SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

Zaffagni, Michela; Harris, Jenna M; Patop, Inés Lucía; Pamudurti, Nagarjuna Reddy; Nguyen, Sinead; Kadener, Sebastián

doi:10.1101/2021.07.02.450964

Cited by 5 publications

(7 citation statements)

References 91 publications

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“…A considerable feature of MERS-CoV and SARS-CoV is the production of double-layered membrane vesicles (DMVs) that the processes of transcription occur within them [45] . Additionally, autopsy and histopathological investigation of the kidney tissue in patients with COVID-19 indicated that SARS-CoV-2 might exist inside the DMVs of the host cells [46] .…”

Section: Resultsmentioning

confidence: 99%

The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms

Musazadeh

Karimi²,

bagheri³

et al. 2022

Biomedicine & Pharmacotherapy

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Section: Resultsmentioning

confidence: 99%

The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms

Musazadeh

Karimi²,

bagheri³

et al. 2022

Biomedicine & Pharmacotherapy

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“…While facilitating viral replication by contributing to RTC assembly, SARS-CoV-2 non-structural proteins, including Nsp9 and Nsp14, directly affect the host cell transcriptome (Zaffagni et al, 2022). In this way SARS-CoV-2 has a direct effect on the transcriptional profile of infected cells (Blanco-Melo et al, 2020;Chakraborty et al, 2021;Sun et al, 2021;Wyler et al, 2021).…”

Section: Nsp23 Nanobody Treatment Blocks Viral Replication Of Sars-co...mentioning

confidence: 99%

Nanobodies against SARS-CoV-2 non-structural protein Nsp9 inhibit viral replication by targeting innate immunity

Venit,

Blavier,

Maseko

et al. 2023

Preprint

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Nanobodies are emerging as critical tools for drug design. Several have been recently created to serve as inhibitors of SARS-Cov-2 entry in the host cell by targeting surface-exposed Spike protein. However, due to the high frequency of mutations that affect Spike, these nanobodies may not target it to their full potential and as a consequence, inhibition of viral entry may not be efficient. Here we have established a pipeline that instead targets highly conserved viral proteins that are made only after viral entry into the host cell when the SARS-Cov-2 RNA-based genome is translated. As proof of principle, we designed nanobodies against the SARS-CoV-2 non-structural protein Nsp9, required for viral genome replication. To find out if this strategy efficiently blocks viral replication, one of these anti-Nsp9 nanobodies, 2NSP23, previously characterized using immunoassays and NMR spectroscopy for epitope mapping, was encapsulated into lipid nanoparticles (LNP) as mRNA. We show that this nanobody, hereby referred to as LNP-mRNA-2NSP23, is internalized and translated in HEK293 cells. We next infected HEK293-ACE2 cells with multiple SARS-CoV-2 variants and subjected them to LNP-mRNA-2NSP23 treatment. Analysis of total RNA isolated from infected cells treated or untreated with LNP-mRNA-2NSP23 using qPCR and RNA deep sequencing shows that the LNP-mRNA-2NSP23 nanobody protects HEK293-ACE2 cells and suppresses replication of several SARS-CoV-2 variants. These observations indicate that following translation, the nanobody 2NSP23 inhibits viral replication by targeting Nsp9 in living cells. We speculate that LNP-mRNA-2NSP23 may be translated into an innovative technology to generate novel antiviral drugs highly efficient across coronaviruses.

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“…The proviral action of the immune factor ISG15 leads to the generation of an autocrine loop, which amplifies and prolongs autocrine signalling and ultimately induces viral drug resistance ( 89 , 90 ). Furthermore, the S protein of SARS-CoV-2 can prevent the virus from being cleared by immune factors, and mutation of the S protein will further enhance the ability of the virus to evade immune responses ( 91 , 92 ). In addition, the expression of viral nsp14 can upregulate the levels of circRNAs related to innate immunity, thereby inhibiting viral replication and immune evasion ( 93 ).…”

Section: Potential Mechanisms Of Circrnas In Sars-cov-2 Infectionmentioning

confidence: 99%

“…For example, Zaffagni M et al. ( 92 , 96 ) found that SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome. Nsp14 altered the splicing of more than 1000 genes and resulted in a dramatic increase in the number of circRNAs that were linked to innate immunity.…”

Section: Potential Mechanisms Of Circrnas In Sars-cov-2 Infectionmentioning

confidence: 99%

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression

Gao¹,

Fang²,

Liang³

et al. 2022

Front. Immunol.

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Coronavirus disease 2019 (COVID-19), an infectious acute respiratory disease caused by a newly emerging RNA virus, is a still-growing pandemic that has caused more than 6 million deaths globally and has seriously threatened the lives and health of people across the world. Currently, several drugs have been used in the clinical treatment of COVID-19, such as small molecules, neutralizing antibodies, and monoclonal antibodies. In addition, several vaccines have been used to prevent the spread of the pandemic, such as adenovirus vector vaccines, inactivated vaccines, recombinant subunit vaccines, and nucleic acid vaccines. However, the efficacy of vaccines and the onset of adverse reactions vary among individuals. Accumulating evidence has demonstrated that circular RNAs (circRNAs) are crucial regulators of viral infections and antiviral immune responses and are heavily involved in COVID-19 pathologies. During novel coronavirus infection, circRNAs not only directly affect the transcription process and interfere with viral replication but also indirectly regulate biological processes, including virus-host receptor binding and the immune response. Consequently, understanding the expression and function of circRNAs during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will provide novel insights into the development of circRNA-based methods. In this review, we summarize recent progress on the roles and underlying mechanisms of circRNAs that regulate the inflammatory response, viral replication, immune evasion, and cytokines induced by SARS-CoV-2 infection, and thus highlighting the diagnostic and therapeutic challenges in the treatment of COVID-19 and future research directions.

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SARS-CoV-2 Nsp14 mediates the effects of viral infection on the host cell transcriptome

Cited by 5 publications

References 91 publications

The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms

The favorable impacts of silibinin polyphenols as adjunctive therapy in reducing the complications of COVID-19: A review of research evidence and underlying mechanisms

Nanobodies against SARS-CoV-2 non-structural protein Nsp9 inhibit viral replication by targeting innate immunity

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression

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