Mitochondrial Reactive Oxygen Species Contribute to Pathological Inflammation During Influenza A Virus Infection in Mice.

Eunice E To,Jonathan R Erlich,Stella Liong,Desiree Anthony,Ross Vlahos,Doug A Brooks,Raymond Luong,Jonathan Mcqualter,John J O'Leary,Steven Bozinovski,Stavros Selemidis,Farisha Esaq,Osezua Oseghale,Felicia Liong

doi:10.1089/ars.2019.7727

Abstract

Aims: Reactive oxygen species (ROS) are highly reactive molecules generated in different subcellular sites or compartments, including endosomes via the NOX2-containing nicotinamide adenine dinucleotide phosphate oxidase during an immune response and in mitochondria during cellular respiration. However, while endosomal NOX2 oxidase promotes innate inflammation to influenza A virus (IAV) infection, the role of mitochondrial ROS (mtROS) has not been comprehensively investigated in the context of viral infections in vivo.Results: In this study, we show that pharmacological inhibition of mtROS, with intranasal delivery of MitoTEMPO, resulted in a reduction in airway/lung inflammation, neutrophil infiltration, viral titers, as well as overall morbidity and mortality in mice infected with IAV (Hkx31, H3N2). MitoTEMPO treatment also attenuated apoptotic and necrotic neutrophils and macrophages in airway and lung tissue. At an early phase of influenza infection, that is, day 3 there were significantly lower amounts of IL-1β protein in the airways, but substantially higher amounts of type I IFN-β following MitoTEMPO treatment. Importantly, blocking mtROS did not appear to alter the initiation of an adaptive immune response by lung dendritic cells, nor did it affect lung B and T cell populations that participate in humoral and cellular immunity.Innovation/Conclusion: Influenza virus infection promotes mtROS production, which drives innate immune inflammation and this exacerbates viral pathogenesis. This pathogenic cascade highlights the therapeutic potential of local mtROS antioxidant delivery to alleviate influenza virus pathology.

Highlights

Influenza A virus (IAV) infections are responsible for annual epidemics and sporadic pandemics, which cause very significant respiratory illness that is a major burden for patients and global health care systems [11, 38]
We have shown that MitoTEMPO treatment 1 day before influenza A virus (IAV) infection significantly reduced macrophage mitochondrial ROS (mtROS) and lung IL-1b production, and this was associated with reduced mortality, airway and lung inflammation, as well as oxidative stress at both early and later stages of infection
At day 3, the number of macrophages and natural killer cells was unaltered by MitoTEMPO treatment, but there was a significant reduction in bronchoalveolar lavage (BAL) fluid (BALF) macrophages at day 5 (Fig. 1D)

Summary

Introduction

Influenza A virus (IAV) infections are responsible for annual epidemics and sporadic pandemics, which cause very significant respiratory illness that is a major burden for patients and global health care systems [11, 38]. In the present study, we examined the role of mtROS in modulating the early innate and subsequent adaptive immune responses in an in vivo mouse model of IAV infection, and in particular assessed the effect on type I IFN and IL-1b expression, as well several other markers of lung inflammation, oxidative stress, and disease severity. To investigate this potential role of mtROS in influenza pathogenesis, we made use of intranasal delivery of the mtROS-specific scavenger MitoTEMPO in our well-established infection model. These data support the idea that excessive mtROS can promote a deleterious early innate inflammatory immune response to influenza virus infection, which may be exploited as a novel therapeutic target via local delivery of mtROS scavengers

Results

Discussion

Experimental Procedures