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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 1

ADS-MVA–induced S-specific immune response enhanced pulmonary pathology in SARS-CoV–infected Chinese rhesus macaques.

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ADS-MVA–induced S-specific immune response enhanced pulmonary pathology ...
(A) Experimental design used to investigate the influence of S-specific immunity on SARS-CoV–induced lung injury. Two groups of Chinese rhesus macaques (n = 8/group) were subjected to i.m. injections of ADS-MVA or control vaccine ADC-MVA at weeks 0 and 4, followed by i.n. challenge with live pathogenic SARS-CoVPUMC (1 × 105 TCID50) at 4 weeks after the second vaccination. Four animals each were sacrificed at 1 and 5 weeks after inoculation. Three healthy macaques were included as controls. (B) Serum neutralizing activity. Sera collected from macaques were tested for a capacity to neutralize SARS-CoV pseudotype virus. (C) Detection of viral RNA in oral swabs. SARS-CoV RNA was detected by nested RT-PCR in the swabs at the indicated time points relative to infection. (D) Pathology changes of the lung tissue. Sections were stained with H&E. D shows symptom of acute DAD exhibited in 6 of 8 ADS-MVA–vaccinated macaques with extensive exudation (yellow arrow), hyaline membranes lining the alveolar walls (black arrows), and massive cell infiltration in alveolar cavities (white arrow). Left image shows a low magnification overview (100×). Middle image shows higher magnification of the boxed area in left image (200×). Right image shows minor inflammation observed in 7 macaques received ADC-MVA (n = 8) with slight alveolar septa broadening and sparse monocyte infiltration (original magnification, 100×). (E) Histopathological scores of the ADS-MVA group, including lung samples collected at both 7 and 35 dpi, were compared against the ADC-MVA control group. See Supplemental Figure 1 for the scoring index based on severity of lung histopathology. Data represent mean ± SEM values. Statistical analysis was undertaken using 2-tailed unpaired Student’s t test. *P < 0.05, n = 4. (F) Correlation of lung histopathological scores of all macaques with sera NAb titers at 0 dpi. Solid lines denote the relationship between histopathology scores and serum neutralizing activity. Statistical analysis was performed using Spearman’s rank correlation test.

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