key: cord-1005704-ycl6ldva
authors: Okada, Yasuo; Yoshimura, Ken; Toya, Shuji; Tsuchimochi, Makoto
title: Pathogenesis of taste impairment and salivary dysfunction in COVID-19 patients
date: 2021-07-09
journal: Jpn Dent Sci Rev
DOI: 10.1016/j.jdsr.2021.07.001
sha: 5362ac35597bab9b97e4b59f1123812d4d31f302
doc_id: 1005704
cord_uid: ycl6ldva

Coronavirus disease 2019 (COVID 2019) is a highly transmissible pandemic disease caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The characteristics of the disease include a broad range of symptoms from mild to serious to death, with mild pneumonia to acute respiratory distress syndrome and complications in extrapulmonary organs. Taste impairment and salivary dysfunction are common early symptoms in COVID-19 patients. The mouth is a significant entry route for SARS-CoV-2, similar to the nose and eyes. The cells of the oral epithelium, taste buds, and minor and major salivary glands express cell entry factors for SARS-CoV-2, such as ACE2, TMPRSS2, and Furin. We describe the occurrence of taste impairment and salivary dysfunction in COVID-19 patients and show immunohistochemical findings regarding the cell entry factors in the oral tissue. We review and describe the pathogeneses of taste impairment and salivary dysfunction. Treatment for the oral disease is also described. Recently, it was reported that some people experience persistent and prolonged taste impairment and salivary dysfunction, described as post-COVID-19 syndrome or long COVID-19, after the acute illness of the infection has healed. To resolve these problems, it is important to understand the pathogenesis of oral complications. Recently, important advances have been reported in the understanding of gustatory impairment and salivary dysfunction. Although some progress has been made, considerable effort is still required for in-depth elucidation of the pathogenesis.

as a source. According to a telephone interview survey of patients in Greece by Printza et al. (2021) , the median time from the onset of COVID-19 to the survey in 150 patients was 61 days. Thirty-eight percent had gustatory disorders, of which 6% were mild, 21% moderate, 5% severe, and 61% very severe. Forty-two patients (79%) regained their sense of taste by 61 days [18] .

On the other hand, a cross-sectional study by Nouchi et al. (2020) reported that 29% of patients with olfactory or gustatory disorders still had persistent disease [19] . In a letter by Nguyen et al. (2021) , 200 patients were randomly selected and surveyed to evaluate their recovery rate at least 6 months after onset [20] . The results showed that of 125 patients with taste and smell disturbances during the acute phase of COVID- 19, 38.5% reported only partial recovery of taste, and 11.5% had no recovery at all. In addition, female patients (73.3%) were more likely to report persistent symptoms than male patients (26.7%), according to the study. This finding suggests that taste deprivation may be a possible sequelae of COVID-19 (Fig. 1A ).

The incidence of xerostomia in various reports was 50% [21] , 30% [22] , 74.5% [23] , 56% [24] , 47.6% [26] , and 46.3% [25] , with an average of approximately 50%. Although it is less common than olfactory dysfunction, nearly half of patients show this symptom, indicating that xerostomia is a trigger for deterioration of oral health status. There are few reports on the duration of xerostomia, but Eghbali Zarch et al. reported it to be 14 days [33] . SARS-CoV-2 is detected in saliva from the earliest stages, ACE2-positive salivary gland epithelial cells are the initial target of SARS-CoV-2, and salivary gland function may be affected in the early stages of infection [34] . In a cross-sectional study of 108 patients in Wuhan with confirmed COVID-19, 46% of patients complained of xerostomia as one of their symptoms [25] .

Oral symptoms may be the initial manifestation of COVID-19 before typical symptoms, such as fever, dry cough, fatigue, and shortness of breath, occur. There are few reports of xerostomia as a sequela after recovery from COVID-19 infection; Gherlone et al. reported that dry mouth was seen in 30% of COVID-19 patients at follow-up after recovery and was significantly associated with diabetes and chronic obstructive pulmonary disease (COPD) [32] .

Although there are a variety of therapeutic medicines for COVID-19, these drugs cause oral mucosal symptoms and xerostomia. For example, chloroquine/hydroxychloroquine, which is used for the treatment of malaria and certain autoimmune diseases, can cause allergic lichenoid reactions and xerostomia. The combination of lopinavir and ritonavir, both approved for the treatment of HIV, may be associated with side effects such as xerostomia, stomatitis, and oral ulcers. Interferon-β, a drug for multiple sclerosis, also can cause xerostomia as a side effect [35] (Fig. 1B) .

