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The nasal symbiont Staphylococcus species restricts the transcription of SARS-CoV-2 entry factors in human nasal epithelium.

ABSTRACT: Emerging evidence indicates that severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is transmitted through the human nasal mucosa via the principal entry factors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which are highly expressed in the nasal epithelium. Therefore, the biologics targeting host entry factors on human nasal mucosa will be necessary for complete control of SARS-CoV-2. Our data reveal that ACE2 was more abundant in human nasal mucosa than lung tissue. Both ACE2 and TMPRSS2 transcriptions significantly decreased in nasal epithelium in response to S. epidermidis and were relatively lower in human nasal mucus with large numbers of S. epidermidis. ACE2 transcription was also reduced in nasal epithelium in response to nasal symbiont S. aureus. This study proposes that Staphylococcus species nasal commensals might potentially restrict SARS-CoV-2 entry to the nasal epithelium via down regulation of cellular receptors coupled with reduction of principal host protease.

SUBMITTER: Ji JY

PROVIDER: S-EPMC8464034 | biostudies-literature | 2021 Oct

REPOSITORIES: biostudies-literature

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The nasal symbiont <i>Staphylococcus species</i> restricts the transcription of SARS-CoV-2 entry factors in human nasal epithelium.

Ji Jeong-Yeon JY Jo Ara A Won Jina J Gil Chan Hee CH Shin Haeun H Kim Sujin S Jeon Yung Jin YJ Kim Hyun Jik HJ

iScience 20210925 10

Emerging evidence indicates that severe acute respiratory syndrome-related coronavirus-2 (SARS-CoV-2) is transmitted through the human nasal mucosa via the principal entry factors angiotensin-converting enzyme 2 (ACE2) and transmembrane serine protease 2 (TMPRSS2), which are highly expressed in the nasal epithelium. Therefore, the biologics targeting host entry factors on human nasal mucosa will be necessary for complete control of SARS-CoV-2. Our data reveal that <i>ACE2</i> was more abundant i ...[more]

PMID: 34604720

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Project description:Nonstructural protein 13 (nsp13), the helicase of SARS-CoV-2, has been shown to possess multiple functions that are essential for viral replication, and is considered an attractive target for the development of novel antivirals. We were initially interested in the interplay between nsp13 and interferon (IFN) signaling, and found that nsp13 inhibited reporter signal in an IFN-β promoter assay. Surprisingly, the ectopic expression of different components of the RIG-I/MDA5 pathway, which were used to stimulate IFN-β promoter, was also mitigated by nsp13. However, endogenous expression of these genes was not affected by nsp13. Interestingly, nsp13 restricted the expression of foreign genes originating from plasmid transfection, but failed to inhibit them after chromosome integration. These data, together with results from a runoff transcription assay and RNA sequencing, suggested a specific inhibition of episomal but not chromosomal gene transcription by nsp13. By using different truncated and mutant forms of nsp13, we demonstrated that its NTPase and helicase activities contributed to the inhibition of episomal DNA transcription, and that this restriction required direct interaction with episomal DNA. Based on these findings, we developed an economical and convenient high-throughput drug screening method targeting nsp13. We evaluated the inhibitory effects of various compounds on nsp13 by the expression of reporter gene plasmid after co-transfection with nsp13. In conclusion, we found that nsp13 can specifically inhibit episomal DNA transcription and developed a high-throughput drug screening method targeting nsp13 to facilitate the development of new antiviral drugs. IMPORTANCE To combat COVID-19, we need to understand SARS-CoV-2 and develop effective antiviral drugs. In our study, we serendipitously found that SARS-CoV-2 nsp13 could suppress episomal DNA transcription without affecting chromosomal DNA. Detailed characterization revealed that nsp13 suppresses episomal gene expression through its NTPase and helicase functions following DNA binding. Furthermore, we developed a high-throughput drug screening system targeting SARS-CoV-2 nsp13. Compared to traditional SARS-CoV-2 drug screening methods, our system is more economical and convenient, facilitating the development of more potent and selective nsp13 inhibitors and enabling the discovery of new antiviral therapies.

Dataset Information

The nasal symbiont Staphylococcus species restricts the transcription of SARS-CoV-2 entry factors in human nasal epithelium.

Publications

The nasal symbiont <i>Staphylococcus species</i> restricts the transcription of SARS-CoV-2 entry factors in human nasal epithelium.

Similar Datasets

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