Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Hadjadj, Jérôme; Yatim, Nader; Barnabei, Laura; Corneau, Aurélien; Boussier, Jérémy; Smith, Nikaïa; Péré, Hélène; Charbit, Bruno; Bondet, Vincent; Chenevier‐Gobeaux, Camille; Breillat, Paul; Carlier, Nicolas; Gauzit, R.; Morbieu, Caroline; Pène, Frédéric; Marin, Nathalie; Roche, Nicolás; Szwebel, Tali Anne; Merkling, Sarah H.; Tréluyer, Jean Marc; Veyer, David; Mouthon, Luc; Blanc, Catherine; Tharaux, Pierre‐Louis; Rozenberg, Flore; Fischer, Alain; Duffy, Darragh; Rieux-Laucat, Frédéric; Kernéis, Solen; Terrier, B.

doi:10.1126/science.abc6027

Cited by 2,680 publications

(3,102 citation statements)

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“…IFITMs are efficiently induced during the innate immune response in SARS-CoV-2 infected individuals (Blanco-Melo et al, Hadjadj et al, 2020). Consequently, the ability to utilize IFITMs as infection cofactor may play a key role in the ability of SARS-CoV-2 to invade the lower respiratory tract under inflammatory conditions, which represents a hallmark of severe COVID-19.…”

Section: Discussionmentioning

confidence: 99%

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

Bozzo

Nchioua

Volcic

et al. 2020

Preprint

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Interferon-induced transmembrane proteins (IFITMs 1, 2 and 3) restrict numerous viral pathogens and are thought to prevent infection by severe acute respiratory syndrome coronaviruses (SARS-CoVs). However, most evidence comes from single-round pseudoparticle infection of cells artificially overexpressing IFITMs. Here, we confirmed that overexpression of IFITMs blocks pseudoparticle infections mediated by the Spike proteins of β-coronaviruses including pandemic SARS-CoV-2. In striking contrast, however, endogenous IFITM expression promoted genuine SARS-CoV-2 infection in human lung cells both in the presence and absence of interferon. IFITM2 was most critical for efficient entry of SARS-CoV-2 and enhanced virus production from Calu-3 cells by several orders of magnitude. IFITMs are expressed and further induced by interferons in the lung representing the primary site of SARS-CoV-2 infection as well as in other relevant tissues. Our finding that IFITMs enhance SARS-CoV-2 infection under conditions approximating the in vivo situation shows that they may promote viral invasion during COVID-19.

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Section: Discussionmentioning

confidence: 99%

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

Bozzo

Nchioua

Volcic

et al. 2020

Preprint

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“…Interestingly, Egr-1 was induced by both cytokines in PBMC and BMDM. These genes are involved in transcriptional regulation and integrating signal transduction pathways that are likely to play an important role in the cytokine storm and shift to hyperinflammatory gene expression in response to coronavirus infections (30,65).…”

Section: Regulation Of Genes By Interferon-α/β and Tnf-α In Bmdm Andmentioning

confidence: 99%

Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses

Ramana

2020

Preprint

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Respiratory virus infection is one of the leading causes of death in the world. Activation of the Jak-Stat pathway by interferon-alpha/beta (IFN-α/β) in lung epithelial cells is critical for innate immunity to respiratory viruses. Genetic and biochemical studies have shown that transcriptional regulation by IFN-α/β required the formation of interferon-stimulated gene factor-3 (ISGF-3) complex consisting of Stat1, Stat2, and Irf9 transcription factors. Furthermore, IFN-α/β receptor activates multiple signal transduction pathways in parallel to the Jak-Stat pathway and induces several transcription factors at mRNA levels resulting in the secondary and tertiary rounds of transcription. Transcriptional factor profiling in the transcriptome and RNA analysis revealed that Early growth response 1 (Egr-1) was rapidly induced by IFN-α/β and Toll-like receptor (TLR) ligands in multiple cell types. Studies in mutant cell lines lacking components of the ISGF-3 complex revealed that IFN-α/β induction of Egr-1 was independent of Stat1, Stat2, or Irf9. Activation of the Mek/Erk-1/2 pathway was implicated in the rapid induction of Egr-1 by IFN-α/β in serum-starved mouse lung epithelial cells. Interrogation of multiple microarray datasets revealed that respiratory viruses including coronaviruses regulated Egr-1 expression in human lung cell lines. Furthermore, Egr-1 inducible genes including transcription factors, mediators of cell growth, and chemokines were differentially regulated in the human lung cell lines after coronavirus infection, and in the lung biopsies of COVID-19 patients. Rapid induction by interferons, TLR ligands, and respiratory viruses suggests a critical role for Egr-1 in antiviral response and inflammation with potential implications for human health and disease.

