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      TLR2 senses the SARS-CoV-2 envelope protein to produce inflammatory cytokines

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          SUMMARY

          The innate immune response is critical for recognizing and controlling infections through the release of cytokines and chemokines. However, severe pathology during some infections, including SARS-CoV-2, is driven by hyperactive cytokine release, or cytokine storm. The innate sensors that activate production of pro-inflammatory cytokines and chemokines during COVID-19 remain poorly characterized. Here we show that both TLR2 and MYD88 expression were associated with COVID-19 disease severity. Mechanistically, TLR2 and MyD88 were required for β-coronavirus–induced inflammatory responses, and TLR2-dependent signaling induced the production of pro-inflammatory cytokines during coronavirus infection independent of viral entry. TLR2 sensed the SARS-CoV-2 envelope protein as its ligand. Additionally, blocking TLR2 signaling in vivo provided protection against the pathogenesis of SARS-CoV-2 infection. Overall, our study provides a critical understanding of the molecular mechanism of β-coronavirus sensing and inflammatory cytokine production, which opens new avenues for therapeutic strategies to counteract the ongoing COVID-19 pandemic.

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          Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China

          Chaolin Huang, Yeming Wang, Xingwang Li … (2020)
          Summary Background A recent cluster of pneumonia cases in Wuhan, China, was caused by a novel betacoronavirus, the 2019 novel coronavirus (2019-nCoV). We report the epidemiological, clinical, laboratory, and radiological characteristics and treatment and clinical outcomes of these patients. Methods All patients with suspected 2019-nCoV were admitted to a designated hospital in Wuhan. We prospectively collected and analysed data on patients with laboratory-confirmed 2019-nCoV infection by real-time RT-PCR and next-generation sequencing. Data were obtained with standardised data collection forms shared by WHO and the International Severe Acute Respiratory and Emerging Infection Consortium from electronic medical records. Researchers also directly communicated with patients or their families to ascertain epidemiological and symptom data. Outcomes were also compared between patients who had been admitted to the intensive care unit (ICU) and those who had not. Findings By Jan 2, 2020, 41 admitted hospital patients had been identified as having laboratory-confirmed 2019-nCoV infection. Most of the infected patients were men (30 [73%] of 41); less than half had underlying diseases (13 [32%]), including diabetes (eight [20%]), hypertension (six [15%]), and cardiovascular disease (six [15%]). Median age was 49·0 years (IQR 41·0–58·0). 27 (66%) of 41 patients had been exposed to Huanan seafood market. One family cluster was found. Common symptoms at onset of illness were fever (40 [98%] of 41 patients), cough (31 [76%]), and myalgia or fatigue (18 [44%]); less common symptoms were sputum production (11 [28%] of 39), headache (three [8%] of 38), haemoptysis (two [5%] of 39), and diarrhoea (one [3%] of 38). Dyspnoea developed in 22 (55%) of 40 patients (median time from illness onset to dyspnoea 8·0 days [IQR 5·0–13·0]). 26 (63%) of 41 patients had lymphopenia. All 41 patients had pneumonia with abnormal findings on chest CT. Complications included acute respiratory distress syndrome (12 [29%]), RNAaemia (six [15%]), acute cardiac injury (five [12%]) and secondary infection (four [10%]). 13 (32%) patients were admitted to an ICU and six (15%) died. Compared with non-ICU patients, ICU patients had higher plasma levels of IL2, IL7, IL10, GSCF, IP10, MCP1, MIP1A, and TNFα. Interpretation The 2019-nCoV infection caused clusters of severe respiratory illness similar to severe acute respiratory syndrome coronavirus and was associated with ICU admission and high mortality. Major gaps in our knowledge of the origin, epidemiology, duration of human transmission, and clinical spectrum of disease need fulfilment by future studies. Funding Ministry of Science and Technology, Chinese Academy of Medical Sciences, National Natural Science Foundation of China, and Beijing Municipal Science and Technology Commission.
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            SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor

            Markus Hoffmann, Hannah Kleine-Weber, Simon Schroeder … (2020)
            Summary The recent emergence of the novel, pathogenic SARS-coronavirus 2 (SARS-CoV-2) in China and its rapid national and international spread pose a global health emergency. Cell entry of coronaviruses depends on binding of the viral spike (S) proteins to cellular receptors and on S protein priming by host cell proteases. Unravelling which cellular factors are used by SARS-CoV-2 for entry might provide insights into viral transmission and reveal therapeutic targets. Here, we demonstrate that SARS-CoV-2 uses the SARS-CoV receptor ACE2 for entry and the serine protease TMPRSS2 for S protein priming. A TMPRSS2 inhibitor approved for clinical use blocked entry and might constitute a treatment option. Finally, we show that the sera from convalescent SARS patients cross-neutralized SARS-2-S-driven entry. Our results reveal important commonalities between SARS-CoV-2 and SARS-CoV infection and identify a potential target for antiviral intervention.
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              NF-κB signaling in inflammation

              Ting Ting Liu, Lingyun Zhang, Donghyun Joo … (2017)
              The transcription factor NF-κB regulates multiple aspects of innate and adaptive immune functions and serves as a pivotal mediator of inflammatory responses. NF-κB induces the expression of various pro-inflammatory genes, including those encoding cytokines and chemokines, and also participates in inflammasome regulation. In addition, NF-κB plays a critical role in regulating the survival, activation and differentiation of innate immune cells and inflammatory T cells. Consequently, deregulated NF-κB activation contributes to the pathogenic processes of various inflammatory diseases. In this review, we will discuss the activation and function of NF-κB in association with inflammatory diseases and highlight the development of therapeutic strategies based on NF-κB inhibition.
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                Author and article information

                Journal
                Journal ID (nlm-journal-id): 100941354
                Journal ID (pubmed-jr-id): 21750
                Journal ID (nlm-ta): Nat Immunol
                Journal ID (iso-abbrev): Nat Immunol
                Title: Nature immunology
                ISSN (Print): 1529-2908
                ISSN (Electronic): 1529-2916
                Publication date Nihms-submitted: 22 January 2022
                Publication date (Print): July 2021
                Publication date (Electronic): 07 May 2021
                Publication date PMC-release: 27 February 2022
                Volume: 22
                Issue: 7
                Pages: 829-838
                Affiliations
                [1 ]Department of Immunology, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
                [2 ]Department of Microbiology, Immunology, & Biochemistry, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
                [3 ]UTHSC Regional Biocontainment Laboratory, University of Tennessee Health Science Center, Memphis, TN, 38163, USA
                [4 ]Animal Resources Center and Veterinary Pathology Core, St. Jude Children’s Research Hospital, Memphis, TN, 38105, USA
                Author notes

                AUTHOR CONTRIBUTIONS STATEMENT

                M.Z. and T.-D.K. conceptualized the study; M.Z. and R.K. designed the methodology; M.Z., R.K., E.P.W., D.Y., E.F., and P.V. performed the experiments; M.Z. and R.K. conducted the analysis; C.B.J. provided critical reagents and scientific discussion; M.Z. and T.-D.K. wrote the manuscript with input from all authors. T.-D.K. acquired the funding and provided overall supervision.

                [* ]Correspondence to: Thirumala-Devi Kanneganti, Department of Immunology, St. Jude Children’s Research Hospital, MS #351, 262 Danny Thomas Place, Memphis TN 38105-3678, Tel: (901) 595-3634; Fax. (901) 595-5766., Thirumala-Devi.Kanneganti@ 123456StJude.org
                Article
                Manuscript ID: NIHMS1695108
                DOI: 10.1038/s41590-021-00937-x
                PMC ID: 8882317
                PubMed ID: 33963333
                SO-VID: d466edf2-7b3e-4851-9edc-c4e82df69127
                License:

                Users may view, print, copy, and download text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use: http://www.nature.com/authors/editorial_policies/license.html#terms

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                Subject: Article

                ScienceOpen disciplines: Immunology
                Keywords: covid-19,mhv,sars-cov-2,β-coronavirus,inflammatory cytokines,cytokine storm,tnf-α,ifn-γ,tlr2,envelope protein,nf-κb,erk,inflammation
                Data availability:
                ScienceOpen disciplines: Immunology
                Keywords: covid-19, mhv, sars-cov-2, β-coronavirus, inflammatory cytokines, cytokine storm, tnf-α, ifn-γ, tlr2, envelope protein, nf-κb, erk, inflammation

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