The human tongue has approximately 3,000 taste buds, with a vertical length of 50-80 μm and a horizontal length of 30-50 μm. Taste buds are composed of 50-90 cells in clusters, and the base is slightly wider than the apex [36] . Four cell types are present:

dark-toned cells (type I cells) occupy 50-70% of taste buds. Light-toned cells (type II cells) occupy 15-30% of the taste buds. Taste cells (type III) occupy 5-15% of the taste buds. Type IV cells (support cells) are present at the base of the taste buds [37] . The five basic tastes currently recognized are sweet, salty, sour, bitter, and umami. In particular, sweet, bitter, and umami are transmitted by G protein-coupled (GPC) receptors in taste buds [38] . A typical sweet stimulus is sucrose, a disaccharide. In 1999, Hoon et al.

identified two taste-specific GPC receptors, TR1 and TR2 (later referred to as Tas1r1 and Tas1r2) [39] . Tas1rs and Tas2rs are expressed separately in type II cells in the taste buds [40] .

Bitter taste receptors are diverse: according to a review by Meyerhof (2005) , approximately 30 families of TAS2R bitter taste receptors have been identified in mammals [41] . They have evolved through adaptive diversification and are linked to chromosomal loci known to influence bitterness in mice and humans. TAS2R widely detects several bitter substances, including amides and alkaloids such as strychnine, caffeine, and quinine, and certain amino acids, urea, fatty acids, phenols, amines, esters, and other compounds that can also induce bitterness. Furthermore, some mineral salts, such as potassium, magnesium, and calcium salts, can also taste bitter. Therefore, the J o u r n a l P r e -p r o o f persistence of bitterness in the loss of taste in COVID-19 may be explained by the fact that it is sensitive to a variety of substances.

The acceptance of umami taste is based on umami receptors, which are heterodimers composed of TAS1R1 (taste receptor type 1, member 1) and TAS1R3 [42] , which collectively detect several amino acids, such as umami-associated L-glutamate and 5'ribonucleotides [38] .

As for the reception of salty taste, it was found to be the passage of sodium ions through specific transport pathways in the apical region of taste buds [43] . Sodium chloride (NaCl) evokes salty taste via amiloride-sensitive and amiloride-insensitive mechanisms in taste cells [40] , and ENaC alpha (also known as SCNN1A) encodes a putative amiloride-sensitive salt taste receptor. However, the specific molecular features of cells mediating sodium-induced taste have not yet been well defined, although there are reports [44] that taste is mediated by type III cells in the taste buds. Similarly, acid taste perception is also mediated by type III cells in the taste buds. The involvement of amiloride-sensitive epithelial sodium channels (ENaC), GPR4, a proton-sensitive GPCR, and the transient receptor potential (TRP) family channel PKD2L1 and its related partner PKD1L3 has been shown, but the details are still unclear [38] .

The renin-angiotensin system (RAS) is a signaling pathway involved in the regulation of blood volume, natriuresis, blood pressure, blood flow, and homeostasis in response to various stimuli. It is a signaling pathway involved in regulation (homeostasis) [45] .

Updated RAS pathways, which include ACE2, are available in the following reference [46] . Generally, ACE2 metabolizes angiotensin I to angiotensin(1-9) or angiotensin II (Ang II) to angiotensin(1-7) (Ang (1-7)), which contribute to vasodilation. Moreover, ACE2 is known to convert angiotensin A to alamandine, an angiotensin-related peptide that contributes to aortic relaxation. Shigemura et al. [47] reported that ACE2, which metabolizes Ang II to Ang (1-7) and is encoded by the GPC receptor Mas and counteracts the effects of Ang II, was found not only in filiform and vallate papillae but also in the lingual epithelium [48] . These results suggest that ACE2 may be localized in taste buds.

These results further suggest that Ang II produced locally in taste buds is rapidly degraded by ACE2, supporting the hypothesis of short-term regulation of taste sensitivity (e.g., GPC receptors that are responsible for bitterness) by the local RAS.

