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Front. Immunol. | doi: 10.3389/fimmu.2018.00854

Protective Role of Nuclear Factor Erythroid 2-Related Factor 2 against Respiratory Syncytial Virus and Human Metapneumovirus Infections

  • 1Pediatrics, University of Texas Medical Branch, United States
  • 2Microbiology and Immunology, University of Texas Medical Branch, United States

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. In studies conducted in vitro, in experimental mouse models and in children with naturally acquired infections we have discovered that in the course of RSV infection reactive oxygen species (ROS) are rapidly generated along with reduction in the expression levels 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 Paramyxoviridae 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.

Keywords: Nrf2, AOEs, H2S, Lung Injury, RSV, HMPV, airway inflammation, Airway Obstruction

Received: 26 Jan 2018; Accepted: 06 Apr 2018.

Edited by:

Steven Varga, University of Iowa, United States

Reviewed by:

Shahram Salek-Ardakani, Pfizer (United States), United States
Markus Weckmann, Universitätsklinikum Schleswig-Holstein, Germany  

Copyright: © 2018 Ivanciuc, Sbrana, Casola and Garofalo. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Prof. Roberto P. Garofalo, MD., University of Texas Medical Branch, Pediatrics, 301 University Boulevard, Galveston, 77555-0372, TX, United States, rpgarofa@utmb.edu