Activation of TCA cycle restrains virus-metabolic hijacking and viral replication in mouse hepatitis virus-infected cells

Abstract

Background One of coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has caused coronavirus disease 2019 (COVID-19) pandemic and threatened worldwide. However, therapy for COVID-19 has rarely been proven to possess specific efficacy. As the virus relies on host metabolism for its survival, several studies have reported metabolic intervention by SARS-CoV-2. Results We investigated the coronavirus-metabolic hijacking using mouse hepatitis virus (MHV) as a surrogate for SARS-CoV-2. Based on the altered host metabolism by MHV infection, an increase of glycolysis with low mitochondrial metabolism, we tried to investigate possible therapeutic molecules which increase the TCA cycle. Endogenous metabolites and metabolic regulators were introduced to restrain viral replication by metabolic intervention. We observed that cells deprived of cellular energy nutrition with low glycolysis strongly suppress viral replication. Furthermore, viral replication was also significantly suppressed by electron transport chain inhibitors which exhaust cellular energy. Apart from glycolysis and ETC, pyruvate supplement suppressed viral replication by the TCA cycle induction. As the non-glucose metabolite, fatty acids supplement decreased viral replication via the TCA cycle. Additionally, as a highly possible therapeutic metabolite, nicotinamide riboside (NR) supplement, which activates the TCA cycle by supplying NAD+, substantially suppressed viral replication. Conclusions This study suggests that metabolite-mediated TCA cycle activation suppresses replication of coronavirus and suggests that NR might play a role as a novel therapeutic metabolite for coronavirus.

Circulating pyruvate is a potent prognostic marker for critical COVID-19 outcomes

“…Interestingly, in a subsample of the two cohorts (n=91), we found a positive correlation between circulating pyruvate levels measured by metabolomic and measured by fluorimetric analysis (R=0.551; P<0.001). With regards to the role of pyruvate in SARS-CoV-2 pathophysiology, it might have an anti-inflammatory function in macrophage activation, similar to the effect observed during influenza A virus infection ( 43 ), and it might also provide therapeutic benefit by suppressing viral replication through Krebs cycle induction ( 51 ).…”

COVID‐19 metabolism: Mechanisms and therapeutic targets

“… 168 Of note, mouse hepatitis virus infection model suggested that endogenous metabolites could alter mitochondrial metabolism and correspondingly modulate viral replication efficacy. 172 Thus, metabolic interventions may be employed to restrain mitochondria metabolism and SARS‐CoV‐2 replication. 172 , 173 It is worthy to mention that previous proteomic studies utilized overexpressed viral proteins as baits to track virus–host interaction.…”

“… 172 Thus, metabolic interventions may be employed to restrain mitochondria metabolism and SARS‐CoV‐2 replication. 172 , 173 It is worthy to mention that previous proteomic studies utilized overexpressed viral proteins as baits to track virus–host interaction. 63 , 123 Further efforts are required to exclude potential experimental artifacts in physical association with mitochondrial enzymes.…”

“…172 Thus, metabolic interventions may be employed to restrain mitochondria metabolism and SARS-CoV-2 replication. 172,173 It is worthy to mention that previous proteomic studies utilized overexpressed viral proteins as baits to track virus-host interaction. 63,123 Mitochondria-derived reactive oxygen species (ROS) act as metabolic signals that modulate SARS-CoV-2 amplification.…”

“…Chemical activation of NRF2 exerted antiviral effects toward SARS‐CoV‐2 infection 168 . Of note, mouse hepatitis virus infection model suggested that endogenous metabolites could alter mitochondrial metabolism and correspondingly modulate viral replication efficacy 172 . Thus, metabolic interventions may be employed to restrain mitochondria metabolism and SARS‐CoV‐2 replication 172,173 .…”