Biosynthetic proteins targeting the SARS-CoV-2 spike as anti-virals.

The binding of the SARS-CoV-2 spike to angiotensin-converting enzyme 2 (ACE2) promotes virus entry into the cell. Targeting this interaction represents a promising strategy to generate antivirals. By screening a phage-display library of biosynthetic protein sequences build on a rigid alpha-helicoidal HEAT-like scaffold (named αReps), we selected candidates recognizing the spike receptor binding domain (RBD). Two of them (F9 and C2) bind the RBD with affinities in the nM range, displaying neutralisation activity in vitro and recognizing distinct sites, F9 overlapping the ACE2 binding motif. The F9-C2 fusion protein and a trivalent αRep form (C2-foldon) display 0.1 nM affinities and EC50 of 8-18 nM for neutralization of SARS-CoV-2. In hamsters, F9-C2 instillation in the nasal cavity before or during infections effectively reduced the replication of a SARS-CoV-2 strain harbouring the D614G mutation in the nasal epithelium. Furthermore, F9-C2 and/or C2-foldon effectively neutralized SARS-CoV-2 variants (including delta and omicron variants) with EC50 values ranging from 13 to 32 nM. With their high stability and their high potency against SARS-CoV-2 variants, αReps provide a promising tool for SARS-CoV-2 therapeutics to target the nasal cavity and mitigate virus dissemination in the proximal environment.

Early corticosteroid treatment enhances recovery from SARS-CoV-2 induced loss of smell in hamster.

Among the numerous long COVID symptoms, olfactory dysfunction persists in ∼10 % of patients suffering from SARS-CoV-2 induced anosmia. Among the few potential therapies, corticoid treatment has been used for its anti-inflammatory effect with mixed success in patients. In this study, we explored its impact using hamster as an animal model. SARS-CoV-2 infected hamsters lose their smell abilities and this loss is correlated with damage of the olfactory epithelium and persistent presence of innate immunity cells. We started a dexamethasone treatment 2 days post infection, when olfaction was already impacted, until 11 days post infection when it started to recover. We observed an improvement of olfactory capacities in the animals treated with corticoid compared to those treated with vehicle. This recovery was not related to differences in the remaining damage to the olfactory epithelium, which was similar in both groups. This improvement was however correlated with a reduced inflammation in the olfactory epithelium with a local increase of the mature olfactory neuron population. Surprisingly, at 11 days post infection, we observed an increased and disorganized presence of immature olfactory neurons, especially in persistent inflammatory zones of the epithelium. This unusual population of immature olfactory neurons coincided with a strong increase of olfactory epithelium proliferation in both groups. Our results indicate that persistent inflammation of the olfactory epithelium following SARS-CoV-2 infection may alter the extent and speed of regeneration of the olfactory neuron population, and that corticoid treatment is effective to limit inflammation and improve olfaction recovery following SARS-CoV-2 infection.

A stochastic lipid structured model for macrophage dynamics in atherosclerotic plaques.

We propose to model certain aspects of the dynamics of a macrophage that moves randomly in a one dimensional space in arterial wall tissue and grows by accumulating localized lipid particles, thus reducing its motility. This phenomenon has been observed in the context of atherosclerotic plaque formation. For this purpose, we use a system of stochastic differential equations satisfied by the position and diffusion coefficient of a Brownian particle whose diffusion coefficient is modified at each visit to the origin and with a dumping coefficient. The novelty of the model, with respect to Bénichou et al. (Phys Rev E 85(2):021137, 2012), Meunier et al. (Acta Appl Math 161:107-126, 2019), is to include offloading of lipids through the dumping term. We find explicit necessary and sufficient conditions for macrophage trapping in the locally enriched region.

Neutrophils play a major role in the destruction of the olfactory epithelium during SARS-CoV-2 infection in hamsters.

