Targeting Metabolic Reprogramming by Influenza Infection for Therapeutic Intervention

Abstract

Summary Influenza is a worldwide health and financial burden posing a significant risk to the immune-compromised, obese, diabetic, elderly, and pediatric populations. We identified increases in glucose metabolism in the lungs of pediatric patients infected with respiratory pathogens. Using quantitative mass spectrometry we found metabolic changes occurring after influenza infection in primary human respiratory cells, and validated infection-associated increases in c-Myc, glycolysis, and glutaminolysis. We confirmed these findings with a metabolic drug screen that identified the PI3K/mTOR inhibitor BEZ235 as a regulator of infectious virus production. BEZ235 treatment ablated the transient induction of c-Myc, restored PI3K/mTOR pathway homeostasis measured by 4E-BP1 and p85 phosphorylation, and reversed infection-induced changes in metabolism. Importantly, BEZ235 reduced infectious progeny but had no effect on the early stages of viral replication. BEZ235 significantly increased survival in mice while reducing viral titer. We show metabolic reprogramming of host cells by influenza virus exposes targets for therapeutic intervention.

Metabolic host response and therapeutic approaches to influenza infection

“…Molecular mechanisms through which the virus can control the metabolic pathways have been thoroughly identified. Smallwood et al have shown that an increase in glucose uptake, glycolysis, and glutaminolysis following influenza infection may be related to the loss of PI3K/AKT/mTOR pathway homeostasis and subsequent increase in c-Myc expression in the infected cells [9]. Regarding the available results, the mechanistic target of rapamycin complex 1 (mTORC1) and mTORC2 signaling can be activated by a variety of influenza virus proteins.…”

“…The aforementioned metabolic processes are not the only pathways affected by influenza virus infection. This virus has the ability to induce higher consumption rates of glutamine during glutaminolysis, which can be attributed to transient c-Myc overexpression [9]. Myc acts to regulate glutamine uptake and its utilization in the cell [111].…”

“…In a new study by Smallwood et al, it was found that although BEZ235 did not interfere with the early stages of the infection, it could finally reduce the viral progeny and result in prolonged survival in mice challenged by the influenza virus. Indeed, BEZ235 induced hemostasis in the PI3K/mTOR pathway via phosphorylation of p85 and 4E-BP1 and through reconstitution of metabolic status, which was already altered by the virus [9].…”

“…Recent research on a mouse model showed that influenza infection could affect more than 100 metabolite markers in serum, lung, and bronchoalveolar lavage fluid [8]. Acquiring the required materials from the host cell to self-replicate, the virus can disrupt biochemical processes such as glycolysis, fatty acid (FA) synthesis, and glutamine pathways [9]. It is of particular importance for scientists to broaden their horizon on the metabolic changes during influenza infection, which in turn paves the way for preventing life-threatening consequences.…”

Alternative Experimental Models for Studying Influenza Proteins, Host–Virus Interactions and Anti-Influenza Drugs

“…Similarly, proteomic analysis on commercially obtained NHBE cells (Lonza) infected with PR8 [281] identified proteins which were associated with host cell defense response, endocytosis and GTPase activity. Influenza virus was also found to increase apoptosis and pyroptosis [282], as well as c-Myc, glycolysis and glutaminolysis in NHBE cells from pediatric patients [283]. Importantly, NHBE cells are also being used for immediate translation of culture tests to clinical uses.…”