Increased Lung Catalase Activity Confers Protection Against Experimental RSV Infection

Abstract

Respiratory syncytial virus (RSV) infection in mouse and human lung is associated with oxidative injury and pathogenic inflammation. RSV impairs antioxidant responses by increasing the degradation of transcription factor NRF2, which controls the expression of several antioxidant enzyme (AOE) genes, including catalase. Since catalase is a key enzyme for the dismutation of virus-mediated generation of hydrogen peroxide (H 2 o 2) we developed a model of intranasal supplementation of polyethylene glycol-conjugated catalase (PG-CAT) for RSV-infected mice. The results of our study show that PG-CAT supplementation was able to increase specific enzymatic activity along with reduction in H 2 o 2 in the airways and had a significant protective effect against RSV-induced clinical disease and airway pathology. PG-CAT treated mice showed amelioration in airway obstruction, reduction in neutrophil elastase and inflammation. Improved airway hyperresponsiveness was also observed in mice that received PG-CAT as a treatment post-viral inoculation. In addition, PG-CAT greatly reduced the concentration of inflammatory cytokines and chemokines, including IL-1, TNF-α, IL-9, CXCL1, CCL2, and CCL5 in the bronchoalveolar lavage fluid of RSV-infected mice, without increasing viral replication in the lung. in conclusion, catalase supplementation may represent a novel pharmacologic approach to be explored in human for prevention or treatment of respiratory infections caused by RSV. Respiratory syncytial virus (RSV) bronchiolitis remains one of the most common respiratory infections in infants and young children. It resulted in an estimated 33.1 million cases of lower respiratory tract infection (LRTIs) globally in 2015, accounting for 3.2 million hospital admissions children 1. There is significant morbidity and mortality associated with severe RSV bronchiolitis, particularly in developing countries 2. While use of palivizumab, a monoclonal antibody, is fairly effective for RSV infection prophylaxis in high risk patients, current management is otherwise supportive 3. Our understanding of the underlying molecular mechanisms responsible for RSV lower respiratory tract disease is still incomplete and remains a critical need to improve patient care and outcomes. Previous work in our laboratory has shown that RSV infection is associated with increased reactive oxygen species (ROS) production, leading to transcription factor activation and chemokine gene expression 4,5. The transcription factor NF-E2-related factor 2 (NRF2), which binds the antioxidant response element (ARE) present in the promoter region of antioxidant enzymes (AOEs) plays a key role in the expression of AOEs 6. NRF2 cellular levels decrease in the course of RSV infection in vitro 7 and in vivo 8 , due to increased degradation 9,10 , leading to inhibition of AOE expression and cellular oxidative damage 7,8 , a process that has been implicated in the pathogenesis of acute and chronic airway diseases 11. Catalase, one of earliest known and best characterized of the AOEs is a homot...

Selective Blockade of TNFR1 Improves Clinical Disease and Bronchoconstriction in Experimental RSV Infection

“…In addition, TNF-TNFR1 binding generates intracellular reactive oxygen species (ROS) that in-turn further upregulate the wide-spread expression of TNFR1 on the cell surface [ 50 , 51 ]. RSV is known to significantly enhance ROS production, and previous studies in our lab have demonstrated that both controlling ROS generation and increasing antioxidant capacity in the lung leads to improved clinical parameters in mice, including body weight loss, illness score, and bronchoconstriction, in association with a significant reduction in TNF-α in the BALF [ 52 , 53 ]. Collectively, this suggests the TNF-TNFR1 interaction may be a key initial event that leads to airway narrowing and clinical manifestations of RSV infections, supporting interference of TNFR1 as a new potential therapeutic strategy for RSV bronchiolitis.…”

COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

“…Exogenous administration of catalase has been shown to mitigate respiratory viral infections. Intranasal catalase protected against respiratory syncytial virus (RSV) infection [ 63 ], a virus that can induce a cytokine storm [ 64 ]. Catalase treatment led to a significant reduction in the levels of the cytokines IL-1 α , TNF- α , and IL-9 and the chemokines CSCL1, CCL2, and CCL5 [ 63 ].…”

“…Intranasal catalase protected against respiratory syncytial virus (RSV) infection [ 63 ], a virus that can induce a cytokine storm [ 64 ]. Catalase treatment led to a significant reduction in the levels of the cytokines IL-1 α , TNF- α , and IL-9 and the chemokines CSCL1, CCL2, and CCL5 [ 63 ]. During the early stages of other types of respiratory infections, increased ROS activates the nuclear factor erythroid 2-related factor 2 (NFE2L2 commonly called Nrf2) transcriptional regulator to induce antioxidant genes such as SOD3 and catalase to protect against the ROS-induced proinflammatory gene expression and subsequent cytokine storm.…”

Evolution of proteomics technologies for understanding respiratory syncytial virus pathogenesis

“…To test whether this disruption of this antioxidant pathway was relevant to disease progression, SOD mimetics and stabilized polyethylene glycol-conjugated catalase were administered in an experimental rodent model of RSV infection [107,108]. These manipulations resulted in reduced viral H 2 O 2 production and produced a significant protective effect on RSV-induced inflammation, clinical disease and airway pathology.…”