The loss of smell (anosmia) related to SARS-CoV-2 infection is one of the most common symptoms of COVID-19. Olfaction starts in the olfactory epithelium mainly composed of olfactory sensory neurons surrounded by supporting cells called sustentacular cells. It is now clear that the loss of smell is related to the massive infection by SARS-CoV-2 of the sustentacular cells in the olfactory epithelium leading to its desquamation. However, the molecular mechanism behind the destabilization of the olfactory epithelium is less clear. Using golden Syrian hamsters infected with an early circulating SARS-CoV-2 strain harboring the D614G mutation in the spike protein; we show here that rather than being related to a first wave of apoptosis as proposed in previous studies, the innate immune cells play a major role in the destruction of the olfactory epithelium. We observed that while apoptosis remains at a low level in the damaged area of the infected epithelium, the latter is invaded by Iba1+ cells, neutrophils and macrophages. By depleting the neutrophil population or blocking the activity of neutrophil elastase-like proteinases, we could reduce the damage induced by the SARS-CoV-2 infection. Surprisingly, the impairment of neutrophil activity led to a decrease in SARS-CoV-2 infection levels in the olfactory epithelium. Our results indicate a counterproductive role of neutrophils leading to the release of infected cells in the lumen of the nasal cavity and thereby enhanced spreading of the virus in the early phase of the SARS-CoV-2 infection.

Dual role of DMXL2 in olfactory information transmission and the first wave of spermatogenesis.

Gonad differentiation is a crucial step conditioning the future fertility of individuals and most of the master genes involved in this process have been investigated in detail. However, transcriptomic analyses of developing gonads from different animal models have revealed that hundreds of genes present sexually dimorphic expression patterns. DMXL2 was one of these genes and its function in mammalian gonads was unknown. We therefore investigated the phenotypes of total and gonad-specific Dmxl2 knockout mouse lines. The total loss-of-function of Dmxl2 was lethal in neonates, with death occurring within 12 hours of birth. Dmxl2-knockout neonates were weak and did not feed. They also presented defects of olfactory information transmission and severe hypoglycemia, suggesting that their premature death might be due to global neuronal and/or metabolic deficiencies. Dmxl2 expression in the gonads increased after birth, during follicle formation in females and spermatogenesis in males. DMXL2 was detected in both the supporting and germinal cells of both sexes. As Dmxl2 loss-of-function was lethal, only limited investigations of the gonads of Dmxl2 KO pups were possible. They revealed no major defects at birth. The gonadal function of Dmxl2 was then assessed by conditional deletions of the gene in gonadal supporting cells, germinal cells, or both. Conditional Dmxl2 ablation in the gonads did not impair fertility in males or females. By contrast, male mice with Dmxl2 deletions, either throughout the testes or exclusively in germ cells, presented a subtle testicular phenotype during the first wave of spermatogenesis that was clearly detectable at puberty. Indeed, Dmxl2 loss-of-function throughout the testes or in germ cells only, led to sperm counts more than 60% lower than normal and defective seminiferous tubule architecture. Transcriptomic and immunohistochemichal analyses on these abnormal testes revealed a deregulation of Sertoli cell phagocytic activity related to germ cell apoptosis augmentation. In conclusion, we show that Dmxl2 exerts its principal function in the testes at the onset of puberty, although its absence does not compromise male fertility in mice.

Modulation of olfactory signal detection in the olfactory epithelium: focus on the internal and external environment, and the emerging role of the immune system.

Detection and discrimination of odorants by the olfactory system plays a pivotal role in animal survival. Olfactory-based behaviors must be adapted to an ever-changing environment. Part of these adaptations includes changes of odorant detection by olfactory sensory neurons localized in the olfactory epithelium. It is now well established that internal signals such as hormones, neurotransmitters, or paracrine signals directly affect the electric activity of olfactory neurons. Furthermore, recent data have shown that activity-dependent survival of olfactory neurons is important in the olfactory epithelium. Finally, as olfactory neurons are directly exposed to environmental toxicants and pathogens, the olfactory epithelium also interacts closely with the immune system leading to neuroimmune modulations. Here, we review how detection of odorants can be modulated in the vertebrate olfactory epithelium. We choose to focus on three cellular types of the olfactory epithelium (the olfactory sensory neuron, the sustentacular and microvillar cells) to present the diversity of modulation of the detection of odorant in the olfactory epithelium. We also present some of the growing literature on the importance of immune cells in the functioning of the olfactory epithelium, although their impact on odorant detection is only just beginning to be unravelled.

The olfactory nerve is not a likely route to brain infection in COVID-19: a critical review of data from humans and animal models.

