(440) Role of polyunsaturated fatty acids in regulating innate immune antiviral and inflammatory response during respiratory syncytial virus infection

Introduction/Rationale: Respiratory syncytial virus (RSV) infection causes of hyper-inflammatory lung diseases such as pneumonia and bronchiolitis in infants and neonates. RSV infection elicits strong innate immune inflammatory responses in macrophages by activating inflammasome pathway, which is involved in generating mature form of pro-inflammatory cytokines such interleukin-1β (IL-1β) and IL-18. However, the role of non-protein factors driving this response during infection remain poorly defined. Dihomo-γ-linolenic acid (DGLA , C20:3), an ω-6 polyunsaturated fatty acid, has recently emerged as an immunomodulatory lipid, but its role during viral infection, particularly RSV infection, has not been investigated.

Methods: Human THP-1 macrophages infected with recombinant RSV expressing mKate2 (mKate2-RSV) were treated with DGLA, oleic acid (18:1), and linoleic acid (18:2). RSV infection status was analyzed by measuring mKate2 expression by western blotting. Inflammasome activation was evaluated by measuring production of IL-1β and cleavage of pre-IL-1β to mature IL-1β (p17) by inflammasome/caspase-1 pathway.

Results: DGLA treatment significantly reduced RSV infection in macrophages. Simultaneously, DGLA triggered release of IL-1β and its mature cleaved p17 form even from uninfected macrophages. Notably, RSV-infected macrophages treated with DGLA showed enhanced IL-1β release compared with untreated infected cells. This effect was specific to DGLA, as no similar increase of IL-1β release was observed following treatment with linoleic acid or oleic acid.

Conclusion: These findings have identified DGLA as a potent regulator of RSV infectivity and inflammasome activation during RSV infection. DGLA-mediated enhancement of IL-1β maturation and release along with DGLA’s effect in reducing RSV infection highlights a previously unrecognized role for ω-6 fatty acid signaling in innate immune response against RSV. The mechanism by which DGLA mediates antiviral response and inflammasome activation will be discussed.