Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) primarily targets the respiratory epithelium, yet severe disease features diffuse lung injury and hyperinflammatory syndromes driven by dysregulated immune activation. Emerging evidence indicates that resident and infiltrating immune cells in the lung can encounter the virus early in infection and, under specific conditions, become infected. This process amplifies local inflammation and facilitates viral propagation in the lower airways and distal lung regions, where angiotensin converting enzyme 2 (ACE2) expression is limited. However, how epithelial and immune cell compartments interact to produce the hallmark pulmonary pathology of SARS-CoV-2 infection remains unresolved. Here we show that secreted ORF8, a SARS-CoV-2 accessory protein, drives inflammatory lung pathology by increasing macrophage permissiveness to infection, triggering pyroptosis, and amplifying viral replication in alveolar epithelial cells. Co-culture of macrophages with human alveolar type II (AT2) cells overrides ORF8’s previously reported inhibition of AT2 infection, restoring infectious viral production. In vivo, IL-17RA blockade counteracts ORF8 activity, lowering viral burden and attenuating pulmonary inflammation and fibrosis. These findings reveal a paracrine role for ORF8 in reprogramming macrophages, thereby establishing a feedforward proviral circuit that accelerates lung pathology in COVID-19 and are clinically relevant given the recurrent emergence of SARS-CoV-2 variants with either intact or deleted ORF8 since the beginning of the pandemic.