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1.
Cells Tissues Organs ; 209(4-6): 155-164, 2020.
Article in English | MEDLINE | ID: covidwho-1042717

ABSTRACT

Usually, pandemic COVID-19 disease, caused by SARS-CoV2, presents with mild respiratory symptoms such as fever, cough, but frequently also with anosmia and neurological symptoms. Virus-cell fusion is mediated by angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2) with their organ expression pattern determining viral tropism. Clinical presentation suggests rapid viral dissemination to the central nervous system leading frequently to severe symptoms including viral meningitis. Here, we provide a comprehensive expression landscape of ACE2 and TMPRSS2 proteins across human postmortem nasal and olfactory tissue. Sagittal sections through the human nose complemented with immunolabelling of respective cell types represent different anatomically defined regions including olfactory epithelium, respiratory epithelium of the nasal conchae and the paranasal sinuses along with the hardly accessible human olfactory bulb. ACE2 can be detected in the olfactory epithelium as well as in the respiratory epithelium of the nasal septum, the nasal conchae, and the paranasal sinuses. ACE2 is located in the sustentacular cells and in the glandular cells in the olfactory epithelium as well as in the basal cells, glandular cells, and epithelial cells of the respiratory epithelium. Intriguingly, ACE2 is not expressed in mature or immature olfactory receptor neurons and basal cells in the olfactory epithelium. Similarly, ACE2 is not localized in the olfactory receptor neurons albeit the olfactory bulb is positive. Vice versa, TMPRSS2 can also be detected in the sustentacular cells and the glandular cells of the olfactory epithelium. Our findings provide the basic anatomical evidence for the expression of ACE2 and TMPRSS2 in the human nose, olfactory epithelium, and olfactory bulb. Thus, they are substantial for future studies that aim to elucidate the symptom of SARS-CoV2 induced anosmia via the olfactory pathway.


Subject(s)
Angiotensin-Converting Enzyme 2/analysis , COVID-19/pathology , Nasal Mucosa/pathology , Olfactory Bulb/pathology , SARS-CoV-2/isolation & purification , Serine Endopeptidases/analysis , COVID-19/diagnosis , Humans , Nasal Mucosa/virology , Nose/pathology , Nose/virology , Olfactory Bulb/virology , Olfactory Mucosa/pathology , Olfactory Mucosa/virology
2.
Adv Skin Wound Care ; 34(1): 31-35, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-978610

ABSTRACT

BACKGROUND: Binding to the angiotensin-converting enzyme 2 (ACE2) receptor is a critical step for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) to enter target cells. This enzyme is expressed in many human tissues including the lungs, but no research has demonstrated that SARS-CoV-2 can infect human skin or subcutaneous fat tissue, despite the increasing number of reported skin manifestations. The aim of this study was to investigate ACE2 gene expression in skin using a public database. METHODS: A search of transcriptomic data sets from a public gene expression database to investigate ACE2 gene expression in human tissues. RESULTS: Human skin keratinocytes and basal cells express more ACE2 than lung epithelial cells. In contrast, both fibroblasts and melanocytes from human skin express less ACE2 than human lung epithelial cells. CONCLUSIONS: The high expression of ACE2 in keratinocytes and basal cells of human skin indicates that they may be directly susceptible to SARS-CoV-2 infection via the ACE2 receptor, especially in conditions of skin barrier dysfunction, and are therefore a potential target for the coronavirus.


Subject(s)
Angiotensin-Converting Enzyme 2/genetics , COVID-19/metabolism , SARS-CoV-2 , Skin/metabolism , Angiotensin-Converting Enzyme 2/metabolism , COVID-19/genetics , COVID-19/pathology , Gene Expression , Humans , Lung/metabolism , Lung/pathology , RNA, Messenger/metabolism , Skin/pathology
3.
mBio ; 11(6)2020 11 06.
Article in English | MEDLINE | ID: covidwho-930294

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates throughout human airways. The polarized human airway epithelium (HAE) cultured at an airway-liquid interface (HAE-ALI) is an in vitro model mimicking the in vivo human mucociliary airway epithelium and supports the replication of SARS-CoV-2. Prior studies characterized only short-period SARS-CoV-2 infection in HAE. In this study, continuously monitoring the SARS-CoV-2 infection in HAE-ALI cultures for a long period of up to 51 days revealed that SARS-CoV-2 infection was long lasting with recurrent replication peaks appearing between an interval of approximately 7 to 10 days, which was consistent in all the tested HAE-ALI cultures derived from 4 lung bronchi of independent donors. We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detected. Notably, virus infection immediately damaged the HAE, which is demonstrated by dispersed zonula occludens-1 (ZO-1) expression without clear tight junctions and partial loss of cilia. Importantly, we identified that SARS-CoV-2 productive infection of HAE requires a high viral load of >2.5 × 105 virions per cm2 of epithelium. Thus, our studies highlight the importance of a high viral load and that epithelial renewal initiates and maintains a recurrent infection of HAE with SARS-CoV-2.IMPORTANCE The pandemic of coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to >35 million confirmed cases and >1 million fatalities worldwide. SARS-CoV-2 mainly replicates in human airway epithelia in COVID-19 patients. In this study, we used in vitro cultures of polarized human bronchial airway epithelium to model SARS-CoV-2 replication for a period of 21 to 51 days. We discovered that in vitro airway epithelial cultures endure a long-lasting SARS-CoV-2 propagation with recurrent peaks of progeny virus release at an interval of approximately 7 to 10 days. Our study also revealed that SARS-CoV-2 infection causes airway epithelia damage with disruption of tight junction function and loss of cilia. Importantly, SARS-CoV-2 exhibits a polarity of infection in airway epithelium only from the apical membrane; it infects ciliated and goblet cells but not basal and club cells. Furthermore, the productive infection of SARS-CoV-2 requires a high viral load of over 2.5 × 105 virions per cm2 of epithelium. Our study highlights that the proliferation of airway basal cells and regeneration of airway epithelium may contribute to the recurrent infections.


