Subversion of Host Cell Mitochondria by RSV to Favor Virus Production is Dependent on Inhibition of Mitochondrial Complex I and ROS Generation

Abstract

Respiratory syncytial virus (RSV) is a key cause of severe respiratory infection in infants, immunosuppressed adults, and the elderly worldwide, but there is no licensed vaccine or effective, widely-available antiviral therapeutic. We recently reported staged redistribution of host cell mitochondria in RSV infected cells, which results in compromised respiratory activities and increased reactive oxygen species (ROS) generation. Here, bioenergetic measurements, mitochondrial redox-sensitive dye, and high-resolution quantitative imaging were performed, revealing for the first time that mitochondrial complex I is key to this effect on the host cell, whereby mitochondrial complex I subunit knock-out (KO) cells, with markedly decreased mitochondrial respiration, show elevated levels of RSV infectious virus production compared to wild-type cells or KO cells with re-expressed complex I subunits. This effect correlates strongly with elevated ROS generation in the KO cells compared to wild-type cells or retrovirus-rescued KO cells re-expressing complex I subunits. Strikingly, blocking mitochondrial ROS levels using the mitochondrial ROS scavenger, mitoquinone mesylate (MitoQ), inhibits RSV virus production, even in the KO cells. The results highlight RSV’s unique ability to usurp host cell mitochondrial ROS to facilitate viral infection and reinforce the idea of MitoQ as a potential therapeutic for RSV.

Host mitochondrial transcriptome response to SARS-CoV-2 in multiple cell models and clinical samples

“…It is plausible that muted expression of Complex I-and therefore lower ROS production-permits SARS-CoV-2 propagation. Additional reports on respiratory viruses such as RSV have indicated that Complex I inhibition could promote efficient viral replication 27 . SARS-CoV-2 not only decreased expression to many NDUF family of genes, but also several mitochondrial ribosome protein related genes in primary cells and BALF, observations of which, however, did not carry over to cell lines.…”

Mitochondrial ROS-Modulated mtDNA: A Potential Target for Cardiac Aging

“…In aging, mitochondria produce the majority of ROS during oxidative phosphorylation (OXPHOS) and ATP generation [50]. Deficient electron transport chains (ETCs) are a potential site for ROS production, including subunit complexes I and III [51,52]. The mitochondrial free radical aging theory hypothesizes that age-related increases in mitochondrial ROS lead to mtDNA mutations and the accumulation of oxidative protein and lipid, which reduce mitochondrial respiratory efficiency [53].…”

SARS-CoV-2 induces a unique mitochondrial transcriptome signature

“…Reports on respiratory viruses such as RSV have indicated that Complex 1 inhibition could promote e cient viral replication. 21 We found that many NDUF Complex 1-associated proteins were downregulated after SARS-CoV-2 infection in NHBE cells, cell lines, BALF, and lung. Primary cells and BALF showed the greatest degree of downregulation of genes related to cellular respiration.…”