Multi-level inhibition of coronavirus replication by chemical ER stress

Shaban, Mohammed Samer; Müller, Christin; Mayr-Buro, Christin; Weiser, H.; Meier-Soelch, Johanna; Albert, Benadict Vincent; Weber, Axel; Linne, Uwe; Hain, Torsten; Babayev, Ilya; Karl, Nadja; Hofmann, Nina; Becker, Stephan; Herold, Susanne; Schmitz, M. Lienhard; Ziebuhr, John; Kracht, Michael

doi:10.1038/s41467-021-25551-1

Cited by 73 publications

(99 citation statements)

References 113 publications

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“…The evolution of a viral mechanism to counteract the effects of ER-stress is consistent with the emergent notion that UPR provides a crucial contribution to the activation of innate antiviral signaling, as seen with flaviviruses (279). Strikingly, treatment of cells with thapsigargin, a guaianolide which induces ER-stress by inhibiting the ER Calcium ATPase, represses replication of SARS-CoV-2 and other CoVs, counteracts virus mediated BiP downregulation, activates IRE1α and outweighs coronavirus mediated inhibition of global protein synthesis, thus becoming an attractive antiviral drug candidate (278,280).…”

Section: The Interaction Of Orf3a With the Apoptosis And Autophagy Pathwayssupporting

confidence: 77%

“…If from one side it appears that the interaction between SARS-CoV-2 proteins and UPR effectors leads to the activation of this stress response, another recent article suggests that, even though CoVs infection initiate ER stress signaling and induces UPR components at the mRNA level, these are inhibited at the protein level (278). This could indicate that coronaviruses, including SARS-CoV-2, might have evolved strategies acting at posttranscriptional or translational level to escape antiviral response placed by BiP, IRE1α, and HERPUD.…”

Section: The Interaction Of Orf3a With the Apoptosis And Autophagy Pathwaysmentioning

confidence: 99%

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SARS-CoV-2 and the Host Cell: A Tale of Interactions

Pizzato¹,

Baraldi²,

Sopetto³

et al. 2022

Front.Virol.

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The ability of a virus to spread between individuals, its replication capacity and the clinical course of the infection are macroscopic consequences of a multifaceted molecular interaction of viral components with the host cell. The heavy impact of COVID-19 on the world population, economics and sanitary systems calls for therapeutic and prophylactic solutions that require a deep characterization of the interactions occurring between virus and host cells. Unveiling how SARS-CoV-2 engages with host factors throughout its life cycle is therefore fundamental to understand the pathogenic mechanisms underlying the viral infection and to design antiviral therapies and prophylactic strategies. Two years into the SARS-CoV-2 pandemic, this review provides an overview of the interplay between SARS-CoV-2 and the host cell, with focus on the machinery and compartments pivotal for virus replication and the antiviral cellular response. Starting with the interaction with the cell surface, following the virus replicative cycle through the characterization of the entry pathways, the survival and replication in the cytoplasm, to the mechanisms of egress from the infected cell, this review unravels the complex network of interactions between SARS-CoV-2 and the host cell, highlighting the knowledge that has the potential to set the basis for the development of innovative antiviral strategies.

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Section: The Interaction Of Orf3a With the Apoptosis And Autophagy Pathwayssupporting

confidence: 77%

Section: The Interaction Of Orf3a With the Apoptosis And Autophagy Pathwaysmentioning

confidence: 99%

SARS-CoV-2 and the Host Cell: A Tale of Interactions

Pizzato¹,

Baraldi²,

Sopetto³

et al. 2022

Front.Virol.

View full text Add to dashboard Cite

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“…We previously showed that the antiviral use of TG was highly effective against influenza viruses of different subtypes [ 12 ], respiratory syncytial virus, coronavirus OC43 and an original isolate of SARS-CoV-2 (2019-nCoV/Italy-INMI1, clade V) [ 11 ]. Other groups have reported effective TG inhibition of paramyxoviruses [ 18 ], and 229E, Middle-East respiratory syndrome and SARS-CoV-2 coronaviruses [ 19 ]. All available data (generated by us and others) as exemplified in influenza virus, RSV and coronaviruses, including SARS-CoV-2, indicate that TG does not prevent viral entry but rather triggers intracellular pathways to inhibit virus replication [ 11 , 12 , 19 ].…”

