Interferon-β-1a Inhibition of Severe Acute Respiratory Syndrome–Coronavirus 2 In Vitro When Administered After Virus Infection

Clementi, Nicola; Ferrarese, Roberto; Criscuolo, Elena; Diotti, Roberta Antonia; Castelli, Matteo; Scagnolari, Carolina; Burioni, Roberto; Antonelli, Guido; Clementi, Massimo; Mancini, Nicasio

doi:10.1093/infdis/jiaa350

Cited by 70 publications

(76 citation statements)

References 15 publications

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“…Importantly, IFN responses were found to be milder than TNF-NFkB signaling in our model. SARS-CoV-2 has been shown to be sensitive to IFNλ and IFNβ treatment, so the absence of a robust IFN response in AT2s, if verified in vivo, would have significant clinical implications and might suggest pathways to augment therapeutically in COVID-19 patients before they progress to ARDS [20][21][22] . In prior studies of cell lines that lacked AT2-specific gene expression, the absence of a robust IFN response was overcome by using a high MOI for infection 21 .…”

Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

Huang

Hume

Abo

et al. 2020

Preprint

102

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ABSTRACTThe most severe and fatal infections with SARS-CoV-2 result in the acute respiratory distress syndrome, a clinical phenotype of coronavirus disease 2019 (COVID-19) that is associated with virions targeting the epithelium of the distal lung, particularly the facultative progenitors of this tissue, alveolar epithelial type 2 cells (AT2s). Little is known about the initial responses of human lung alveoli to SARS-CoV-2 infection due in part to inability to access these cells from patients, particularly at early stages of disease. Here we present an in vitro human model that simulates the initial apical infection of the distal lung epithelium with SARS-CoV-2, using AT2s that have been adapted to air-liquid interface culture after their derivation from induced pluripotent stem cells (iAT2s). We find that SARS-CoV-2 induces a rapid global transcriptomic change in infected iAT2s characterized by a shift to an inflammatory phenotype predominated by the secretion of cytokines encoded by NF-kB target genes, delayed epithelial interferon responses, and rapid loss of the mature lung alveolar epithelial program. Over time, infected iAT2s exhibit cellular toxicity that can result in the death of these key alveolar facultative progenitors, as is observed in vivo in COVID-19 lung autopsies. Importantly, drug testing using iAT2s confirmed the efficacy of TMPRSS2 protease inhibition, validating putative mechanisms used for viral entry in human alveolar cells. Our model system reveals the cell-intrinsic responses of a key lung target cell to infection, providing a platform for further drug development and facilitating a deeper understanding of COVID-19 pathogenesis.

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Section: Discussionmentioning

confidence: 99%

SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

Huang

Hume

Abo

et al. 2020

Preprint

102

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“…Many studies have shown the protective effect of type I IFN associated with antiviral therapies for patients with SARS and MERS [reviewed by Sallard et al (334)], which arouses the interest of the scientific community in type I IFN as a potential treatment against SARS-CoV-2 (334)(335)(336)(337). Despite their efficacy against SARS-CoV-2 (338,339), the results of in vitro studies using IFN-a and -b to treat COVID-19 patients remain inconclusive.…”

Section: Antiviralsmentioning

confidence: 99%

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

et al. 2020

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Coronavirus Disease 2019 (COVID-19) has been classified as a global threat, affecting millions of people and killing thousands. It is caused by the SARS-CoV-2 virus, which emerged at the end of 2019 in Wuhan, China, quickly spreading worldwide. COVID-19 is a disease with symptoms that range from fever and breathing difficulty to acute respiratory distress and death, critically affecting older patients and people with previous comorbidities. SARS-CoV-2 uses the angiotensin-converting enzyme 2 (ACE2) receptor and mainly spreads through the respiratory tract, which it then uses to reach several organs. The immune system of infected patients has been demonstrated to suffer important alterations, such as lymphopenia, exhausted lymphocytes, excessive amounts of inflammatory monocytes and macrophages, especially in the lungs, and cytokine storms, which may contribute to its severity and difficulty of establishing an effective treatment. Even though no specific treatment is currently available, several studies have been investigating potential therapeutic strategies, including the use of previously approved drugs and immunotherapy. In this context, this review addresses the interaction between SARS-CoV-2 and the patient's host immune system during infection, in addition to discussing the main immunopathological mechanisms involved in the development of the disease and potential new therapeutic approaches.

