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. 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.
【저자키워드】 Cytokines, macrophages, immunoglobulins, Infectious disease, Pulmonology, 【초록키워드】 Treatment, viruses, IgG, Inflammation, coronavirus, SARS-CoV, Antibody Response, hypercytokinemia, Lung injury, MERS-CoV, viral clearance, acute lung injury, proinflammatory, Characteristics, sera, response, Lungs, Patient, IL-8, CoV, macaque, recruitment, specimens, patients, mechanism, alveolar macrophage, anti-spike antibody, macaques, Deceased, H7N9, acute respiratory syndrome, syndrome, Chinese, SARS-CoV infection, neutralizing antibody responses, blockade, FcγR, driving, middle, MCP1, Effects, responsible, SARS patient, died, reduced, functional, absence, faster, demonstrated, cause, abrogated, promoted, accumulated, 【제목키워드】 IgG, acute lung injury, SARS-CoV infection, Macrophage response, cause,