J o u r n a l P r e -p r o o f

The glands that secrete saliva consist of the parotid, submandibular, and sublingual glands, which are called the three major salivary glands. In addition, there are minor salivary glands that are distributed throughout the submucosa of the oral cavity, excluding the gingiva and the anterior part of the hard palate [49, 50] . The parotid gland secretes serous saliva, the submandibular gland secretes a mixture of serous and mucous saliva, and the sublingual gland secretes predominantly mucous saliva. The minor salivary glands (with the exception of the lingual serous gland, known as Ebner's gland)

principally secrete mucous saliva [49, 50] . The salivary glands are controlled under the treatments for chronic xerostomia and salivary gland atrophy [49, 50] . Saliva has several mucosal protectant, buffering, tooth remineralization, antibacterial, tissue repair, digestive, and gustatory aid functions. When saliva production is reduced, oral mucosa and tooth protection, buffering, antibacterial, taste alteration, digestion, and tissue repair activities are diminished. Due to the lack of innate antimicrobial defenses, xerostomia increases the risk of tooth decay and bacterial and fungal infections [49, 50, 51] .

SARS-CoV-2 enters cells through host membrane-bound peptidases, ACE2 and TMPRSS2 (pathway I, Fig. 2 ). This entry mechanism is similar to that of SARS-CoV-1, which caused an outbreak of severe acute respiratory syndrome in 2003. Spike proteins J o u r n a l P r e -p r o o f of SARS-CoV-2 bind to ACE2 first as the receptor. The spike of the virus is a trimer of glycoproteins that consist of an S1 subunit and an S2 subunit. The S1 subunit contains an ACE2 recognition motif in the receptor-binding domain (RBD) [52] . After viral attachment to the host ACE2, the spike protein subunit S1 is proteolytically cleaved between the S1 and S2 domains (S1/S2) and disassociated by Furin, which is a proprotein convertase localized to the host cell membrane. Subsequently, TMPRSS2 cleaves the S2' site of the S2 subunit. These cleavages cause a series of conformational changes in the spike protein, and the structural change in the S2 subunit has an important role in membrane fusion, which results in transfer of the viral RNA into the host cell cytoplasm [53] [54] [55] [56] .

SARS-CoV-2 can utilize another entry route for infection (pathway II, Fig. 2 ), in which S1/S2 site cleavage of the spike protein prior to invading the host cell membrane is not required [57] . This endosomal route, clathrin-and non-clathrin-mediated endocytosis, is accomplished without plasma membrane proteases, such as TMPRSS2 [58, 59] . After severe acute respiratory syndrome coronavirus (SARS-CoV) binds to ACE2 and internalizes into endosomes, cathepsin L is essential for fusion between the virus envelope and the endosome vesicular membrane [58] . SARS-CoV-2 is also able to internalize and release its viral genome via this endosomal route.

Coronaviruses, including SARS-CoV-2, can enter host cells via both routes, with a preference for the cell surface pathway over the endosomal pathway [60, 61] . Many cell line-based studies show that the viral tropism of SARS-CoV-2 for various cell types likely reflects the differential expression of key host proteins involved in viral attachment and entry [61, 62] . The varying expression of the SARS-CoV-2 cellular receptor ACE2 and proteases, such as Furin, TMPRSS2, cathepsin L, elastase, and trypsin, affects the infectivity and clinical symptoms of the disease.

Coronaviruses have fewer mutations than most RNA viruses because they employ genetic proofreading machinery during replication. However, since the pandemic began infectivity and transmission [63, 64] . The D614G mutation has become common to nearly all variants. This mutation is likely to make spike proteins more or less able to bind ACE2.

The resulting conformational changes in the variants cause cell entry enhancement [65] ( Fig. 2 ).

The SARS-CoV-2 receptor on human cells is ACE2, which is the same as the SARS-CoV receptor [55, [66] [67] [68] [69] [70] . ACE2 is abundantly expressed in a variety of cells residing in many different human organs, such as the lung, small intestine, kidney, and skin [71, 72] .

Xu et al. reported the expression of ACE2 in oral tissue using a public RNA-sequencing database [8] . Since then, the expression of ACE2 in the oral mucosal epithelium has been reported, including in our report (31 of 36 cases, 86.1%) [9] [10] [11] [13] [14] [15] (Fig. 3B , F, J).

It has been reported that saliva is the cause of SARS-CoV-2 infection. This hypothesis suggests that oral tissue, including salivary glands, plays a role as an organ for viral growth in subclinical SARS-CoV-2 infections [73, 74] . Accordingly, the expression of ACE2 in the salivary glands (22 of 25 cases, 88.0%) and ducts (26 of 27 cases, 96.3%) has been reported, including in our report [9] [10] [11] [13] [14] [15] . We reported that ACE2 expression occurs in most of the serous cells but very few mucous cells [15] (Fig. 4B , F, J).

