Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses

Banerjee, Arinjay; El-Sayes, Nader; Budylowski, Patrick; Jacob, Rajesh; Richard, Daniel; Maan, Hassaan; Aguiar, Jennifer A.; Demian, Wael L. L.; Baid, Kaushal; D’Agostino, Michael R.; Ang, Jann C.; Murdza, Tetyana; Tremblay, Benjamin; Afkhami, Sam; Karimzadeh, Mehran; Irving, Aaron T.; Yip, Lily; Ostrowski, Mario; Hirota, Jeremy A.; Kozak, Robert; Capellini, Terence D.; Miller, Matthew S.; Wang, Bo; Mubareka, Samira; McGeer, Allison; McArthur, Andrew G; Doxey, Andrew C.; Mossman, Karen

doi:10.1016/j.isci.2021.102477

Cited by 58 publications

(42 citation statements)

References 94 publications

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“…An unrelated set of 92 genes was differentially expressed at 12 hpi and 58 genes at 24 hpi. Genes induced at 24 hpi were preferentially involved with type I interferon production and signaling, consistent with a recent report (Banerjee et al, 2021b). Only minor changes to alternative splicing or APA during virus infection was observed (Supplemental Figure 7).…”

Section: Resultssupporting

confidence: 92%

Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

Chan

Farias

Lee

et al. 2021

Preprint

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SARS-CoV-2, depends on host cell components for replication, therefore the identification of virus-host dependencies offers an effective way to elucidate mechanisms involved in viral infection. Such host factors may be necessary for infection and replication of SARS CoV-2 and, if druggable, presents an attractive strategy for anti-viral therapy. We performed genome wide CRISPR knockout screens in Vero E6 cells and 4 human cell lines including Calu-3, Caco-2, Hek293 and Huh7 to identify genetic regulators of SARS-CoV-2 infection. Our findings identified only ACE2, the cognate SARS-CoV-2 entry receptor, as a common host dependency factor across all cell lines, while all other host genes identified were cell line specific including known factors TMPRSS2 and CTSL. Several of the discovered host-dependency factors converged on pathways involved in cell signalling, lipid metabolism, immune pathways and chromatin modulation. Notably, chromatin modulator genes KMT2C and KDM6A in Calu-3 cells had the strongest impact in preventing SARS CoV-2 infection when perturbed. Overall, the network of host factors that have been identified will be broadly applicable to understanding the impact of SARS-CoV-2 on human cells and facilitate the development of host directed therapies.

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Section: Resultssupporting

confidence: 92%

Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

Chan

Farias

Lee

et al. 2021

Preprint

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“…Even with intense study, we do not yet appreciate precisely how SARS-CoV-2 infection causes severe COVID-19 in some patients and mild disease in others though a mismanaged or delayed IFN response and an overactive cytokine response is thought to underlie severe outcomes [65][66][67][68][69][70] . Despite some contrasting reports, [71][72][73], what is clear is that SARS-CoV-2 proteins use a multitude of mechanisms to outcompete cellular antiviral responses [68,[74][75][76][77][78][79][80][81][82][83][84][85].…”

Section: Introductionmentioning

confidence: 99%

Human coronaviruses disassemble processing bodies

Robinson

Kleer

Mulloy

et al. 2020

Preprint

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The Coronaviridae are a family of viruses with large RNA genomes. Seven coronaviruses (CoVs) have been shown to infect humans, including the recently emerged severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease of 2019 (COVID-19). The host response to CoV infection is complex and regulated, in part, by intracellular antiviral signaling pathways triggered in the first cells that are infected. Emerging evidence suggests that CoVs hijack these antiviral responses to reshape the production of interferons and proinflammatory cytokines. Processing bodies (PBs) are membraneless ribonucleoprotein granules that mediate decay or translational suppression of cellular mRNAs; this is particularly relevant for proinflammatory cytokine mRNA which normally reside in PBs and are repressed. Emerging evidence also suggests that PBs or their components play important direct-acting antiviral roles, providing a compelling reason for their frequent disassembly by many viruses. No information is known about how human CoVs impact PBs. Here, we provide data to show that infection with the human CoV, OC43, causes PB disassembly. Moreover, we show that several SARS-CoV-2 gene products also mediate PB loss and virus-induced PB loss correlates with elevated levels of proinflammatory cytokine mRNAs that would normally be repressed in PBs. Finally, we demonstrate that stimulating PB formation prior to OC43 infection restricts viral replication. These data suggest that SARS-CoV-2 and other CoVs disassemble PBs during infection to support viral replication and evade innate immune responses. As an unintended side effect, the disassembly of PBs enhances translation of proinflammatory cytokine mRNAs which normally reside in PBs, thereby reshaping the subsequent immune response.

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“…Although the study was not a longitudinal analysis and formal proof is still missing, the segregation of patient outcome by ISG-signature supports COVID-19 6 as a multi-step disease, which progresses from an ISG high to an ISG low pathology, acquiring peculiar immunological features during the transition. This pathobiology was confirmed in moderate vs severe COVID-19: a type I IFN signature, high amount of pSTAT-1 and 2 together with high expression of IL10 characterizes moderate illness, whereas severe disease is mainly defined by high expression of IL6, IL8, TNF, and vascular endothelial growth factor (VEGF), thus strengthening notion that there is a biologic transition from a high IFN phase to a relatively low IFN phase in which a broad inflammation prevails (46). It is still an open issue whether SARS-CoV-2 can be a mild (36,47) or potent (48) inducer of IFN responses; alternatively the host response might change over time as a consequence of adaptation to persisting immune stress.…”

Section: The Evolving Immune Landscapementioning

confidence: 76%

Immune-Guided Therapy of COVID-19

Ferraccioli

Gremese

Goletti

et al. 2022

Cancer Immunology Research

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Vaccination has been a game changer in our efforts to address the coronavirus disease 2019 (COVID-19) pandemic. However, the disease might still represent a clinical crisis for several more years, in part because of the inevitable emergence of variants capable of evading the preexisting immunity. Drugs affecting viral spread will help curtail transmission, but therapeutics are needed to treat the more severe cases requiring hospitalization. A deep analysis of the evolving immune landscape of COVID-19 suggests that understanding the molecular bases of the distinct clinical stages is paramount if we are to limit the burden of inflammation, which can lead to death in frail individuals, according to age, sex, and comorbidities. Different phases can be defined using immune biomarkers and need specific therapeutic approaches, tailored to the underlying immune contexture.

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Experimental and natural evidence of SARS-CoV-2-infection-induced activation of type I interferon responses

Cited by 58 publications

References 94 publications

Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

Systematic genome-scale identification of host factors for SARS-CoV-2 infection across models yields a core single gene dependency; ACE2

Human coronaviruses disassemble processing bodies

Immune-Guided Therapy of COVID-19

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