerge early in the course of the disease, seem to be more common in SARS-CoV-2 infection than in other upper respiratory tract infections, and could in some cases persist for long after resolution of respiratory symptoms. Current evidence suggests that STD probably result from a loss of function of olfactory sensory neurons and taste buds, mainly caused by infection, inflammation, and subsequent dysfunction of supporting non-neuronal cells in the mucosa. However, the possible occurrence of other mechanisms leading to chemosensory dysfunction has also been hypothesized, and contrasting data have been reported regarding the direct infection of sensory neurons by SARS-CoV-2. In this mini-review, we summarize the currently available literature on pathogenesis, clinical manifestations, diagnosis, and outcomes of STD in COVID-19 and discuss possible future directions of research on this topic.
Topics: COVID-19; Humans; Mouth Mucosa; Olfaction Disorders; Olfactory Mucosa; Olfactory Receptor Neurons; SARS-CoV-2; Smell; Taste; Taste Buds; Taste Disorders
PubMed: 33600902
DOI: 10.1016/j.neulet.2021.135694 -
Cell Aug 2022Aedes aegypti mosquitoes are a persistent human foe, transmitting arboviruses including dengue when they feed on human blood. Mosquitoes are intensely attracted to body...
Aedes aegypti mosquitoes are a persistent human foe, transmitting arboviruses including dengue when they feed on human blood. Mosquitoes are intensely attracted to body odor and carbon dioxide, which they detect using ionotropic chemosensory receptors encoded by three large multi-gene families. Genetic mutations that disrupt the olfactory system have modest effects on human attraction, suggesting redundancy in odor coding. The canonical view is that olfactory sensory neurons each express a single chemosensory receptor that defines its ligand selectivity. We discovered that Ae. aegypti uses a different organizational principle, with many neurons co-expressing multiple chemosensory receptor genes. In vivo electrophysiology demonstrates that the broad ligand-sensitivity of mosquito olfactory neurons depends on this non-canonical co-expression. The redundancy afforded by an olfactory system in which neurons co-express multiple chemosensory receptors may increase the robustness of the mosquito olfactory system and explain our long-standing inability to disrupt the detection of humans by mosquitoes.
Topics: Aedes; Animals; Humans; Ligands; Odorants; Olfactory Receptor Neurons
PubMed: 35985288
DOI: 10.1016/j.cell.2022.07.024 -
Science (New York, N.Y.) Nov 2020The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is...
The causative agent of coronavirus disease 2019 (COVID-19) is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). For many viruses, tissue tropism is determined by the availability of virus receptors and entry cofactors on the surface of host cells. In this study, we found that neuropilin-1 (NRP1), known to bind furin-cleaved substrates, significantly potentiates SARS-CoV-2 infectivity, an effect blocked by a monoclonal blocking antibody against NRP1. A SARS-CoV-2 mutant with an altered furin cleavage site did not depend on NRP1 for infectivity. Pathological analysis of olfactory epithelium obtained from human COVID-19 autopsies revealed that SARS-CoV-2 infected NRP1-positive cells facing the nasal cavity. Our data provide insight into SARS-CoV-2 cell infectivity and define a potential target for antiviral intervention.
Topics: Angiotensin-Converting Enzyme 2; Animals; Antibodies, Monoclonal; Betacoronavirus; COVID-19; Caco-2 Cells; Coronavirus Infections; Female; HEK293 Cells; Host Microbial Interactions; Humans; Lung; Male; Metal Nanoparticles; Mice; Mice, Inbred C57BL; Mutation; Neuropilin-1; Neuropilin-2; Olfactory Mucosa; Pandemics; Peptide Fragments; Peptidyl-Dipeptidase A; Pneumonia, Viral; Protein Binding; Protein Domains; Respiratory Mucosa; SARS-CoV-2; Serine Endopeptidases; Spike Glycoprotein, Coronavirus; Virus Internalization
PubMed: 33082293
DOI: 10.1126/science.abd2985 -
Nature Neuroscience Mar 2020The presence of active neurogenic niches in adult humans is controversial. We focused attention to the human olfactory neuroepithelium, an extracranial site supplying...
The presence of active neurogenic niches in adult humans is controversial. We focused attention to the human olfactory neuroepithelium, an extracranial site supplying input to the olfactory bulbs of the brain. Using single-cell RNA sequencing analyzing 28,726 cells, we identified neural stem cell and neural progenitor cell pools and neurons. Additionally, we detailed the expression of 140 olfactory receptors. These data from the olfactory neuroepithelium niche provide evidence that neuron production may continue for decades in humans.
Topics: Adult; Aging; Humans; Neural Stem Cells; Neurogenesis; Olfactory Mucosa; Olfactory Receptor Neurons; Sequence Analysis, RNA; Single-Cell Analysis; Smell
PubMed: 32066986
DOI: 10.1038/s41593-020-0587-9 -
Cell Oct 2022Olfactory sensory neurons (OSNs) convert the stochastic choice of one of >1,000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific...
