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Anti–spike IgG causes severe acute lung injury by skewing macrophage responses during acute SARS-CoV infection
Li Liu, … , Kwok-Yung Yuen, Zhiwei Chen
Li Liu, … , Kwok-Yung Yuen, Zhiwei Chen
Published February 21, 2019
Citation Information: JCI Insight. 2019;4(4):e123158. https://doi.org/10.1172/jci.insight.123158.
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Research Article Infectious disease Pulmonology

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

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Abstract

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.

Authors

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

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Figure 3

SARS-CoV infection and monocytes/macrophages infiltration in the lungs of C-IgG– and S-IgG–treated macaques at 2 dpi.

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SARS-CoV infection and monocytes/macrophages infiltration in the lungs o...
(A) Representative images of SARS-CoV RNA+ (TRITC) and AE1/AE3+ (FITC) cells in the lungs of infected macaques (white arrows). The upper photo shows a low magnification overview (200×); the bottom photo shows the boxed area in the upper photo. (B) Representative images of viral protein (NP) immunostaining of the lungs and hilar lymph nodes (LN) of 7 infected and 3 uninfected animals (TRITC, white arrows) (original magnification, 200×). (C) Representative images of viral NP and monocytes/macrophages. These sections showed significantly increased IMMs in the lungs of the S-IgG group compared with the C-IgG group (MAC387+, CD163+, or CD68+; blue arrows). Tissue samples are double-immunostained for the SARS-CoV NP (TRITC) and markers for macrophages, including MAC387 (FITC), CD163 (FITC), and CD68 (FITC). Within the panel of representative images for the C-IgG and S-IgG groups, the left panel shows a low magnification overview; the right panel shows the boxed area in the left panel (original magnification, 200×).

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