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      Type III interferons disrupt the lung epithelial barrier upon viral recognition

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          Abstract

          Lower respiratory tract viral infections are a leading cause of mortality. Mounting evidence indicates that most severe cases are characterized by aberrant immune responses and do not depend on viral burden. Here, we assessed how type III interferons (IFN-λ) contribute to the pathogenesis induced by RNA viruses. We report IFN-λ is present in the lower, but not upper, airways of COVID-19 patients. In mice, we demonstrate IFN-λ produced by lung dendritic cells in response to a synthetic viral RNA induces barrier damage, causing susceptibility to lethal bacterial superinfections. These findings provide a strong rationale for rethinking the pathophysiological role of IFN-λ and its possible use in the clinical practice against endemic viruses, such as influenza virus, as well as the emerging SARS-CoV-2 viral infection.

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          Virological assessment of hospitalized patients with COVID-2019

          Roman Wölfel, Victor M Corman, Wolfgang Guggemos … (2020)
          Coronavirus disease 2019 (COVID-19) is an acute infection of the respiratory tract that emerged in late 20191,2. Initial outbreaks in China involved 13.8% of cases with severe courses, and 6.1% of cases with critical courses3. This severe presentation may result from the virus using a virus receptor that is expressed predominantly in the lung2,4; the same receptor tropism is thought to have determined the pathogenicity-but also aided in the control-of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of cases of COVID-19 in which the patient shows mild upper respiratory tract symptoms, which suggests the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on virus replication, immunity and infectivity in specific sites of the body. Here we report a detailed virological analysis of nine cases of COVID-19 that provides proof of active virus replication in tissues of the upper respiratory tract. Pharyngeal virus shedding was very high during the first week of symptoms, with a peak at 7.11 × 108 RNA copies per throat swab on day 4. Infectious virus was readily isolated from samples derived from the throat or lung, but not from stool samples-in spite of high concentrations of virus RNA. Blood and urine samples never yielded virus. Active replication in the throat was confirmed by the presence of viral replicative RNA intermediates in the throat samples. We consistently detected sequence-distinct virus populations in throat and lung samples from one patient, proving independent replication. The shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (and by day 14 in all patients), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild illness of the upper respiratory tract. The confirmation of active virus replication in the upper respiratory tract has implications for the containment of COVID-19.
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            Imbalanced Host Response to SARS-CoV-2 Drives Development of COVID-19

            Daniel Blanco-Melo, Benjamin E. Nilsson-Payant, Wen-Chun Liu … (2021)
            Summary Viral pandemics, such as the one caused by SARS-CoV-2, pose an imminent threat to humanity. Because of its recent emergence, there is a paucity of information regarding viral behavior and host response following SARS-CoV-2 infection. Here we offer an in-depth analysis of the transcriptional response to SARS-CoV-2 compared with other respiratory viruses. Cell and animal models of SARS-CoV-2 infection, in addition to transcriptional and serum profiling of COVID-19 patients, consistently revealed a unique and inappropriate inflammatory response. This response is defined by low levels of type I and III interferons juxtaposed to elevated chemokines and high expression of IL-6. We propose that reduced innate antiviral defenses coupled with exuberant inflammatory cytokine production are the defining and driving features of COVID-19.
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              Pathological inflammation in patients with COVID-19: a key role for monocytes and macrophages

              Miriam Merad, Jérôme C. Martin, John Lambris (2020)
              The COVID-19 pandemic caused by infection with SARS-CoV-2 has led to more than 200,000 deaths worldwide. Several studies have now established that the hyperinflammatory response induced by SARS-CoV-2 is a major cause of disease severity and death in infected patients. Macrophages are a population of innate immune cells that sense and respond to microbial threats by producing inflammatory molecules that eliminate pathogens and promote tissue repair. However, a dysregulated macrophage response can be damaging to the host, as is seen in the macrophage activation syndrome induced by severe infections, including in infections with the related virus SARS-CoV. Here we describe the potentially pathological roles of macrophages during SARS-CoV-2 infection and discuss ongoing and prospective therapeutic strategies to modulate macrophage activation in patients with COVID-19.
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                Author and article information

                Journal
                Journal ID (nlm-ta): Science
                Journal ID (iso-abbrev): Science
                Journal ID (publisher-id): SCIENCE
                Title: Science (New York, N.y.)
                Publisher: American Association for the Advancement of Science
                ISSN (Print): 0036-8075
                ISSN (Electronic): 1095-9203
                Publication date (Electronic): 11 June 2020
                Electronic Location Identifier: eabc3545
                Affiliations
                [1 ]Harvard Medical School, Boston Children’s Hospital, Division of Immunology, Boston, MA, USA.
                [2 ]Department of Biotechnology and Biosciences, University of Milano - Bicocca, Milan, Italy.
                [3 ]Institute for Quantitative and Computational Biosciences, University of California, Los Angeles, CA, USA.
                [4 ]Laboratory of Medical Microbiology and Virology, Vita-Salute San Raffaele University, Milan, Italy.
                [5 ]Rheumatology and Clinical Immunology, Humanitas Clinical and Research Center - IRCCS, Rozzano, Italy.
                [6 ]IRCCS San Raffaele Hospital, Milan, Italy.
                [7 ]INGM-National Institute of Molecular Genetics “Romeo ed Enrica Invernizzi” Milan, Italy.
                [8 ]Harvard Medical School, Boston Children’s Hospital, Division of Gastroenterology, Boston, MA, USA.
                Author notes
                [*]

                These authors contributed equally to this work.

                [†]

                Present address: Vir Biotechnology, San Francisco, CA, USA.

                [‡ ]Corresponding author. Email: ivan.zanoni@ 123456childrens.harvard.edu
                Author information
                https://orcid.org/0000-0002-7244-2401
                https://orcid.org/0000-0003-2956-4830
                https://orcid.org/0000-0001-9507-187X
                https://orcid.org/0000-0002-7729-9472
                https://orcid.org/0000-0001-5888-3668
                https://orcid.org/0000-0002-1822-9861
                https://orcid.org/0000-0002-3196-1336
                https://orcid.org/0000-0003-0637-0910
                https://orcid.org/0000-0002-7046-4914
                https://orcid.org/0000-0002-3423-7474
                Article
                Publisher ID: abc3545
                DOI: 10.1126/science.abc3545
                PMC ID: 7292499
                PubMed ID: 32527925
                SO-VID: bebd8aab-4f26-4a28-ba35-68a891140fc1
                Copyright © Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works. Distributed under a Creative Commons Attribution License 4.0 (CC BY).
                License:

                This is an open-access article distributed under the terms of the Creative Commons Attribution license, which permits use, distribution, and reproduction in any medium, so long as the resultant use is not for commercial advantage and provided the original work is properly cited.

                History
                Date received : 21 April 2020
                Date accepted : 08 June 2020
                Funding
                Funded by: doi http://dx.doi.org/10.13039/100000062, National Institute of Diabetes and Digestive and Kidney Diseases;
                Award ID: 1R01DK115217
                Categories
                Subject: Report
                Subject: Reports
                Subject: Reports
                Subject: Immunology
                Custom metadata
                Number-color-figs 1
                Number-figs 4

                ScienceOpen disciplines: Uncategorized
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                ScienceOpen disciplines: Uncategorized

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