Expression of ACE2 in the taste buds of the tongue has been reported [9] . Han et al.

reported the single-cell profiles of tongue tissues with typical gene markers of taste buds, such as TAS1R3, TAS2R4, TAS2R14, SNAP25, and NCAM1. They reported that the distribution of ACE2-positive cells is correlated with that of taste-related gene-marked cells [12] . Type II taste cell marker genes include TAS1R2 and TAS1R3 for sweet taste, TAS1R1 and TAS1R3 for umami taste, and TAS2Rs for bitter taste, and type III taste cell marker genes include NCAM1 and SNAP25. The distribution of type II and type III J o u r n a l P r e -p r o o f marker genes in the tongue suggests the coexistence of ACE2 and individual taste cells [38, 75] . Wang reported that ACE2 is enriched in a subpopulation of epithelial cells in nongustatory filiform papillae but not in taste papillae or taste buds of adult mice [5] .

The expression of ACE2 in vascular endothelial cells and adipocytes has been reported [66, 71, 76] . We reported that ACE2 expression was found in capillary 

The expression of TMPRSS2 in the esophagus, jejunum and ileum has been reported [71] . It has been reported that TMPRSS2 is expressed in the oral mucosal epithelium and the salivary glands [6, 9, 13, 14] . The expression of TMPRSS2 was shown to be stronger in serous acini than in mucous acini [14] . TMPRSS2 expression has been reported to be positive in the salivary gland duct [9] . However, it has been reported that ACE2 expression is absent in the striated ducts [14] . The expression of TMPRSS2 in the taste buds of the tongue has been reported [9] . Our immunostaining revealed TMPRSS2 expression in the tongue, buccal and oral floor mucosal epithelium, serous glands, salivary gland ducts, vascular endothelial cells, and adipocytes (Fig. 3C , G, K, L, Fig. 4C , G, K).

The expression of Furin in the lachrymal glands, colon, liver, and kidneys has been reported [77] . It has been reported that Furin is expressed in the oral mucosal epithelium [7, 9] . The expression of Furin in the taste buds of the tongue and the salivary glands (serous glands) has been reported [9] . It has been reported that Furin is expressed in the endothelial cells of oral mucosal tissues [7] . Our immunohistochemical staining revealed ACE2 is expressed in the taste buds and the peripheral oral mucosa, stratified squamous epithelium of the dorsal tongue, and gingiva in humans [9] . In a mouse study, ACE2 mRNA was expressed in fungiform and circumvallate papillae [47] . Replication However, olfactory sensory neurons in the olfactory neuroepithelium showed an absence of ACE2 protein expression [84] . In a study of postmortem tissue from COVID-19

patients, quantitative PCR with reverse transcription, immunohistochemistry, and electron microscopy analyses revealed that viral RNA was most common in the olfactory mucosa, which is composed of the olfactory epithelium, olfactory neurons, sustentacular cells, Bowman's glands, and blood vessels. Electron microscopic analysis of the olfactory mucosa from one individual with a high viral RNA load revealed intact viral particles in the olfactory mucosa. Furthermore, SARS-CoV spike protein has been detected in olfactory sensory neurons, which do not express ACE2 [85, 86] . SARS-CoV-2 therefore infects the olfactory mucosa and possibly infects olfactory sensory neurons in an indirect manner (Fig. 5 ).

One possible mechanism is direct cell-to-cell viral transmission. The actin-myosin showed the presence of virus particles on their surface [88] . This finding may explain why non-ACE2-expressing gustatory cells are infected through ACE2-positive neighboring cells (Fig. 5 ).

It is known that human coronaviruses are neuroinvasive and neurotropic and can induce overactivation of the immune system [89, 90] .

Additionally, similar to pathogens of two preceding epidemics (SARS-CoV-1 and Middle

East respiratory syndrome coronavirus (MERS-CoV)), SARS-CoV-2 also exhibits neuroinvasion [91] . Neurological manifestations, ranging from anosmia, dysgeusia, headache, encephalitis, etc., in patients with COVID-19 are one of the main characteristics of the disease [92, 93] . SARS-CoV-2 infection may directly damage the nervous system in a cytopathic manner [94] . SARS-CoV-2 neuroinvasion can occur at the neural-mucosal interface by transmucosal entry via regional nervous structures [85, 95] . This mechanism may be the case for infection of gustatory neurons in the taste buds and subsequent alterations of taste perception. However, it remains to be confirmed whether this concept is applicable for direct neural invasion of SARS-CoV-2 [96, 97] (Fig.   5 ).

Viruses, including coronaviruses, can attach to the cilia of epithelial cells [98] .

