Abstract Rationale Human rhinoviruses (HRVs) are a leading cause of asthma and COPD exacerbations. Despite their clinical significance, there are currently no approved vaccines or antiviral therapies targeting HRV infections, highlighting a critical unmet need. The minor surfactant phospholipids, palmitoyl-oleoyl-phosphatidylglycerol (POPG) and phosphatidylinositol (PI), have shown antiviral activity against enveloped respiratory viruses such as respiratory syncytial virus (RSV) and influenza A virus. Our previous work identified PI, but not POPG, as an inhibitor of HRV-A16, indicating selective effects.This study investigates the antiviral impacts of POPG and PI against HRV-A1B, a non-enveloped, minor-group strain with distinct receptor usage, using human airway epithelial cells at air-liquid interface (ALI) and a murine model. Findings may support surfactant phospholipids as novel, host-directed antivirals for HRV-induced airway disease. Methods The antiviral effects of POPG and PI were assessed in HRV-A1B-infected bronchial epithelial cell (BEC) ALI cultures by measuring viral load, antiviral gene expression, and chemokine production. In vivo efficacy of POPG was evaluated using a mouse model of HRV-A1B infection. Results Co-administration of POPG or PI with HRV-A1B for 48 hours markedly reduced cell-associated viral RNA in primary human BECs cultured at ALI, by 49% and 91%, respectively, as measured by RT-qPCR. Both phospholipids also significantly suppressed the expression of key antiviral and inflammatory genes. POPG and PI reduced expression of MDA5 by 49% and 78%, IRF7 by 34% and 69%, IFN-λ by 24% and 80%, and CXCL11 by 66% and 96%, respectively. In BALB/c mice, POPG treatment reduced total cell counts in bronchoalveolar lavage fluid (BALF) by 26% and neutrophil counts by 75% at 48 hours post-infection, as compared to virus infection alone. Viral binding assays indicated that neither POPG nor PI inhibited HRV-A1B attachment to BECs. Additionally, plaque assays confirmed that the lipids lacked direct virucidal activity. Conclusions POPG and PI effectively suppressed HRV-A1B burden and dampened the associated antiviral response in differentiated human airway epithelial cells. In vivo, POPG reduced immune cell infiltration in the lungs, consistent with diminished viral replication. These findings highlight the potential of POPG and PI as promising antiviral candidates for treating HRV-A1B infections. This abstract is funded by: 2U19 Al 125357, NIH P01 HL132821, FAMRI CIA 160010, National Emphysema Foundation
White et al. (Fri,) studied this question.