One of the most frequent symptoms of COVID-19 is the loss of smell and taste. Based on the lack of expression of the virus entry proteins in olfactory receptor neurons, it was originally assumed that the new coronavirus (severe acute respiratory syndrome coronavirus 2, SARS-CoV-2) does not infect olfactory neurons. Recent studies have reported otherwise, opening the possibility that the virus can directly infect the brain by traveling along the olfactory nerve. Multiple animal models have been employed to assess mechanisms and routes of brain infection of SARS-CoV-2, often with conflicting results. We here review the current evidence for an olfactory route to brain infection and conclude that the case for infection of olfactory neurons is weak, based on animal and human studies. Consistent brain infection after SARS-CoV-2 inoculation in mouse models is only seen when the virus entry proteins are expressed abnormally, and the timeline and progression of rare neuro-invasion in these and in other animal models points to alternative routes to the brain, other than along the olfactory projections. COVID-19 patients can be assured that loss of smell does not necessarily mean that the SARS-CoV-2 virus has gained access to and has infected their brains.

Respiratory syncytial virus tropism for olfactory sensory neurons in mice.

The olfactory mucosa, where the first step of odor detection occurs, is a privileged pathway for environmental toxicants and pathogens toward the central nervous system. Indeed, some pathogens can infect olfactory sensory neurons including their axons projecting to the olfactory bulb allowing them to bypass the blood-brain barrier and reach the central nervous system (CNS) through the so-called olfactory pathway. The respiratory syncytial virus (RSV) is a major respiratory tract pathogen but there is growing evidence that RSV may lead to CNS impairments. However, the mechanisms involved in RSV entering into the CNS have been poorly described. In this study, we wanted to explore the capacity of RSV to reach the CNS via the olfactory pathway and to better characterize RSV cellular tropism in the nasal cavity. We first explored the distribution of RSV infectious sites in the nasal cavity by in vivo bioluminescence imaging and a tissue clearing protocol combined with deep-tissue imaging and 3D image analyses. This whole tissue characterization was confirmed with immunohistochemistry and molecular biology approaches. Together, our results provide a novel 3D atlas of mouse nasal cavity anatomy and show that RSV can infect olfactory sensory neurons giving access to the central nervous system by entering the olfactory bulb. Cover Image for this issue: doi: 10.1111/jnc.14765.

The olfactory mucosa, first actor of olfactory detection, is sensitive to glucocorticoid hormone.

The olfactory mucosa (OM) is the primary site of odorant detection, and its axonal projections relay information to brain structures for signal processing. We have previously observed that olfactory function can be affected during a prolonged stress challenge in Wistar rats. The stress response is a neuroendocrine retro-controlled loop allowing pleiotropic adaptive tissue alterations, which are partly mediated through the release of glucocorticoid hormones. We hypothesised that, as part of their wide-ranging pleiotropic effects, glucocorticoids might affect the first step of olfactory detection. To study this, we used a number of approaches ranging from the molecular detection and functional characterisation of glucocorticoid receptors (GRs) in OM cells, to the study of GR acute activation in vivo at the molecular, electrophysiological and behavioural levels. In contrast to previous reports, where GR was reported to be exclusive in olfactory sensory neurones, we located functional GR expression mostly in olfactory ensheathing cells. Dexamethasone (2 mg/kg) was injected intraperitoneally to activate GR in vivo, and this led to functional odorant electrophysiological response (electro-olfactogram) and OM gene expression changes. In a habituation/cross-habituation test of olfactory sensitivity, we observed that DEX-treated rats exhibited higher responsiveness to a complex odorant mixture. These findings support the idea that olfactory perception is altered in stressed animals, as glucocorticoids might enhance odour detection, starting at the first step of detection.

Massive transient damage of the olfactory epithelium associated with infection of sustentacular cells by SARS-CoV-2 in golden Syrian hamsters.

Anosmia is one of the most prevalent symptoms of SARS-CoV-2 infection during the COVID-19 pandemic. However, the cellular mechanism behind the sudden loss of smell has not yet been investigated. The initial step of odour detection takes place in the pseudostratified olfactory epithelium (OE) mainly composed of olfactory sensory neurons surrounded by supporting cells known as sustentacular cells. The olfactory neurons project their axons to the olfactory bulb in the central nervous system offering a potential pathway for pathogens to enter the central nervous system by bypassing the blood brain barrier. In the present study, we explored the impact of SARS-CoV-2 infection on the olfactory system in golden Syrian hamsters. We observed massive damage of the OE as early as 2 days post nasal instillation of SARS-CoV-2, resulting in a major loss of cilia necessary for odour detection. These damages were associated with infection of a large proportion of sustentacular cells but not of olfactory neurons, and we did not detect any presence of the virus in the olfactory bulbs. We observed massive infiltration of immune cells in the OE and lamina propria of infected animals, which may contribute to the desquamation of the OE. The OE was partially restored 14 days post infection. Anosmia observed in COVID-19 patient is therefore likely to be linked to a massive and fast desquamation of the OE following sustentacular cells infection with SARS-CoV-2 and subsequent recruitment of immune cells in the OE and lamina propria.

