(903) Type 1 interferons (T1 IFNs) regulate cellular redox balance by suppressing the host antioxidant response during influenza A virus infection in vivo
Doctoral student University of Georgia Athens, Georgia, United States
Disclosure(s):
Syamily Shaji, DVM, MS: No financial relationships to disclose
Introduction/Rationale: Influenza A virus (IAV) infection leads to a wide spectrum of outcomes, from asymptomatic cases to severe disease, emphasizing the pivotal role of the host immune response in determining disease severity. NRF2, a key transcription factor that governs the cellular antioxidant (AOX) response, is critical in maintaining redox balance during viral infections. Disruption of NRF2 activity can lead to accumulation of reactive oxygen species (ROS) and insufficient AOX defenses, a characteristic of influenza pathogenesis. Type I interferons (T1 IFNs) are well-established host factors implicated in antiviral immunity as well as influenza severity. We hypothesize that elevated T1 IFNs may exacerbate disease severity in response to influenza infection by altering cellular redox balance through suppression of the NRF2-driven AOX responses.
Methods: To test this hypothesis, we infected WT and Ifnar1-/- mice with influenza A virus and sorted alveolar macrophages (AMs), inflammatory monocytes (IM), and neutrophils (PMNs) at D3 post infection for assessment of the NRF2-regulated AOX response.
Results: Influenza-infected mice showed increased transcription of NRF2-regulated AOX genes in AMs and PMNs from Ifnar-/- mice compared to WT mice, with the most dramatic effects observed within neutrophils. However, acute stimulation of purified neutrophils directly with T1 IFNs or T3 IFNs (IFN-lambda) increased rather than decreased the expression of NRF2-dependent AOXs.
Conclusion: These observations suggest that autocrine T1 IFNs produced in response to influenza infection profoundly alter neutrophil redox balance in vivo but this effect may be indirect or subject to differential kinetic regulation. Furthermore, manipulating the T1 IFN-NRF2-AOX axis could represent an approach for intervening in influenza-induced acute lung injury, such as acute respiratory disease syndrome.