An ultrastructural study regarding the nasal mucosal changes in common cold patients was reported. The loss of cilia and ciliated cells was found in a previous study [99] .

Another transmission electron microscopic study in a human subject showed that coronaviruses adhered to the microvilli and cilia in nasal epithelial cells [100] . In a SARS-CoV-2-inoculated macaque experiment, the virus antigen was present in ciliated nasal epithelial cells [101] . Murine leukemia virus, with a single-stranded RNA genome, can J o u r n a l P r e -p r o o f induce lateral movement along microvilli of polarized epithelial cells before cell entry [102] . Similar to nasal epithelial cells, taste cells possess microvilli at the apical end of the cells. The microvilli protrude from the pores of taste buds toward the oral cavity to capture tastants [103, 104] . It is presumed that microvilli of taste sensory cells allow SARS-CoV-2 entry into the cells (Fig. 5 ). 

Some patients suffer from a long-lasting impairment of smell and taste [18, 30, 31] .

Approximately 10% of patients in a two-month follow-up survey [18] and 11% of patients in a 6-month survey of infected individuals did not show any recovery, and only partial recovery was present in 30% of the cases [31] . It is interesting that for these chemosensory systems, smell and taste, deficiency occurs simultaneously in COVID-19; furthermore, Cathepsins, which are proteases that cleave the SARS-CoV-2 spike protein, are abundant in these two cell types [96] . Although type I and type IV taste sensory cells have not been investigated, it is interesting that SARS-CoV-2 may have a cytotropic nature for gustatory sensing disturbances. Forty-one taste-deficient COVID-19 patients were prospectively surveyed, and it was found that a significant loss of sour (33.3%), salty (17.9%), and sweet and bitter tastes (10.3%) were recognized [111] . These results may reflect virus neurotropic invasion and possible nervous system damage. Each different gustatory sensory cell (for sweet, bitter, umami, and sour sensors) connects each appropriate taste partner ganglion neuron in a taste bud. SARS-CoV-2 may invade these afferent neurons, and the colonization by the virus interferes with sensory nerve conduction for a long time.

There are many examples of long-term sequelae after viral infection. Measles, Ebola virus, Chikungunya virus, and Epstein-Barr virus have the potential to lead to autoimmune reactions [112, 113] . Although more research is required to elucidate the pathogenesis of long COVID, another hypothesis for the persistence of the long-lasting impairment may include a disturbed immune response in neuron compartments [28, 114] .

The expression of ACE2 in minor salivary glands was shown to be higher than that in lungs [115] . In an animal study using Chinese macaques, ACE2 was found to be expressed in epithelial cells lining salivary gland ducts. After intranasal inoculations of a pseudovirus for SARS-CoV-1 that targets the same entry factor, ACE2, as SARS-CoV-2, epithelial cells lining salivary gland ducts were productively infected by the pseudovirus [116] . The results suggested that SARS-CoV-2 could infect salivary gland cells. Salivary gland specimens from COVID-19 patient autopsies were studied with ACE2 and SARS-CoV-2 spike in situ hybridization (ISH) and immunohistochemistry J o u r n a l P r e -p r o o f [16] . Chronic sialadenitis, including focal lymphocytic sialadenitis, was the most common feature. SARS-CoV-2 mRNA was detected in ACE2-expressing ducts and acini of the minor and parotid salivary glands. Viral transcript expression was regionally dependent on the acinar unit. Additionally, in an acutely infected individual, the replication of SARS-CoV-2 was confirmed. Sialadenitis was correlated with the T cell response, and mild-to-moderate sialadenitis was demonstrated with focal lymphocytic inflammation and epithelial injury. These study results may explain the cause of xerostomia. SARS-CoV-1 RNA can be detected in saliva before disease-associated lung lesions appear [115] . and infiltration were predominant in focal lymphocytic sialadenitis [16] . These inflammatory and immune responses to SARS-CoV-2 in taste buds and salivary gland tissues may vary in individuals, including based on sex, age, and genetic variation.

