NADPH Oxidase 1 Is Associated with Altered Host Survival and T Cell Phenotypes after Influenza A Virus Infection in Mice

Abstract

The role of the reactive oxygen species-producing NADPH oxidase family of enzymes in the pathology of influenza A virus infection remains enigmatic. Previous reports implicated NADPH oxidase 2 in influenza A virus-induced inflammation. In contrast, NADPH oxidase 1 (Nox1) was reported to decrease inflammation in mice within 7 days post-influenza A virus infection. However, the effect of NADPH oxidase 1 on lethality and adaptive immunity after influenza A virus challenge has not been explored. Here we report improved survival and decreased morbidity in mice with catalytically inactive NADPH oxidase 1 (Nox1*/Y) compared with controls after challenge with A/PR/8/34 influenza A virus. While changes in lung inflammation were not obvious between Nox1*/Y and control mice, we observed alterations in the T cell response to influenza A virus by day 15 post-infection, including increased interleukin-7 receptor-expressing virus-specific CD8+ T cells in lungs and draining lymph nodes of Nox1*/Y, and increased cytokine-producing T cells in lungs and spleen. Furthermore, a greater percentage of conventional and interstitial dendritic cells from Nox1*/Y draining lymph nodes expressed the co-stimulatory ligand CD40 within 6 days post-infection. Results indicate that NADPH oxidase 1 modulates the innate and adaptive cellular immune response to influenza virus infection, while also playing a role in host survival. Results suggest that NADPH oxidase 1 inhibitors may be beneficial as adjunct therapeutics during acute influenza infection.

Redox Biology of Respiratory Viral Infections

“…However, recent work from another group pointed to a role for Nox1 in the induction of ROS. Survival of IV-infected mice with inactive Nox1 was prolonged [ 63 ], suggesting that Nox1 is a source of ROS that is hazardous. In HRV-infected polarized airway epithelial cells Nox1-derived ROS are responsible for triggering barrier dysfunction, a dangerous process leading to decreased transepithelial resistance, thus making the host susceptible to bacterial pathogens [ 64 , 65 ].…”

Redox control in the pathophysiology of influenza virus infection

“…The production of superoxide anion in bronchoalveolar lavage fluid-derived fibroblasts from H3N2-infected Nox1 –/– KO mice was inhibited at day 7 after infection, although it did not differ from that observed in wild-type littermates at day 3 after infection (in the early stages of infection) [ 77 ]. Mice expressing an inactive Nox1 (Nox1*/γ) exhibited a higher survival rate after an influenza type A virus challenge than did control mice [ 78 ] [ 76 ]. The adaptive immune response was altered after the IV challenge in these mice, as shown by a decrease in the number of virus-specific CD8+ T cells in the lung, an increase in the number of virus-specific CD8+ T cells expressing CD127 (IL-7 receptor) in the lung, and draining of lymph nodes.…”

Glycemic Variability in Diabetes Increases the Severity of Influenza

“…Oxidative stress can further impair antiviral CD8 ϩ T cell responses (22). This effect is most pronounced with memory T cells (22,23). These data suggest that glycemic oscillations may increase the severity of influenza in persons living with diabetes by altering endothelial cell function and/or affecting antiviral immunity.…”