IL-17c is involved in olfactory mucosa responses to Poly(I:C) mimicking virus presence.

At the interface of the environment and the nervous system, the olfactory mucosa (OM) is a privileged pathway for environmental toxicants and pathogens towards the central nervous system. The OM is known to produce antimicrobial and immunological components but the mechanisms of action of the immune system on the OM remain poorly explored. IL-17c is a potent mediator of respiratory epithelial innate immune responses, whose receptors are highly expressed in the OM of mice. We first characterized the presence of the IL-17c and its receptors in the OM. While IL-17c was weakly expressed in the control condition, it was strongly expressed in vivo after intranasal administration of polyinosinic-polycytidylic (Poly I:C), a Toll Like Receptor 3 agonist, mimicking a viral infection. Using calcium imaging and electrophysiological recordings, we found that IL-17c can effectively activate OM cells through the release of ATP. In the longer term, intranasal chronic instillations of IL-17c increased the cellular dynamics of the epithelium and promoted immune cells infiltrations. Finally, IL-17c decreased cell death induced by Poly(I:C) in an OM primary culture. The OM is thus a tissue highly responsive to immune mediators, proving its central role as a barrier against airway pathogens.

A stochastic model for cell adhesion to the vascular wall.

Cell dynamics in the vicinity of the vascular wall involves several factors of mechanical or biochemical origins. It is driven by the competition between the drag force of the blood flow and the resistive force generated by the bonds created between the circulating cell and the endothelial wall. Here, we propose a minimal mathematical model for the adhesive interaction between a circulating cell and the blood vessel wall in shear flow when the cell shape is neglected. The bond dynamics in cell adhesion is modeled as a nonlinear Markovian Jump process that takes into account the growth of adhesion complexes. Performing scaling limits in the spirit of Joffe and Metivier (Adv Appl Probab 18(1):20, 1986), Ethier and Kurtz (Markov processes: characterization and convergence, Wiley, New York, 2009), we obtain deterministic and stochastic continuous models, whose analysis allow to identify a threshold shear velocity associated with the transition from cell rolling and firm adhesion. We also give an estimation of the mean stopping time of the cell resulting from this dynamics. We believe these results can have strong implications for the understanding of major biological phenomena such as cell immunity and metastatic development.

Where is the TMT? GC-MS analyses of fox feces and behavioral responses of rats to fear-inducing odors.

TMT (2,5-dihydro-2,4,5-trimethylthiazoline) is known as a component of fox feces inducing fear in rodents. However, no recent chemical analyses of fox feces are available, and few studies make direct comparisons between TMT and fox feces. Fox feces from 3 individuals were used to prepare 24 samples to be analyzed for the presence of TMT using gas chromatography-mass spectrometry (GC-MS). When TMT was added in low amounts (50-2000 nmol/g), TMT was detected in 10 out of 11 samples. When no TMT was added, TMT was detected in only 1 out of 13 samples. In a second experiment, we tested the behavioral response of male Brown Norway (BN) and Wistar rats to either fox feces, a low amount of TMT (0.6 nmol) or 1-hexanol. TMT induced freezing in the rats, but fox feces induced significantly more freezing episodes and longer total duration of freezing in both rat strains. In experiment 3, male BN rats were exposed over several days to fox feces, rat feces, 1-hexanol, cadaverine, 2-phenylethylamine, and TMT, one odor at a time. Fox feces induced significantly more freezing episodes of a longer total duration than any of the other odors, with rat feces and 1-hexanol giving rise to the lowest amount of freezing. This finding, together with our inability to verify the presence of TMT in fox feces, indicates that the concentration of TMT in our fox feces samples was below 50 nmol/g. It may also be that other compounds in fox feces play a role in its fear-inducing properties.

A 1D model of leukocyte adhesion coupling bond dynamics with blood velocity.