The duration of dysgeusia varies from 4 to 17 days [106] [107] [108] [109] . Seventy-nine percent of patients reportedly improve and do not require immediate treatment. However, it has been reported that 11.5% of patients do not recover at all and have residual disability. In particular, SARS-CoV-2 exhibits neural invasion [91] . Therefore, neurostimulants (steroids, B vitamins, and ATP) may be expected to treat taste disorders in COVID-19

patients. Levy et al. [121] provided a commentary on the recommended treatment for the sequelae of olfactory and gustatory abnormalities, stating that at present there are few interventions for the treatment of olfactory and gustatory dysfunction after infection but that oral and topical corticosteroids, phosphodiesterase inhibitors, nasal calcium buffers, nasal sodium citrate, nasal vitamin A, which may act to promote olfactory neurogenesis, and nerve regeneration or antiinflammatory agents are effective [122, 123] , which may act via regeneration or antiinflammation activity, but that there is little quality evidence to justify their routine use in clinical practice.

There are no reports on the response of xerostomia to the sequelae of COVID-19, but infection treatment and oral hygiene have been reported to reduce the severity of the disease [124] . There are also various therapeutic agents for COVID-19, but these J o u r n a l P r e -p r o o f medications can cause oral mucosal symptoms as well as xerostomia. For example, chloroquine/hydroxychloroquine, used to treat malaria and certain autoimmune diseases, can cause allergic lichenoid reactions and xerostomia as oral symptoms. The combination of lopinavir and ritonavir, both approved for the treatment of HIV, may be associated with side effects such as xerostomia, stomatitis, and oral ulcers. Interferon-β, a medication for multiple sclerosis, also can cause xerostomia as a side effect [35] . Existing saliva secretagogues, such as cevimeline hydrochloride hydrate, pilocarpine hydrochloride, and Chinese herbal medicine, may also be promising [125] [126] [127] [128] . Zinc supplementation can also be a potential treatment for xerostomia as well as taste dysfunction. The reason for this is that human salivary glands express metabotropic zinc receptor/GPC receptor 39 (ZnR/GPR39), which regulates saliva secretion from the submandibular gland. However, many patients with COVID-19 show decreased serum zinc levels [129, 130] , and zinc deficiency is thus believed to be a contributing factor to xerostomia associated with COVID-19. However, to evaluate the treatment of xerostomia, it is necessary to perform objective evaluations, such as measuring saliva volume and analyzing salivary components, before and after COVID-19 diagnosis to show a close correlation with the virus infection [22] .

Taste impairment and salivary dysfunction are high-incidence symptoms in COVID- (S1 subunit) initially binds to the host receptor ACE2. Subsequently, Furin cleaves the spike protein at the S1/S2 site, and then the S1 subunit is dissociated from the rest of the spike protein. Another membrane-bound protease, TMPRSS2, then cleaves at the S2' site of the S2 subunit to expose the fusion peptide for host cell membrane fusion. These events lead to a series of conformational changes that result in fusion between the viral envelope and the host cell membrane. The viral genome is released into the host cell cytoplasm.

(II) Following interaction of the spike protein with the host cell receptor ACE2 on the cell membrane, the virus is endocytosed. The spike protein is processed by cathepsin L for cleavage to S1 and S2 in the endosome, which allows fusion of the viral membrane with the endosomal membrane. After that, the virus genome is released.

J o u r n a l P r e -p r o o f 

Summary of Recent Changes, Interim Clinical Guidance for Management of Patients with Confirmed Coronavirus Disease (COVID-19) Updated

Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention

Critical Trends, Mortality Analyses

Taste buds: cells, signals and synapses

Is Enriched in a Subpopulation of Mouse Tongue Epithelial Cells in Nongustatory Papillae but Not in Taste Buds or Embryonic Oral Epithelium

Systematic analysis of ACE2 and TMPRSS2 expression in salivary glands reveals underlying transmission mechanism caused by SARS-CoV-2

ACE2 and Furin Expressions in Oral Epithelial Cells Possibly Facilitate COVID-19 Infection via Respiratory and Fecal-Oral Routes

High expression of ACE2 receptor of 2019-nCoV on the epithelial cells of oral mucosa

Existence of SARS-CoV-2 Entry Molecules in the Oral Cavity

Protein Landscape in the Head and Neck Region: The Conundrum of SARS-CoV-2

Brief communication: Immunohistochemical detection of ACE2 in human salivary gland

Taste Cell Is Abundant in the Expression of ACE2 Receptor of 2019-nCoV

ACE2 & TMPRSS2 Expressions in Head & Neck Tissues: A Systematic Review

Expression of SARS-CoV-2 entry factors in human oral tissue

Morphological analysis of angiotensin-converting enzyme 2 expression in the salivary glands and associated tissues

SARS-CoV-2 infection of the oral cavity and saliva

Oral Manifestations in Patients with COVID-19: A Living Systematic Review

Smell and Taste Loss Recovery Time in COVID-19 Patients and Disease Severity

Prevalence of hyposmia and hypogeusia in 390 COVID-19 hospitalized patients and outpatients: a cross-sectional study

