Respiratory syncytial virus co-opts host mitochondrial function to favour infectious virus production

Abstract

Although respiratory syncytial virus (RSV) is responsible for more human deaths each year than influenza, its pathogenic mechanisms are poorly understood. Here high-resolution quantitative imaging, bioenergetics measurements and mitochondrial membrane potential- and redox-sensitive dyes are used to define RSV’s impact on host mitochondria for the first time, delineating RSV-induced microtubule/dynein-dependent mitochondrial perinuclear clustering, and translocation towards the microtubule-organizing centre. These changes are concomitant with impaired mitochondrial respiration, loss of mitochondrial membrane potential and increased production of mitochondrial reactive oxygen species (ROS). Strikingly, agents that target microtubule integrity the dynein motor protein, or inhibit mitochondrial ROS production strongly suppresses RSV virus production, including in a mouse model with concomitantly reduced virus-induced lung inflammation. The results establish RSV’s unique ability to co-opt host cell mitochondria to facilitate viral infection, revealing the RSV-mitochondrial interface for the first time as a viable target for therapeutic intervention.

SARS-CoV-2 Spike protein promotes hyper-inflammatory response that can be ameliorated by Spike-antagonistic peptide and FDA-approved ER stress and MAP kinase inhibitors in vitro

“…To investigate if SARS-CoV-2 spike protein induces production of pro-inflammatory cytokines, we used a minimally immortalised human bronchial epithelial cell line BCi-NS1.1, which was derived from human primary bronchial epithelial cells (Hayman et al, 2019;Hu et al, 2019;Kedzierski et al, 2017;Walters et al, 2013). BCi-NS1.1 was stimulated with histidine (His)-tagged CoV2-S1, CoV2-RBD, or CoV-S1 or CoV-RBD.…”

“…BCi-NS1.1 cells were obtained from Prof. Ronald Crystal Laboratory at Weill Cornell Medical College, and Memorial Sloan-Kettering Cancer Center, New York, NY, USA) (Walters et al, 2013). The cells were cultured in hormone supplemented Bronchial Epithelial Cell Growth Media (BEGM; Lonza, Switzerland) supplemented with 50U/mL penicillin and streptomycin (Hayman et al, 2019;Hu et al, 2019;Kedzierski et al, 2017).…”

Metabolic changes during respiratory syncytial virus infection of epithelial cells

“…Several reports have shown that HRSV induces oxidative stress in infected cells, resulting in increased levels of oxidized glutathione [25][26][27][28]. Actually, increased production of mitochondrial reactive oxygen species (ROS) favors HRSV production, suggesting new potential therapeutic approaches against this virus [63]. The cells usually upregulate the synthesis of glutathione and polyamines (putrescine, spermidine, and spermine) to counteract that stress.…”

Mitochondrial Reactive Oxygen Species: Double-Edged Weapon in Host Defense and Pathological Inflammation During Infection

“…In addition, exaggerated production of mtROS results in fungus-mediated pathological inflammation in airway epithelial cells (40) and T. cruzi-mediated cardiomyopathy in Chagas disease (46). Also, mtROS inhibition suppressed respiratory syncytial virus replication and virus-mediated lung inflammation (47). These data suggest the pathogenic role of mtROS during infections of various pathogens.…”

“…Numerous viruses co-opt host mitochondrial functions and mtROS to favor their pathogenesis and virulence ( Table 1). A recent study showed that respiratory syncytial virus infection resulted in the impairment of mitochondrial respiration, loss of mitochondrial membrane potential, and increased mtROS, which promoted and favored viral replication in the cells (47). In addition, human immunodeficiency virus (HIV) can suppress or enhance mtROS generation in both productive and non-productive stages for its own benefit.…”