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

Liu, Li; Wei, Qiang; Lin, Qingqing; Fang, Jun; Wang, Haibo; Kwok, Hauyee; Tang, Hangying; Nishiura, Kenji; Peng, Jie; Tan, Zhiwu; Wu, Tongjin; Cheung, Ka-Wai; Chan, Kwok-Hung; Alvarez, Xavier; Qin, Chuan; Lackner, Andrew; Perlman, Stanley; Yuen, Kwok-Yung; Chen, Zhiwei

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.