TDP-43 promotes allergen-induced inflammation and influenza A virus replication in airway epithelium

Abstract Current targeted therapeutics for asthma focus on the T2 immune response, providing symptomatic management without addressing the issues of recurrence. Identifying key pathophysiological determinants in airway epithelium enables novel therapeutics to prevent asthma recurrence. Here we demonstrate that TDP-43, as the master regulator of RNA metabolism, is induced in airway epithelial cells by host allergen exposure and promotes asthmatic airway responses through dampening nonsense-mediated decay (NMD) by modulating UPF1 expression, resulting in accumulation of pathogenic and NMD-sensitive transcripts including CHRM1 encoding receptor that transduces the signaling of vagally-derived neurotransmitter acetylcholine. TDP-43 also facilitates airway influenza A virus replication. Intranasal application of lipid nanoparticles carrying antisense oligonucleotides targeting TDP-43 effectively reduce asthma-like pathologies in mice. Our findings indicate that targeting airway TDP-43 is therapeutically possible for asthma and influenza A virus infection-complicated asthma exacerbations.