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      Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection

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          Abstract

          <p class="first" id="d6184371e340">Newly emerging viruses, such as severe acute respiratory syndrome coronavirus (SARS-CoV), Middle Eastern respiratory syndrome CoVs (MERS-CoV), and H7N9, cause fatal acute lung injury (ALI) by driving hypercytokinemia and aggressive inflammation through mechanisms that remain elusive. In SARS-CoV/macaque models, we determined that anti–spike IgG (S-IgG), in productively infected lungs, causes severe ALI by skewing inflammation-resolving response. Alveolar macrophages underwent functional polarization in acutely infected macaques, demonstrating simultaneously both proinflammatory and wound-healing characteristics. The presence of S-IgG prior to viral clearance, however, abrogated wound-healing responses and promoted MCP1 and IL-8 production and proinflammatory monocyte/macrophage recruitment and accumulation. Critically, patients who eventually died of SARS (hereafter referred to as deceased patients) displayed similarly accumulated pulmonary proinflammatory, absence of wound-healing macrophages, and faster neutralizing antibody responses. Their sera enhanced SARS-CoV–induced MCP1 and IL-8 production by human monocyte–derived wound-healing macrophages, whereas blockade of FcγR reduced such effects. Our findings reveal a mechanism responsible for virus-mediated ALI, define a pathological consequence of viral specific antibody response, and provide a potential target for treatment of SARS-CoV or other virus-mediated lung injury. </p><p class="first" id="d6184371e343">Using Chinese macaques and SARS patient specimens, anti-spike antibodies were demonstrated to cause severe ALI during acute SARS-CoV infection by skewing inflammation-resolving response. </p>

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          Identification of a Novel Coronavirus in Patients with Severe Acute Respiratory Syndrome

          The severe acute respiratory syndrome (SARS) has recently been identified as a new clinical entity. SARS is thought to be caused by an unknown infectious agent. Clinical specimens from patients with SARS were searched for unknown viruses with the use of cell cultures and molecular techniques. A novel coronavirus was identified in patients with SARS. The virus was isolated in cell culture, and a sequence 300 nucleotides in length was obtained by a polymerase-chain-reaction (PCR)-based random-amplification procedure. Genetic characterization indicated that the virus is only distantly related to known coronaviruses (identical in 50 to 60 percent of the nucleotide sequence). On the basis of the obtained sequence, conventional and real-time PCR assays for specific and sensitive detection of the novel virus were established. Virus was detected in a variety of clinical specimens from patients with SARS but not in controls. High concentrations of viral RNA of up to 100 million molecules per milliliter were found in sputum. Viral RNA was also detected at extremely low concentrations in plasma during the acute phase and in feces during the late convalescent phase. Infected patients showed seroconversion on the Vero cells in which the virus was isolated. The novel coronavirus might have a role in causing SARS. Copyright 2003 Massachusetts Medical Society
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            A novel coronavirus associated with severe acute respiratory syndrome.

            A worldwide outbreak of severe acute respiratory syndrome (SARS) has been associated with exposures originating from a single ill health care worker from Guangdong Province, China. We conducted studies to identify the etiologic agent of this outbreak. We received clinical specimens from patients in seven countries and tested them, using virus-isolation techniques, electron-microscopical and histologic studies, and molecular and serologic assays, in an attempt to identify a wide range of potential pathogens. None of the previously described respiratory pathogens were consistently identified. However, a novel coronavirus was isolated from patients who met the case definition of SARS. Cytopathological features were noted in Vero E6 cells inoculated with a throat-swab specimen. Electron-microscopical examination revealed ultrastructural features characteristic of coronaviruses. Immunohistochemical and immunofluorescence staining revealed reactivity with group I coronavirus polyclonal antibodies. Consensus coronavirus primers designed to amplify a fragment of the polymerase gene by reverse transcription-polymerase chain reaction (RT-PCR) were used to obtain a sequence that clearly identified the isolate as a unique coronavirus only distantly related to previously sequenced coronaviruses. With specific diagnostic RT-PCR primers we identified several identical nucleotide sequences in 12 patients from several locations, a finding consistent with a point-source outbreak. Indirect fluorescence antibody tests and enzyme-linked immunosorbent assays made with the new isolate have been used to demonstrate a virus-specific serologic response. This virus may never before have circulated in the U.S. population. A novel coronavirus is associated with this outbreak, and the evidence indicates that this virus has an etiologic role in SARS. Because of the death of Dr. Carlo Urbani, we propose that our first isolate be named the Urbani strain of SARS-associated coronavirus. Copyright 2003 Massachusetts Medical Society
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              Immunopathogenesis of coronavirus infections: implications for SARS

              Key Points The severe acute respiratory syndrome (SARS), which was first identified in 2003, is caused by a novel coronavirus: the SARS coronavirus (SARS-CoV). Many features of the infection indicate that an excessive, but perhaps 'normal', immune response contributes to SARS. Several coronaviruses cause diseases that result in considerable morbidity and mortality in animals. Some of these diseases are also immune mediated and provide insights into the pathogenesis of SARS. Feline infectious peritonitis virus (FIPV) causes a fatal, immune-mediated disease of felines. Macrophage infection, lymphocyte depletion and antibody-dependent disease enhancement are hallmarks of this disease. Infection with the murine coronavirus murine hepatitis virus (MHV) strain JHM results in immune-mediated demyelination. Similar to SARS, macrophage activation is a key component in the pathogenic process. Another strain of MHV, MHV-3, causes a fatal, fulminant hepatitis. MHV-3 infection of macrophages, with subsequent activation and induction of expression of a novel procoagulant, fibrinogen-like protein 2 (FGL2), is required for severe disease. Chickens that are infected with avian infectious bronchitis virus (IBV) develop respiratory and renal disease. An excessive innate immune response contributes to the pathogenic process in these animals. To develop effective therapies for SARS will require understanding of the contributions of direct injury by virus and of the host immune response to pathogenesis. This requires further studies of the interactions of SARS-CoV with its target cells and necessitates the development of an animal model that reproduces the pulmonary infection that is observed in infected humans.
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                Author and article information

                Journal
                JCI Insight
                American Society for Clinical Investigation
                2379-3708
                February 21 2019
                February 21 2019
                February 21 2019
                February 21 2019
                : 4
                : 4
                Article
                10.1172/jci.insight.123158
                6478436
                30830861
                c1ee34bd-f6f4-4d85-b4da-7c749a84ed8a
                © 2019
                History

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