Long-term persistence of olfactory and gustatory disorders in COVID-19 patients

Symptomatology in head and neck district in coronavirus disease (COVID-19): A possible neuroinvasive action of SARS-CoV-2

SARS-CoV-2 and Oral Manifestation: An Observational, Human Study

gustatory and olfactory dysfunctions in patients with COVID-19

Olfactory and Oral Manifestations of COVID-19: Sex-Related Symptoms-A Potential Pathway to Early Diagnosis. Otolaryngology--head and neck surgery

Detection of SARS-CoV-2 in saliva and characterization of oral symptoms in COVID-19 patients

Oral manifestations in mild-to-moderate cases of COVID-19 viral infection in the adult population

Post-acute COVID-19 syndrome

Immune determinants of COVID-19 disease presentation and severity

Sequelae in Adults at 6 Months After COVID-19 Infection

Smell and taste loss in COVID-19 patients: assessment outcomes in a Victorian population

Long-term follow-up of olfactory and gustatory dysfunction in COVID-19: 6 months case-control study of health workers

Frequent and Persistent Salivary Gland Ectasia and Oral Disease After COVID-19

COVID-19 from the perspective of dentists: A case report and brief review of more than 170 cases

Saliva: a diagnostic option and a transmission route for 2019-nCoV

COVID-19 Pandemic: Oral Health Challenges and Recommendations

Oral cavity and associated glands; Taste buds

Signal transduction and information processing in mammalian taste buds

Putative mammalian taste receptors: a class of taste-specific GPCRs with distinct topographic selectivity

The receptors and cells for mammalian taste

Elucidation of mammalian bitter taste

An amino-acid taste receptor

Salt taste transduction occurs through an amiloride-sensitive sodium transport pathway

Sodium-Taste Cells Require <i>Skn-1a</i> for Generation and Share Molecular Features with Sweet, Umami, and Bitter Taste Cells. eNeuro

Angiotensin-converting enzyme 2 and renal disease

Renin-angiotensin system -Homo sapiens (human) KEGG PATHWAY Database KEGG: Kyoto Encyclopedia of Genes and Genomes

Expression of Renin-Angiotensin System Components in the Taste Organ of Mice

Angiotensin-(1-7) Mas-receptor deficiency decreases peroxisome proliferator-activated receptor gamma expression in adipocytes

Salivary secretion in health and disease

Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses

Furin at the cutting edge: from protein traffic to embryogenesis and disease

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Cell entry mechanisms of SARS-CoV-2

Coronavirus membrane fusion mechanism offers a potential target for antiviral development

Clathrindependent entry of severe acute respiratory syndrome coronavirus into target cells expressing ACE2 with the cytoplasmic tail deleted

TMPRSS2 Contributes to Virus Spread and Immunopathology in the Airways of Murine Models after Coronavirus Infection

Wild-type human coronaviruses prefer cellsurface TMPRSS2 to endosomal cathepsins for cell entry

SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

SARS-CoV-2 tropism, entry, replication, and propagation: Considerations for drug discovery and development

Genetic Variants of SARS-CoV-2-What Do They Mean?

SARS-CoV-2 Vaccines and the Growing Threat of Viral Variants

The coronavirus is mutating -does it matter?

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

A pneumonia outbreak associated with a new coronavirus of probable bat origin

Characterization of spike glycoprotein of SARS-CoV-2 on virus entry and its immune cross-reactivity with SARS-CoV

Receptor Recognition by the Novel Coronavirus from Wuhan: an Analysis Based on Decade-Long Structural Studies of SARS Coronavirus

A virus that has gone viral: amino acid mutation in S protein of Indian isolate of Coronavirus COVID-19 might impact receptor binding, and thus, infectivity

SARS-CoV-2 and the pathophysiology of coronavirus disease 2019 (COVID-19)

The Expression and Polymorphism of Entry Machinery for COVID-19

Juxtaposing Population Groups, Gender, and Different Tissues

Saliva is a reliable tool to detect SARS-CoV-2

Saliva: potential diagnostic value and transmission of 2019-nCoV

Oral Symptoms Associated with COVID-19 and Their Pathogenic Mechanisms: A Literature Review

COVID-19, Renin-Angiotensin System and Endothelial Dysfunction

Virus strain from a mild COVID-Hangzhou represents a new trend in SARS-CoV-2 evolution potentially related to Furin cleavage site