Section: Discussionmentioning

confidence: 99%

“…Other groups have reported effective TG inhibition of paramyxoviruses [ 18 ], and 229E, Middle-East respiratory syndrome and SARS-CoV-2 coronaviruses [ 19 ]. All available data (generated by us and others) as exemplified in influenza virus, RSV and coronaviruses, including SARS-CoV-2, indicate that TG does not prevent viral entry but rather triggers intracellular pathways to inhibit virus replication [ 11 , 12 , 19 ]. As a host-centric antiviral, TG hits several central host mechanisms connected to endoplasmic reticulum stress-unfolded protein response to inhibit several stages of virus replication.…”

Section: Discussionmentioning

confidence: 99%

Emergent SARS-CoV-2 variants: comparative replication dynamics and high sensitivity to thapsigargin

et al. 2021

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The struggle to control the COVID-19 pandemic is made challenging by the emergence of virulent SARS-CoV-2 variants. To gain insight into their replication dynamics, emergent Alpha (A), Beta (B) and Delta (D) SARS-CoV-2 variants were assessed for their infection performance in single variant- and co-infections. The effectiveness of thapsigargin (TG), a recently discovered broad-spectrum antiviral, against these variants was also examined. Of the 3 viruses, the D variant exhibited the highest replication rate and was most able to spread to in-contact cells; its replication rate at 24 h post-infection (hpi) based on progeny viral RNA production was over 4 times that of variant A and 9 times more than the B variant. In co-infections, the D variant boosted the replication of its co-infected partners at the expense of its own initial performance. Furthermore, co-infection with AD or AB combination conferred replication synergy where total progeny (RNA) output was greater than the sum of corresponding single-variant infections. All variants were highly sensitive to TG inhibition. A single pre-infection priming dose of TG effectively blocked all single-variant infections and every combination (AB, AD, BD variants) of co-infection at greater than 95% (relative to controls) at 72 hpi. Likewise, TG was effective in inhibiting each variant in active preexisting infection. In conclusion, against the current backdrop of the dominant D variant that could be further complicated by co-infection synergy with new variants, the growing list of viruses susceptible to TG, a promising host-centric antiviral, now includes a spectrum of contemporary SARS-CoV-2 viruses.

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“…PEDV and TGEV infect and destroy villous epithelial cells of the jejunum and ileum, resulting in lethal watery diarrhea and piglet dehydration (Van Nieuwstadt et al, 1989;Cruz et al, 2011). The two human α-coronavirus (HCoV-229E and HCoV-NL63) cause mild symptoms mainly restricted to the upper respiratory tract (Shaban et al, 2021). Human coronaviruses (SARS-CoV, SARS-CoV-2 and MERS-CoV) are a member of β-coronavirus.…”

Section: Introductionmentioning

confidence: 99%

The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

Xue

Feng

2021

Front. Microbiol.

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Coronavirus is an important pathogen with a wide spectrum of infection and potential threats to humans and animals. Its replication occurs in the cytoplasm and is closely related to the endoplasmic reticulum (ER). Studies reported that coronavirus infection causes ER stress, and cells simultaneously initiate unfolded protein response (UPR) to alleviate the disturbance of ER homeostasis. Activation of the three branches of UPR (PERK, IRE1, and ATF6) modulates various signaling pathways, such as innate immune response, microRNA, autophagy, and apoptosis. Therefore, a comprehensive understanding of the relationship between coronavirus and ER stress is helpful to understand the replication and pathogenesis of coronavirus. This paper summarizes the current knowledge of the complex interplay between coronavirus and UPR branches, focuses on the effect of ER stress on coronavirus replication and coronavirus resistance to host innate immunity, and summarizes possible drug targets to regulate the impact of coronavirus infection.

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Multi-level inhibition of coronavirus replication by chemical ER stress

Cited by 73 publications

References 113 publications

SARS-CoV-2 and the Host Cell: A Tale of Interactions

SARS-CoV-2 and the Host Cell: A Tale of Interactions

Emergent SARS-CoV-2 variants: comparative replication dynamics and high sensitivity to thapsigargin

The Role of Unfolded Protein Response in Coronavirus Infection and Its Implications for Drug Design

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