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“…[15,16] Additionally, a recent investigation revealed that several severe cases of COVID-19 presented with a rare, X-chromosome lossof-function mutation that impaired Type I interferon response, [17] while another demonstrated an association between COVID-19 severity and Type I interferon deficiency. [18] Various studies have found reasons to support the use of Type I interferons in combination with other antivirals to promote positive outcomes among patients with COVID-19, but many are restricted by the number of patients they treated with interferon. [19] Interestingly, these interferons perform their functions by activating JAK pathway.…”

Section: Introductionmentioning

confidence: 99%

JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

Walz

Cohen

Rebaza

et al. 2020

Preprint

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Background The spread of a highly pathogenic, novel coronavirus (SARS-CoV-2) has emerged as a once-in-a-century pandemic, having already infected over 17 million. Novel therapies are urgently needed. Janus kinase-inhibitors and Type I interferons have emerged as potential antiviral candidates for COVID-19 patients for their proven efficacy against diseases with excessive cytokine release and due to direct antiviral ability against viruses including coronaviruses, respectively. We conducted a systemic review and meta-analysis to evaluate the effect of Janus kinase-inhibitors and Type I interferons and their ability to produce positive patient outcomes in COVID-19 patients. Methods A search of MEDLINE and MedRxiv was conducted by three investigators from inception until July 30 th 2020, including any study type that compared treatment outcomes of humans treated with JAK-inhibitor or Type I interferon against controls. Inclusion necessitated data with clearly indicated risk estimates or those that permitted their back-calculation. Outcomes were synthesized using RevMan. Results Of 733 searched studies, we included four randomized and eleven non-randomized trials. Five of the studies were unpublished. Those who received Janus kinase-inhibitor had significantly reduced odds of mortality (OR, 0.12; 95% CI, 0.03 – 0.39, p<0.001) and ICU admission (OR, 0.05; 95% CI, 0.01 – 0.26, p<0.001), and had significantly increased odds of hospital discharge (OR, 22.76; 95% CI, 10.68 – 48.54, p<0.00001), when compared to standard treatment group. Type I interferon recipients had significantly reduced odds of mortality (OR, 0.19; 95% CI, 0.04 – 0.85, p<0.05), and increased odds of discharge bordering significance (OR, 1.89; 95% CI, 1.00 – 3.59, p=0.05). Conclusions Janus kinase-inhibitor treatment is significantly associated with positive clinical outcomes in terms of mortality, ICU admission, and discharge. Type I interferon treatment is associated with positive clinical outcomes in regard to mortality and discharge. While these data show promise, additional well-conducted RCTs are needed to further elucidate the relationship between clinical outcomes and Janus kinase-inhibitors and Type I interferons in COVID-19 patients.

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Impaired type I interferon activity and inflammatory responses in severe COVID-19 patients

Cited by 2,680 publications

References 34 publications

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

IFITM proteins promote SARS-CoV-2 infection and are targets for virus inhibition

Regulation of early growth response-1 (Egr-1) gene expression by Stat1-independent type I interferon signaling and respiratory viruses

JAK-Inhibitor and Type I Interferon Ability to Produce Favorable Clinical Outcomes in COVID-19 Patients: A Systematic Review and Meta-Analysis

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