Expression of proteolytic cathepsins B, D, and L in periodontal gingival fibroblasts and tissues

A cross-talk between epithelium and endothelium mediates human alveolar-capillary injury during SARS-CoV-2 infection

Morphogenesis and cytopathic effect of SARS-CoV-2 infection in human airway epithelial cells

COVID-19 pulmonary pathology: a multi-institutional autopsy cohort from Italy and

Inflammasomes and Pyroptosis as Therapeutic Targets for COVID-19

Longitudinal analyses reveal immunological misfiring in severe COVID-19

Elevated ACE-2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory SARS-CoV-2 entry and replication

Olfactory transmucosal SARS-CoV-2 invasion as a port of central nervous system entry in individuals with COVID-19

CoV-2 detected in olfactory neurons

Viral and host heterogeneity and their effects on the viral life cycle

Ultrastructural analysis of SARS-CoV-2 interactions with the host cell via high resolution J o u r n a l P r e -p r o o f scanning electron microscopy

Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2

Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans

Neurotropism of SARS-CoV-2 and its neuropathological alterations: Similarities with other coronaviruses

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings

COVID-19: immunopathology, pathophysiological mechanisms, and treatment options

SARS-CoV-2 and nervous system: From pathogenesis to clinical manifestation

COVID-19 and the Chemical Senses: Supporting Players Take Center Stage

COVID 19-Induced Smell and Taste Impairments: Putative Impact on Physiology

COVID-19, cilia, and smell

Ultrastructural changes in human nasal cilia caused by the common cold and recovery of ciliated epithelium

Ultrastructure of human nasal epithelium during an episode of coronavirus infection

Comparative pathogenesis of COVID-19, MERS, and SARS in a nonhuman primate model

Actin-and myosindriven movement of viruses along filopodia precedes their entry into cells

The cell biology of taste

Immunohistochemical detection of TAS2R38 protein in human taste cells

Smell and taste disorders in COVID-19: From pathogenesis to clinical features and outcomes

Time course of anosmia and dysgeusia in patients with mild SARS-CoV-2 infection

Olfactory Dysfunction: A Highly Prevalent Symptom of COVID-19 With Public Health Significance

Subjective smell and taste changes during the COVID-19 pandemic: Short term recovery

Ear nose throat-related symptoms with a focus on loss of smell and/or taste in COVID-19 patients

Rewiring the taste system

Objective gustatory and olfactory dysfunction in COVID-19 patients: a prospective crosssectional study

Subacute sclerosing panencephalitis: more cases of this fatal disease are prevented by measles immunization than was previously recognized

Confronting the pathophysiology of long covid

The known unknowns of T cell immunity to COVID-19

Salivary Glands: Potential Reservoirs for COVID-19 Asymptomatic Infection

Epithelial cells lining salivary gland ducts are early target cells of severe acute respiratory syndrome coronavirus infection in the upper respiratory tracts of rhesus macaques

Viral dynamics in mild and severe cases of COVID-19

ACE2 and diabetes: ACE of ACEs?

A metabolic handbook for the COVID-19 pandemic

The trinity of COVID-19: immunity, inflammation and intervention

Treatment Recommendations for Persistent Smell and Taste Dysfunction Following COVID-19-The Coming Deluge

Clinical Diagnosis and Current Management Strategies for Olfactory Dysfunction: A Review

Supplementation in Patients With Smell Dysfunction Following Endoscopic Sellar and Parasellar Tumor Resection: A Multicenter Prospective Randomized Controlled Trial

SARS-CoV-2 Infection and Oral Health: Therapeutic Opportunities and Challenges

Treatment of xerostomia and hyposalivation in the elderly: A systematic review

Xerostomia of Various Etiologies: A Review of the Literature

A Review of Evidence for a Therapeutic Application of Traditional Japanese Kampo Medicine for Oral Diseases/Disorders. Medicines (Basel, Switzerland)

Management of dry mouth in Sjogren's syndrome

COVID-19: Poor outcomes in patients with zinc deficiency

Low Zinc Levels at Admission Associates with Poor Clinical Outcomes in SARS-CoV-2 Infection

Olfactory and gustatory dysfunctions as a clinical presentation of mild-tomoderate forms of the coronavirus disease (COVID-19): a multicenter European study

An Online Observational Study of Patients With Olfactory and Gustory Alterations Secondary to SARS-CoV-2 Infection. Front Public Health

Systematic Review and Meta-analysis of Smell and Taste Disorders in COVID-19