The coronavirus SARS-CoV-2 is the causative agent of the ongoing severe acute respiratory disease pandemic COVID-19. Tissue and cellular tropism is one key to understanding the pathogenesis of SARS-CoV-2. We investigate the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of human donors using a diverse panel of banked tissues. Here, we report our discovery that the ACE2 receptor protein robustly localizes within the motile cilia of airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during host respiratory transmission. We further determine whether ciliary ACE2 expression in the upper airway is influenced by patient demographics, clinical characteristics, comorbidities, or medication use, and show the first mechanistic evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) does not increase susceptibility to SARS-CoV-2 infection through enhancing the expression of ciliary ACE2 receptor. These findings are crucial to our understanding of the transmission of SARS-CoV-2 for prevention and control of this virulent pathogen.

Background The clinical characteristics of central‐compartment‐type chronic rhinosinusitis (CRS) in East Asian individuals are not clear. We sought to investigate the clinical features and the cytokine profiles of central‐compartment‐type CRS in our patient group. Methods Adult patients diagnosed with bilateral CRS were recruited, and patients who had previously undergone sinus surgery and pansinusitis (Lund‐Mackay scores >23) were excluded. Central‐compartment‐type CRS was defined by both endoscopic and radiological features. The symptoms, inhalant allergen sensitization status, endoscopic findings, and radiological assessments were recorded and compared between patients with central‐compartment‐type CRS and other types of CRS. We also examined the extent of tissue eosinophilia and specific cytokine protein levels (eosinophil cationic protein [ECP], myeloperoxidase [MPO], immunoglobulin E [IgE], interleukin [IL]‐4, IL‐5, and IL‐13) in the sinonasal tissues. Results Central‐compartment‐type CRS was found in 16 (23.9%) patients, and non–central‐compartment‐type CRS was found in 51 (76.1%) patients. Hyposmia or anosmia as the major symptom was more common in the central‐compartment‐type CRS group. The numbers of eosinophils in tissue and serum were significantly higher in the central‐compartment‐type CRS patients. The presence of allergen sensitization was not significantly different between groups. The levels of IL‐5 and IL‐13 were increased in middle turbinate tissues of patients with central‐compartment‐type CRS. Conclusion Central‐compartment‐type CRS was associated with hyposmia or anosmia, eosinophilic subtypes, and elevated levels of IL‐5 and IL‐13 in middle turbinate tissues but not necessarily correlated with allergic disease in our patients.

We investigated the expression and subcellular localization of the SARS-CoV-2 receptor, angiotensin-converting enzyme 2 (ACE2), within the upper (nasal) and lower (pulmonary) respiratory tracts of healthy human donors. We detected ACE2 protein expression within the cilia organelle of ciliated airway epithelial cells, which likely represents the initial or early subcellular site of SARS-CoV-2 viral entry during respiratory transmission. We further determined whether ACE2 expression in the cilia of upper respiratory cells was influenced by patient demographics, clinical characteristics, co-morbidities, or medication use, and found no evidence that the use of angiotensin-converting enzyme inhibitors (ACEI) or angiotensin II receptor blockers (ARBs) increases ACE2 protein expression.Coronavirus disease 2019 is an ongoing pandemic infection caused by the positivesense RNA virus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) 1 . The high transmissibility of the virus, along with case fatality estimates ranging from 1% to above 5%, has raised concerns worldwide. Patients with comorbid conditions including hypertension, diabetes, and pulmonary disease are highly represented among hospitalized patients with COVID-19 disease, suggesting the presence of risk factors that may determine susceptibility to SARS-CoV-2 infection [2][3][4][5] .A molecular connection between SARS-CoV-2 and hypertension, in particular, is suggested by the discovery that ACE2 is the major essential receptor for SARS-CoV-2 6,7 . ACE2 plays an important role in the renin-angiotensin-aldosterone system (RAAS), which consists of a cascade of vasoactive peptides that maintain blood pressure and electrolyte homeostasis. ACE2 converts vasoconstrictor peptides, angiotensin (Ang) II and Ang I, into the vasodilator peptides, Ang (1-7) and Ang (1-9), respectively 8 . These actions counterbalance the enzymatic effect of the related ACE, which generates angiotensin II from angiotensin I. ACEI and ARBs are commonly used antihypertensive drugs that target components of the RAAS. Several recent correspondences have raised concerns that ACEI and ARBs may increase expression of ACE2 and thereby elevate the risk of infection by SARS-CoV-2, thus potentially explaining why hypertension is a common comorbidity in patients with COVID-19 9-12 . This hypothesis is also rooted in human and rodent studies showing upregulation of ACE2 mRNA in the heart, kidney, and urine after ACEI/ARB administration [13][14][15] . Notably, however, the effects of ACEI and ARBs on the expression of ACE2 in the respiratory tract are currently unknown. Given SARS-CoV-2 causes respiratory infections, whether ACE2 expression is altered in the airway of patients taking ACEI or ARBs is a critical question that needs to be addressed to support continued clinical use of these antihypertensive drugs.We first determined the expression patterns of the ACE2 protein in the upper and lower respiratory tract. Gene expression analyses have identified ACE2 expression in the nasopharynx, oral muc...

Understanding viral tropism is an essential step towards reducing SARS-CoV-2 transmission, decreasing mortality from COVID-19, and limiting opportunities for mutant strains to arise. Currently, little is known about the extent to which distinct tissue sites in the human head & neck region and proximal respiratory tract selectively permit SARS-CoV-2 infection and replication. In this translational study, we discover key variabilities in the expression of ACE2 and TMPRSS2, essential SARS-CoV-2 entry factors, among the mucosal tissues of the human proximal airways. We show that SARS-CoV-2 infection is present in all examined head & neck tissues, with a notable tropism for the nasal cavity and tracheal mucosa. Finally, we uncover an association between smoking and higher SARS-CoV-2 viral infection in the human proximal airway, which may explain the increased susceptibility of smokers to developing severe COVID-19. This is at least partially explained by differences in IFN-β1 levels between smokers and non-smokers.

Betel quid is one of the most widely used psychoactive substances, and is consumed by approximately 10% of the world’s population. In addition to its carcinogenicity, betel quid has also been reported to affect many organs, including the brain, heart, lungs, gastrointestinal tract, and reproductive organs. As betel quid contains several neurotoxic ingredients, we hypothesize that it also possesses ototoxicity and may lead to sensorineural hearing impairment (SNHI). In this study, we investigated the contribution of betel quid consumption to SNHI in a large clinical cohort, and validated the pathogenetic mechanisms in ex vivo tissue explants. We enrolled a total of 2364 volunteers, and determined their audiologic results based on Z-scores converted from their original frequency-specific hearing thresholds. Using generalized linear regression, we identified a positive correlation between betel quid consumption and the Z-scores across different frequencies. Subsequently, we explored the toxicity of arecoline, the main neuroactive component of betel quid, on tissue explants from murine cochleae. Arecoline reduced cell activity in the explant cultures and induced apoptosis in the hair cells, probably through the effects of oxidative stress. These findings have expanded the potential hazards of betel quid to common neurological disorders, and provide insights into preventive strategies against SNHI caused by neurotoxic substances.