Cell adhesion on the vascular wall is a highly coupled process where blood flow and adhesion dynamics are closely linked. Cell dynamics in the vicinity of the vascular wall is driven mechanically by the competition between the drag force of the blood flow and the force exerted by the bonds created between the cell and the wall. Bonds exert a friction force. Here, we propose a mathematical model of such a competitive system, namely leukocytes whose capacity to create bonds with the vascular wall and transmigratory ability are coupled by integrins and chemokines. The model predicts that this coupling gives rise to a dichotomic cell dynamic, whereby cells switch from sliding to firm arrest, through non linear effects. Cells can then transmigrate through the wall. These predicted dynamic regimes are compared to in-vitro trajectories of leukocytes. We expect that competition between friction and drag force in particle dynamics (such as shear stress-controlled nanoparticle capture) can lead to similar dichotomic mode.

Daily oscillation of odorant detection in rat olfactory epithelium.

Most of biological variables follow a daily rhythm. It holds true as well for sensory capacities as two decades of research have demonstrated that the odorant induced activity in the olfactory bulbs oscillates during the day. Olfactory bulbs are the first central nervous system structures, which receive inputs from the olfactory neurons located in the nose olfactory epithelium in vertebrates. So far, data on variation in odorant detection in the olfactory epithelium throughout the day are missing. Using electroolfactogram recordings in rats housed under daily light and dark cycles, we found that the olfactory epithelium responsiveness varies during the day with a maximum in the beginning of the light phase. This fluctuation was consistent with cycling of transduction pathway gene expression in the olfactory epithelium examined by qPCR. It was also consistent with the levels of two transduction pathway proteins (olfactory-type G protein and adenylyl cyclase III) examined by western blot. Daily variations were also observed at the level of olfactory sensory neurons responses recorded by patch-clamp. To rule out a potential effect of the feeding status of the animal, we examined the variation in odorant response in starved animals during the day. We observed a similar pattern to ad libidum fed animals. Taken together, our results reveal that the olfactory epithelium sensitivity varies during the day in part due to modulation of the very first step of odorant detection.

A Predictive Model for Yeast Cell Polarization in Pheromone Gradients.

Budding yeast cells exist in two mating types, a and α, which use peptide pheromones to communicate with each other during mating. Mating depends on the ability of cells to polarize up pheromone gradients, but cells also respond to spatially uniform fields of pheromone by polarizing along a single axis. We used quantitative measurements of the response of a cells to α-factor to produce a predictive model of yeast polarization towards a pheromone gradient. We found that cells make a sharp transition between budding cycles and mating induced polarization and that they detect pheromone gradients accurately only over a narrow range of pheromone concentrations corresponding to this transition. We fit all the parameters of the mathematical model by using quantitative data on spontaneous polarization in uniform pheromone concentration. Once these parameters have been computed, and without any further fit, our model quantitatively predicts the yeast cell response to pheromone gradient providing an important step toward understanding how cells communicate with each other.

Postnatal odorant exposure induces peripheral olfactory plasticity at the cellular level.

Mammalian olfactory sensory neurons (OSNs) form the primary elements of the olfactory system. Inserted in the olfactory mucosa lining of the nasal cavity, they are exposed to the environment and their lifespan is brief. Several reports say that OSNs are regularly regenerated during the entire life and that odorant environment affects the olfactory epithelium. However, little is known about the impact of the odorant environment on OSNs at the cellular level and more precisely in the context of early postnatal olfactory exposure. Here we exposed MOR23-green fluorescent protein (GFP) and M71-GFP mice to lyral or acetophenone, ligands for MOR23 or M71, respectively. Daily postnatal exposure to lyral induces plasticity in the population of OSNs expressing MOR23. Their density decreases after odorant exposure, whereas the amount of MOR23 mRNA and protein remain stable in the whole epithelium. Meanwhile, quantitative PCR indicates that each MOR23 neuron has higher levels of olfactory receptor transcripts and also expresses more CNGA2 and phosphodiesterase 1C, fundamental olfactory transduction pathway proteins. Transcript levels return to baseline after 4 weeks recovery. Patch-clamp recordings reveal that exposed MOR23 neurons respond to lyral with higher sensitivity and broader dynamic range while the responses' kinetics were faster. These effects are specific to the odorant-receptor pair lyral-MOR23: there was no effect of acetophenone on MOR23 neurons and no effect of acetophenone and lyral on the M71 population. Together, our results clearly demonstrate that OSNs undergo specific anatomical, molecular, and functional adaptation when chronically exposed to odorants in the early stage of life.

Endothelin uncouples gap junctions in sustentacular cells and olfactory ensheathing cells of the olfactory mucosa.

