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.
View: Text | PDF
Research Article Infectious disease Pulmonology

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

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

×

Figure 8

Sera from deceased SARS patients skewed wound-healing macrophage response partially through FcγR.

Options: View larger image (or click on image) Download as PowerPoint
Sera from deceased SARS patients skewed wound-healing macrophage respons...
In vitro–polarized alternatively activated MDM were either left unstimulated or were incubated with SARS-CoV pseudovirus alone or cocultured with SARS-CoV pseudovirus and 1–400,000 serials diluted or 1/4,000 diluted sera from deceased (n = 5) or recovered SARS patients (n = 7) for 20 hours. Cells treated with sera from patients alone served as controls. Secreted cytokine and chemokine levels were measured in the culture supernatant and are shown in data represented as a column graph (A, C, and D) and fold or percentage over supernatants from macrophages treated with virus alone (B and F). A and B show that addition of sera from deceased patient (D1) dose-dependently enhanced production of IL-8, IL-6, and MCP1 by SARS-CoV–treated alternatively activated MDM. C and D show significantly enhanced IL-8 and MCP1 production by alternatively activated macrophages treated with sera from deceased SARS patients and virus compared with cells treated with virus alone. Sera treatment alone did not induce IL-8 or MCP1 production. (E) Correlation of IL-8 production with NAb titers of sera of deceased patients. Solid lines denote the relationship between histopathology scores and serum neutralizing activity. (F) Blockade of human FcγR significantly reduced antiserum-enhanced IL-8 secretion and partially reduced MCP1 secretion. In vitro–polarized alternatively activated human monocyte–derived macrophages were cocultured with SARS-CoV pseudovirus and 1–4,000 diluted sera from deceased patient (D1) with or without FcγR blocking antibody for 20 hours. Secreted cytokine and chemokine levels were measured in the culture supernatant and are shown in data represented as increase over supernatants from macrophages treated with virus alone. Data represent mean values or mean values ± SEM of at least 3 independent experiments. Two-tailed unpaired Student’s t test and Spearman’s rank correlation test were used for statistical analysis.