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      Intranasal inoculation of female BALB/c mice with replication-deficient human adenovirus type 5 expressing SARS-CoV‐2 nucleocapsid protein aggravates lung pathology upon re-encountering the antigen

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          Highlights

          • •

            Intranasal inoculation of Ad5 expressing SARS-CoV-2 N aggravates lung pathology.

          • •

            Enhanced infiltration of T cells in Ad5-N group.

          • •

            More T cells and granulocytes undergo necroptosis in Ad5-N group.

          • •

            Accumulated T cells are antigen-experienced and express more IFN-γ.

          Abstract

          Preclinical studies indicate that SARS-CoV-2 nucleocapsid (N)-based vaccines, along with other viral protein(s), confer protection in various animal models against infection by SARS-CoV-2 ancestral virus and variants of concern. However, the optimal vaccination procedure and the role of N-specific host adaptive immune responses remain elusive. Here, we report that intranasal inoculation with replication-deficient human adenovirus type 5 expressing SARS-CoV‐2 N protein (Ad5-N) conferred no protection in the lung of female BALB/c mice upon re-encountering the antigen, either by 10-fold Ad5-N re-exposure or sublethal infection of mouse-adapted SARS-CoV-2. By contrast, this procedure led to aggravated lung pathology with more necroptotic CD3 + T cells and Ly6G + granulocytes, which was associated with the accumulation of IFN‐γ‐expressing antigen-experienced CD4 + and CD8 + T cells. These findings pre-caution the clinical application of this vaccination procedure. Furthermore, our data suggest that excessive host adaptive immune responses against N protein contributes to COVID-19 pathogenesis.

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          A new coronavirus associated with human respiratory disease in China

          Fan Wu, Su Zhao, Bin Yu … (2020)
          Emerging infectious diseases, such as severe acute respiratory syndrome (SARS) and Zika virus disease, present a major threat to public health 1–3 . Despite intense research efforts, how, when and where new diseases appear are still a source of considerable uncertainty. A severe respiratory disease was recently reported in Wuhan, Hubei province, China. As of 25 January 2020, at least 1,975 cases had been reported since the first patient was hospitalized on 12 December 2019. Epidemiological investigations have suggested that the outbreak was associated with a seafood market in Wuhan. Here we study a single patient who was a worker at the market and who was admitted to the Central Hospital of Wuhan on 26 December 2019 while experiencing a severe respiratory syndrome that included fever, dizziness and a cough. Metagenomic RNA sequencing 4 of a sample of bronchoalveolar lavage fluid from the patient identified a new RNA virus strain from the family Coronaviridae, which is designated here ‘WH-Human 1’ coronavirus (and has also been referred to as ‘2019-nCoV’). Phylogenetic analysis of the complete viral genome (29,903 nucleotides) revealed that the virus was most closely related (89.1% nucleotide similarity) to a group of SARS-like coronaviruses (genus Betacoronavirus, subgenus Sarbecovirus) that had previously been found in bats in China 5 . This outbreak highlights the ongoing ability of viral spill-over from animals to cause severe disease in humans.
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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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              Targets of T cell responses to SARS-CoV-2 coronavirus in humans with COVID-19 disease and unexposed individuals

              Alba Grifoni, Daniela Weiskopf, Sydney Ramirez … (2020)
              Summary Understanding adaptive immunity to SARS-CoV-2 is important for vaccine development, interpreting coronavirus disease 2019 (COVID-19) pathogenesis, and calibration of pandemic control measures. Using HLA class I and II predicted peptide ‘megapools’, circulating SARS-CoV-2−specific CD8+ and CD4+ T cells were identified in ∼70% and 100% of COVID-19 convalescent patients, respectively. CD4+ T cell responses to spike, the main target of most vaccine efforts, were robust and correlated with the magnitude of the anti-SARS-CoV-2 IgG and IgA titers. The M, spike and N proteins each accounted for 11-27% of the total CD4+ response, with additional responses commonly targeting nsp3, nsp4, ORF3a and ORF8, among others. For CD8+ T cells, spike and M were recognized, with at least eight SARS-CoV-2 ORFs targeted. Importantly, we detected SARS-CoV-2−reactive CD4+ T cells in ∼40-60% of unexposed individuals, suggesting cross-reactive T cell recognition between circulating ‘common cold’ coronaviruses and SARS-CoV-2.
              Article 0 comments Cited 1962 times – based on 0 reviews     Review now
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                Author and article information

                Contributors
                Jiyan Zhang
                Hui Wang
                Journal
                Journal ID (nlm-ta): Virus Res
                Journal ID (iso-abbrev): Virus Res
                Title: Virus Research
                Publisher: Elsevier
                ISSN (Print): 0168-1702
                ISSN (Electronic): 1872-7492
                Publication date PMC-release: 18 August 2023
                Publication date Collection: 02 October 2023
                Publication date (Electronic): 18 August 2023
                Volume: 335
                Electronic Location Identifier: 199201
                Affiliations
                [a ]Beijing Institute of Basic Medical Sciences, Beijing 100850, China
                [b ]Beijing Institute of Microbiology and Epidemiology, Beijing 100071, China
                [c ]University of South China, Hengyang Medical School, Hengyang 421001, China
                [d ]Anhui Medical University, Hefei 230032, China
                [e ]Chinese Institute for Brain Research, Beijing 102206, China
                Author notes
                [f]

                These authors contributed equally: Junxia Cao, Hongjing Gu, Xueting Zhang

                Article
                Publisher Item ID: S0168-1702(23)00163-6 Publisher ID: 199201
                DOI: 10.1016/j.virusres.2023.199201
                PMC ID: 10470087
                PubMed ID: 37595663
                SO-VID: f1a9d302-a6ca-4ed4-8364-b5c8ac3dbf5d
                Copyright © © 2023 The Authors. Published by Elsevier B.V.
                License:

                This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).

                History
                Date received : 29 May 2023
                Date revision received : 27 July 2023
                Date accepted : 15 August 2023
                Categories
                Subject: Article

                ScienceOpen disciplines: Microbiology & Virology
                Keywords: sars‐cov-2,nucleocapsid,intranasal vaccination,necroptosis,t cells
                Data availability:
                ScienceOpen disciplines: Microbiology & Virology
                Keywords: sars‐cov-2, nucleocapsid, intranasal vaccination, necroptosis, t cells

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