Several factors modulate the first step of odour detection in the rat olfactory mucosa (OM). Among others, vasoactive peptides such as endothelin might play multifaceted roles in the different OM cells. Like their counterparts in the central nervous system, the olfactory sensory neurons are encompassed by different glial-like non-neuronal OM cells; sustentacular cells (SCs) surround their cell bodies, whereas olfactory ensheathing cells (OECs) wrap their axons. Whereas SCs maintain both the structural and ionic integrity of the OM, OECs assure protection, local blood flow control and guiding of olfactory sensory neuron axons toward the olfactory bulb. We previously showed that these non-neuronal OM cells are particularly responsive to endothelin in vitro. Here, we confirmed that the endothelin system is strongly expressed in the OM using in situ hybridization. We then further explored the effects of endothelin on SCs and OECs using electrophysiological recordings and calcium imaging approaches on both in vitro and ex vivo OM preparations. Endothelin induced both robust calcium signals and gap junction uncoupling in both types of cells. This latter effect was mimicked by carbenoxolone, a known gap junction uncoupling agent. However, although endothelin is known for its antiapoptotic effect in the OM, the uncoupling of gap junctions by carbenoxolone was not sufficient to limit the cellular death induced by serum deprivation in OM primary culture. The functional consequence of the endothelin 1-induced reduction of the gap junctional communication between OM non-neuronal cells thus remains to be elucidated.

Using scalar products to refine the interpretative value of an orientation choice test.

Choice tests, which are often used to examine animal preferences, can be difficult to interpret when no clear choice has been made or when using very young animals which exclude test repetition. We present a new method to evaluate the behavior in a choice test based on the orientation of the animal and illustrate its use when facing those conditions. Using rat pups in an open field maze with a choice of odors, we obtained x,y coordinates of 2 markers (head and body center) using a video-tracking freeware. Two vectors were calculated: an animal orientation vector (body to head) and a perfect orientation vector (body to odor source). The angle between the 2 vectors in each frame was converted into a scalar product ranging from 1 (pup oriented directly towards the odor source) to -1 (facing the opposite direction). A mean scalar product was calculated for each odor source, with the difference between the 2 mean scalar products indicating degree of preference for an odor. The information provided by the mean scalar product difference (MSPD) could not be obtained from other measures, such as binary choice, velocity, or distance moved. The MSPD provides a single, noncategorical value for each animal to describe degree of preference in a choice test. This variable was more effective in differentiating animals, thus allowing a reduction in the number of animals or tests necessary to reach significance.

[Olfaction and respiratory viruses A relationship revealed by Covid-19]. / Odorat et virus respiratoires :une relation révélée par la Covid-19.

The sense of smell has been underestimated for a long time in humans. It has been brought to the fore by its sudden disappearance during the Covid-19 pandemic of which anosmia (complete loss of smell) is one of the major symptoms. However, respiratory viruses have long been associated with smell disorders, 25% of which are linked to a viral infection. Olfaction begins in the nose within the olfactory epithelium which has the particularity of containing neurons in direct contact with the environment. Several respiratory viruses are known for their replicative capacity within this epithelium. This is particularly the case for the flu virus (influenza) and bronchiolitis (respiratory syncytial virus) but their tropism for this tissue is much lower than SARS-CoV-2. The understanding of the SARS-CoV-2 pathophysiology in the nasal cavity makes it possible to reveal part of the links between viral infection and olfactory disorders.

Title: Odorat et virus respiratoires :une relation révélée par la Covid-19. Abstract: L'odorat, sens pendant longtemps sous-estimé chez l'homme, a été mis sur le devant de la scène par sa soudaine disparition, survenue pendant la pandémie de Covid-19, dont l'anosmie est un des symptômes majeurs. Pourtant, depuis longtemps, les virus respiratoires ont été associés aux troubles de l'odorat, dont 25 % seraient liés à une infection virale. L'olfaction débute dans le nez, au sein d'un épithélium olfactif qui a la particularité de contenir des neurones en contact direct avec l'environnement. Plusieurs virus respiratoires sont connus pour leur capacité réplicative au sein de cet épithélium. C'est notamment le cas du virus de la grippe (influenza) et du virus de la bronchiolite (VRS, pour virus respiratoire syncytial), mais leur tropisme pour ce tissu est bien moindre que celui du SARS-CoV-2. La physiopathologie de ce virus dans la cavité nasale a permis de commencer à comprendre les liens existant entre une infection virale et les troubles de l'olfaction.