Influenza virus infection affects insulin signaling, fatty acid-metabolizing enzyme expressions, and the tricarboxylic acid cycle in mice

Abstract

Although the severity of influenza virus infections has been associated with host energy metabolism, the related mechanisms have not yet been clarified. Here we examined the effects of influenza virus infection on host energy metabolism in mice. After infecting mice with intranasal applications of 500 plaque-forming units of A/Puerto Rico/8/34 (H1N1; PR8) virus, the serum levels of most intermediates in the tricarboxylic acid (TCA) cycle and related metabolic pathways were significantly reduced. These data suggest that substrate supply to the TCA cycle is reduced under these conditions, rather than specific metabolic reactions being inhibited. Then, we focused on glucose and fatty acid metabolism that supply substrates to the TCA cycle. Akt phosphorylation following insulin injections was attenuated in the livers of PR8 virus-infected mice. Furthermore, glucose tolerance tests revealed that the PR8 virus-infected mice showed higher blood glucose levels than the vehicle-inoculated control mice. These results suggest that influenza virus infection impairs insulin signaling, which regulates glucose uptake. However, increases in the hepatic expressions of fatty acid-metabolizing enzymes suggest that fatty acids accumulate in liver cells of infected mice. Collectively, our data indicate that influenza virus infection dysregulates host energy metabolism. This line of investigation provides novel insights into the pathogenesis of influenza. Influenza virus infection causes respiratory diseases and remains a major health concern, causing approximately half a million deaths per year globally 1. Several types of antiviral drugs are commercially available for influenza treatment. However, influenza viruses change their protein structure constantly, thereby reducing their susceptibility to antiviral drugs, and prolonged treatment of patients receiving antivirals increases the chance of drug resistance of influenza viruses. In addition, the therapeutic effects of antiviral drugs are the highest when applied during the early stages of infection to prevent virus replication efficiently. Therefore, antiviral drug treatment is not suitable for patients with severe advanced stages of influenza. As long as we use antiviral drugs, these complications are always unavoidable. There is a need for the development of therapeutic strategies targeting host factors that are directly related to pathogenicity and symptoms. Compared with influenza viruses themselves, host responses to virus infections are poorly understood. Although host immune responses, particularly excess cytokine secretion, are considered to be involved in influenza pathogenesis, the downstream responses of cytokine signaling have not yet been specified. In addition to inflammation, energy metabolism disorders, such as obesity, diabetes, and deficiencies of fatty acid oxidation, have been known to be related to influenza severity in mouse models and in humans 2-6. Given the indispensable roles of inflammatory signaling in the development of a high-fat diet (HFD)-induced in...

Critical role of oxidized LDL receptor-1 in intravascular thrombosis in a severe influenza mouse model

“…The effect of influenza virus infection on the blood coagulation system of the host was investigated in a severe influenza mouse model, in which weight loss of 25% or more, a criterion for a humane endpoint, is induced within 7 days of infection 18 . PR8 virus was intranasally infected to male mice at a dose of 500 plaque-forming units (PFUs)/mouse, and samples were collected at 1, 3, and 6 days post-infection (dpi).…”

“…In addition to systemically secreted cytokines, of course, the possibility that the virus directly infects the cells of blood vessels 32 and induces Olr1 needs to be taken into account. However, given that Olr1 is induced by various factors, its expression may have been induced by others aside from inflammatory molecules, such as oxidized LDL, angiotensin II, and metabolic abnormalities 26 , 33 , 34 , which have been previously reported to be induced during acute influenza 18 , 35 , 36 . Further studies on the mechanisms of Olr1 induction by a viral infection will provide insights into biological responses to and pathogenesis of infectious diseases far beyond just cytokine induction.…”

“…Virus infection and sample collection was carried out as previously reported 18 . PR8 virus particles at 500 PFUs in 50 µL phosphate-buffered saline (PBS) or PBS only (control) were intranasally inoculated into mice under inhalation anesthesia with isoflurane.…”

“…This study evaluated influenza-associated abnormal blood coagulation utilizing a severe influenza mouse model that was previously established 18 . Furthermore, blood coagulation profiles were compared between wild-type (WT) and Olr1 global knockout (KO) mice to investigate the roles of OLR1 as a host factor in cytokine production, coagulation abnormality, and lung intravascular thrombosis during influenza.…”

Acetylation, Methylation and Allysine Modification Profile of Viral and Host Proteins during Influenza A Virus Infection

“…In addition to these clusters, four enzymes of the tricarboxylic acid cycle (TCA cycle), namely aconitate hydratase (K138, K245), isocitrate dehydrogenase (K272), malate dehydrogenase (K238, R248), succinate dehydrogenase (K80) were found to be methylated on largely conserved residues ( Supplementary Tables S4 and S5 ). Evidently, a reduced TCA cycle activity has been reported in IAV-infected mice [ 60 ].…”