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“…A recent study of SARS-CoV-2 infection has reported that type III and type-I interferons are downregulated both in SARS-CoV-2 infected cells and in the lung tissue of patients deceased with COVID-19 (7), suggesting a pathogenic mechanism similar to that hypothesized for SARS-CoV and MERS-CoV (8). Furthermore, some from our group have recently shown that IFNβ inhibits replication of SARS-CoV-2 in vitro (9).…”

Section: Introduction Background and Rationale {6a}mentioning

confidence: 80%

“…[Time frame: baseline, days3,5,7,9,11,13,15, 21, 29]. IFNβ-1a has direct in vitro antiviral activity against SARS-CoV-2(9), while IFNβ-1b has been identi ed as the key therapeutic reducing the time to negative conversion of SARS-CoV-2 nasopharyngeal swabs in a recent trial(11).Secondary outcomes I)a. Improvement in clinical severity score, de ned as percentage of patients reporting each severity rating on a 7-point ordinal scale (as de ned above in the Eligibility criteria {10}).…”

mentioning

confidence: 99%

Interferon β-1a (IFNβ-1a) in COVID-19 patients (INTERCOP): study protocol for a randomized controlled trial.

Bosi

Querini

et al. 2020

Preprint

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Background: Pharmacological therapies of proven efficacy in coronavirus disease 2019 (COVID-19) are still lacking. We have identified IFNβ-1a as the most promising drug to be repurposed for COVID-19. The rationale relies on the evidence of IFNβ anti-viral activity in vitro against SARS-CoV-2 and animal models resembling SARS-CoV-2 infection and on a recent clinical trial where IFNβ was indicated as the key component of a successful therapeutic combination. Methods: This is a randomized, controlled, open-label, monocentric, phase II trial (INTERCOP trial). 126 patients with positive swab detection of SARS-CoV-2, radiological signs of pneumonia, and mild-to-moderate disease will be randomized 2:1 to IFNβ-1a in addition to standard of care vs standard of care alone. No other anti-viral drugs will be used as part of the regimens, both in the control and the intervention arms. IFNβ-1a will be administered subcutaneously at the dose of 44 mcg (equivalent to 12 million international units) three times per week, at least 48 hours apart, for a total of two weeks. The primary outcome is the time to negative conversion of SARS-CoV-2 nasopharyngeal swabs. Secondary outcomes include improvement or worsening in a clinical severity score measured on a 7-point ordinal scale (including transfer to intensive care unit and death), oxygen- and ventilator-free days, mortality, changes in pulmonary computed tomography severity score, hospital stay duration, reduction of viral load measured on nasopharyngeal swabs, number of serious adverse events, changes in biochemical markers of organ dysfunction. Exploratory outcomes include blood cell counts, cytokine and inflammatory profile, peripheral mRNA expression profiles of interferon-stimulated genes, antibodies to SARS-CoV-2 and to IFNβ-1a. INTERCOP is the first study to specifically investigate the clinical benefits of IFNβ-1a in COVID-19 patients.Discussion: Potential implications of this trial are multifaceted: should the primary outcome be fulfilled and the treatment be safe, one may envisage that IFNβ-1a be used to reduce the infectivity of patients with mild-to moderate disease. In case IFNβ-1a reduced the duration of hospital stay and/or ameliorated the clinical status, it may become a cornerstone of COVID-19 treatment.Trial registration: EudraCT 2020-002458-25. Registered on May 11, 2020ClinicalTrials.gov Identifier: NCT04449380

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Interferon-β-1a Inhibition of Severe Acute Respiratory Syndrome–Coronavirus 2 In Vitro When Administered After Virus Infection

Cited by 70 publications

References 15 publications

SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

SARS-CoV-2 Infection of Pluripotent Stem Cell-derived Human Lung Alveolar Type 2 Cells Elicits a Rapid Epithelial-Intrinsic Inflammatory Response

A 21st Century Evil: Immunopathology and New Therapies of COVID-19

Interferon β-1a (IFNβ-1a) in COVID-19 patients (INTERCOP): study protocol for a randomized controlled trial.

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