Abstract
The pathogenesis of respiratory syncytial virus (RSV) infections is characterized by lower airway obstruction driven at great extent by the exuberant production of inflammatory cytokines. We have previously shown that RSV infection in vitro and in vivo results in production of reactive oxygen species along with reduction in the expression of antioxidant enzymes (AOEs), which are involved in maintaining the cellular oxidant–antioxidant balance. These events were associated with the concomitant reduction in nuclear factor erythroid 2-related factor 2 (Nrf2), a key transcription factor that controls AOE expression. The objective of the current study was to establish the role of Nrf2 in shaping innate immune responses, clinical disease, airway inflammation, and viral replication in established experimental models of intranasal RSV and human metapneumovirus (hMPV) infections, by employing mice genetically deficient for the Nrf2 gene. Compared to control wild type (WT), mice genetically deficient in Nrf2 (Nrf2 KO) developed enhanced clinical disease, airway inflammation and pathology, and significantly greater lung viral titers following experimental infection with either RSV or hMPV. In particular, compared to control mice, RSV-infected Nrf2 KO mice lost more body weight and had increased airway obstruction at time points characterized by a remarkable increase in inflammatory cytokines and airway neutrophilia. Airway levels of AOEs and enzymes that regulate synthesis of the endogenous hydrogen sulfide (H2S) pathway, which we showed to play an important antiviral function, were also decreased in RSV-infected Nrf2 KO compared to WT. In conclusion, these results suggest that Nrf2 is a critical regulator of innate, inflammatory, and disease-associated responses in the airways of mice infected with viruses that are members of the Pneumoviridae family. Importantly, the results of this study suggest that Nrf2-dependent genes, including those controlling the cellular antioxidant and H2S-generating enzymes and cytokines can affect several aspects of the antiviral response, such as airway neutrophilia, clinical disease, airway obstruction, and viral replication.
Highlights
Acute bronchiolitis is a viral lower respiratory tract infection (LRTI) that represents the primary cause of hospitalization for children in the first year of life
The results of this study show that mice genetically deficient in nuclear factor (NF)-E2-related factor 2 (Nrf2) developed enhanced clinical disease, airway inflammation and pathology, and significantly greater lung viral titers following experimental infection with respiratory syncytial virus (RSV)
We have shown that compared to control mice, Nrf2 KO mice lost more body weight and had increased airway obstruction at day 1 post-infection (Figure 1), a time point which was characterized by a remarkable increase in airway neutrophilia (Figure 4)
Summary
Acute bronchiolitis is a viral lower respiratory tract infection (LRTI) that represents the primary cause of hospitalization for children in the first year of life. Given the fact that RSV infections do not provide permanent immunity, reinfections can reoccur throughout life and cause serious respiratory disease in certain adult populations, including frail elderly and subjects with chronic heart and lung diseases [3]. Infants with certain risk factors (prematurity, chronic lung disease, congenital heart disease, or immunodeficiencies) have an increased risk for more severe RSV disease, the large majority of infants with RSV infections that require hospitalization were previously healthy [4, 5]. The spectrum of RSV disease severity in otherwise previously healthy infants, points to both host determinants and virus-specific factors that determine the outcome of infection [4]. Infants with greater viral quantities in the respiratory tract secretions are at greater risk for prolonged hospitalization, intensive care unit stay, and mechanical ventilation [10], possibly by causing direct lung injury
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