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

TLDR

Emerging coronaviruses such as SARS‑CoV trigger fatal acute lung injury by provoking hypercytokinemia and aggressive inflammation, mechanisms that remain poorly understood. In macaque models of SARS‑CoV infection, anti‑spike IgG drives severe acute lung injury by skewing the inflammation‑resolving response. Anti‑spike IgG skews alveolar macrophages toward a proinflammatory phenotype, abrogating wound‑healing responses, increasing MCP1 and IL‑8 production, recruiting proinflammatory monocytes, and correlating with fatal outcomes, thereby revealing a targetable mechanism for virus‑mediated lung injury.

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.