Olfactory sensory neurons (OSNs) convert the stochastic choice of one of >1,000 olfactory receptor (OR) genes into precise and stereotyped axon targeting of OR-specific glomeruli in the olfactory bulb. Here, we show that the PERK arm of the unfolded protein response (UPR) regulates both the glomerular coalescence of like axons and the specificity of their projections. Subtle differences in OR protein sequences lead to distinct patterns of endoplasmic reticulum (ER) stress during OSN development, converting OR identity into distinct gene expression signatures. We identify the transcription factor Ddit3 as a key effector of PERK signaling that maps OR-dependent ER stress patterns to the transcriptional regulation of axon guidance and cell-adhesion genes, instructing targeting precision. Our results extend the known functions of the UPR from a quality-control pathway that protects cells from misfolded proteins to a sensor of cellular identity that interprets physiological states to direct axon wiring.
Topics: Animals; Axons; Endoplasmic Reticulum Stress; Mice; Olfactory Bulb; Olfactory Receptor Neurons; Receptors, Odorant; Transcription Factors
PubMed: 36167070
DOI: 10.1016/j.cell.2022.08.025 -
Cell Nov 2021Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction...
Anosmia, the loss of smell, is a common and often the sole symptom of COVID-19. The onset of the sequence of pathobiological events leading to olfactory dysfunction remains obscure. Here, we have developed a postmortem bedside surgical procedure to harvest endoscopically samples of respiratory and olfactory mucosae and whole olfactory bulbs. Our cohort of 85 cases included COVID-19 patients who died a few days after infection with SARS-CoV-2, enabling us to catch the virus while it was still replicating. We found that sustentacular cells are the major target cell type in the olfactory mucosa. We failed to find evidence for infection of olfactory sensory neurons, and the parenchyma of the olfactory bulb is spared as well. Thus, SARS-CoV-2 does not appear to be a neurotropic virus. We postulate that transient insufficient support from sustentacular cells triggers transient olfactory dysfunction in COVID-19. Olfactory sensory neurons would become affected without getting infected.
Topics: Aged; Anosmia; Autopsy; COVID-19; Endoscopy; Female; Glucuronosyltransferase; Humans; Immunohistochemistry; In Situ Hybridization; Male; Microscopy, Fluorescence; Middle Aged; Olfaction Disorders; Olfactory Bulb; Olfactory Mucosa; Olfactory Receptor Neurons; Respiratory Mucosa; Respiratory System; SARS-CoV-2; Smell
PubMed: 34798069
DOI: 10.1016/j.cell.2021.10.027 -
Cell Stem Cell Oct 2019Although olfactory mucosa possesses long-lived horizontal basal stem cells (HBCs) and remarkable regenerative capacity, the function of human olfactory neuroepithelium...
Although olfactory mucosa possesses long-lived horizontal basal stem cells (HBCs) and remarkable regenerative capacity, the function of human olfactory neuroepithelium is significantly impaired in chronic inflammatory rhinosinusitis. Here, we show that, while inflammation initially damages olfactory neurons and activates HBC-mediated regeneration, continued inflammation locks HBCs in an undifferentiated state. Global gene expression in mouse HBCs reveals broad upregulation of NF-κB-regulated cytokines and chemokines including CCL19, CCL20, and CXCL10, accompanied by enhancement of "stemness"-related transcription factors. Loss-of-function studies identify an NF-κB-dependent role of HBCs in amplifying inflammatory signaling, contributing to macrophage and T cell local proliferation. Chronically activated HBCs signal macrophages to maintain immune defense and prevent Treg development. In diseased human olfactory tissue, activated HBCs in a P63 undifferentiated state similarly contribute to inflammation through chemokine production. These observations establish a mechanism of chronic rhinosinusitis-associated olfactory loss, caused by a functional switch of neuroepithelial stem cells from regeneration to immune defense.
Topics: Animals; Cell Differentiation; Cell Proliferation; Cell Self Renewal; Cells, Cultured; Chronic Disease; Humans; Immunity; Inflammation; Mice; Mice, Transgenic; NF-kappa B; Neurons; Olfactory Mucosa; Regeneration; Rhinitis; Sinusitis; Stem Cells
PubMed: 31523027
DOI: 10.1016/j.stem.2019.08.011 -
Physiological Reviews Oct 2023Anosmia, the loss of the sense of smell, is one of the main neurological manifestations of COVID-19. Although the SARS-CoV-2 virus targets the nasal olfactory... (Review)
Review
Anosmia, the loss of the sense of smell, is one of the main neurological manifestations of COVID-19. Although the SARS-CoV-2 virus targets the nasal olfactory epithelium, current evidence suggests that neuronal infection is extremely rare in both the olfactory periphery and the brain, prompting the need for mechanistic models that can explain the widespread anosmia in COVID-19 patients. Starting from work identifying the non-neuronal cell types that are infected by SARS-CoV-2 in the olfactory system, we review the effects of infection of these supportive cells in the olfactory epithelium and in the brain and posit the downstream mechanisms through which sense of smell is impaired in COVID-19 patients. We propose that indirect mechanisms contribute to altered olfactory system function in COVID-19-associated anosmia, as opposed to neuronal infection or neuroinvasion into the brain. Such indirect mechanisms include tissue damage, inflammatory responses through immune cell infiltration or systemic circulation of cytokines, and downregulation of odorant receptor genes in olfactory sensory neurons in response to local and systemic signals. We also highlight key unresolved questions raised by recent findings.
Topics: Anosmia; Humans; COVID-19; Olfactory Receptor Neurons; Animals; SARS-CoV-2
PubMed: 37342077
DOI: 10.1152/physrev.00012.2023