Subject(s)
Betacoronavirus/physiology , Models, Biological , Respiratory Mucosa/virology , Bronchi/cytology , Cells, Cultured , Epithelial Cells/pathology , Epithelial Cells/virology , Humans , Kinetics , Respiratory Mucosa/cytology , Respiratory Mucosa/pathology , SARS-CoV-2 , Viral Load , Viral Tropism , Virus Release , Virus Replication
4.
bioRxiv ; 2020 Aug 28.
Article in English | MEDLINE | ID: covidwho-900750

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replicates throughout human airways. The polarized human airway epithelium (HAE) cultured at an airway-liquid interface (HAE-ALI) is an in vitro model mimicking the in vivo human mucociliary airway epithelium and supports the replication of SARS-CoV-2. However, previous studies only characterized short-period SARS-CoV-2 infection in HAE. In this study, continuously monitoring the SARS-CoV-2 infection in HAE-ALI cultures for a long period of up to 51 days revealed that SARS-CoV-2 infection was long lasting with recurrent replication peaks appearing between an interval of approximately 7-10 days, which was consistent in all the tested HAE-ALI cultures derived from 4 lung bronchi of independent donors. We also identified that SARS-CoV-2 does not infect HAE from the basolateral side, and the dominant SARS-CoV-2 permissive epithelial cells are ciliated cells and goblet cells, whereas virus replication in basal cells and club cells was not detectable. Notably, virus infection immediately damaged the HAE, which is demonstrated by dispersed Zonula occludens-1 (ZO-1) expression without clear tight junctions and partial loss of cilia. Importantly, we identified that SARS-CoV-2 productive infection of HAE requires a high viral load of 2.5 × 10 5 virions per cm 2 of epithelium. Thus, our studies highlight the importance of a high viral load and that epithelial renewal initiates and maintains a recurrent infection of HAE with SARS-CoV-2.

5.
SSRN ; : 3611279, 2020 May 27.
Article in English | MEDLINE | ID: covidwho-679374

ABSTRACT

To predict the tropism of human coronaviruses, we profile 28 SCARFs using scRNA-seq data from a wide range of healthy human tissues. SCARFs include cellular factors both facilitating and restricting viral entry. Among adult organs, enterocytes and goblet cells of small intestine and colon, kidney proximal tubule cells, and gallbladder basal cells appear permissive to SARS-CoV-2, consistent with clinical data. Our analysis also suggests alternate entry paths for SARS-CoV-2 infection of the lung, CNS, and heart. We predict spermatogonial cells and prostate endocrine cells, but not ovarian cells, are highly permissive to SARS-CoV-2, suggesting male-specific vulnerabilities. Early embryonic and placental development show a moderate risk of infection. The nasal epithelium is characterized by high expression of both promoting and restricting factors and a potential age-dependent shift in SCARF expression. Lastly, SCARF expression appears broadly conserved across primate organs examined. Our study establishes an important resource for investigations of coronavirus pathology. Funding: M.S. is supported by a Presidential Postdoctoral Fellowship from Cornell University. V.B. is supported by a Career Development Fellowship at DZNE Tuebingen. Work on host-virus interactions in the Feschotte lab is funded by R35 GM122550 from the National Institutes of Health. Conflict of Interest: The authors declare that there is no conflict of interest.

6.
Am J Respir Crit Care Med ; 202(2): 219-229, 2020 07 15.
Article in English | MEDLINE | ID: covidwho-324576

ABSTRACT

Rationale: Infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease (COVID-19), a predominantly respiratory illness. The first step in SARS-CoV-2 infection is binding of the virus to ACE2 (angiotensin-converting enzyme 2) on the airway epithelium.Objectives: The objective was to gain insight into the expression of ACE2 in the human airway epithelium.Methods: Airway epithelia sampled by fiberoptic bronchoscopy of trachea, large airway epithelia (LAE), and small airway epithelia (SAE) of nonsmokers and smokers were analyzed for expression of ACE2 and other coronavirus infection-related genes using microarray, RNA sequencing, and 10x single-cell transcriptome analysis, with associated examination of ACE2-related microRNA.Measurements and Main Results: 1) ACE2 is expressed similarly in the trachea and LAE, with lower expression in the SAE; 2) in the SAE, ACE2 is expressed in basal, intermediate, club, mucus, and ciliated cells; 3) ACE2 is upregulated in the SAE by smoking, significantly in men; 4) levels of miR-1246 expression could play a role in ACE2 upregulation in the SAE of smokers; and 5) ACE2 is expressed in airway epithelium differentiated in vitro on air-liquid interface cultures from primary airway basal stem/progenitor cells; this can be replicated using LAE and SAE immortalized basal cell lines derived from healthy nonsmokers.Conclusions: ACE2, the gene encoding the receptor for SARS-CoV-2, is expressed in the human airway epithelium, with variations in expression relevant to the biology of initial steps in SARS-CoV-2 infection.


Subject(s)
Betacoronavirus , Coronavirus Infections/metabolism , Peptidyl-Dipeptidase A/genetics , Peptidyl-Dipeptidase A/metabolism , Pneumonia, Viral/metabolism , Respiratory Mucosa/metabolism , Angiotensin-Converting Enzyme 2 , COVID-19 , Case-Control Studies , Female , Humans , Lung/metabolism , Male , Pandemics , RNA, Messenger/genetics , RNA, Messenger/metabolism , SARS-CoV-2 , Sex Factors , Smoking/metabolism , Trachea/metabolism
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