Glucose metabolism and Influenza Flashcards
Glycolytic control of vacuolar-type ATPase activity as a mechanism to regulate influenza viral infection (Virology, Vol 444, issues 1-2, September 2013
What happens when you increase glucose levels?
Increases Influenza A viral infection of MDCK cells: higher accumulation of viral protein within cells, especially HA and higher % of infected cells
What inhibits Influenza A viral infection?
Inhibition of glycolytic enzyme HEXOKINASE –> disassembly of V-ATPase, also inhibition of V-ATPase by certain drugs (e.g. Bafilomycin)
What bypasses V-ATPase disassembly (and inhibition of Influenza A infection?)
ATP
What correlates with Influenza A infection?
State of V-ATPase assembly
What are Influenza viruses?
Respiratory viruses, members of the Orthomyxovirus family
What mediates Influenza viral infection?
2 viral proteins: HEMAGGLUTININ (HA) and MATRIX PROTEIN 2 (M2)
What does HA do?
Binds to sialic acid residues on cell surface –> endocytosis into and endocytic vesicle
How is the pH in the endocytic vesicle (endosome)?
ACIDIC
What happens when the pH is acidic within the endosome?
2 things happen: 1) HA changes conformation and fuses viral envelope + endosome membrane and 2) M2 proton channel activates and transports protons –> viral core
What happens when there are protons inside the viral core?
Lowers pH within the virion –> viral uncoating –> viral genome is transported from the virion –>cytosol
What is V-ATPase?
Vacuolar-type H+ ATPase (proton pump): multi-molecular protein complex with a peripheral and an integral domains
Where is V-ATPase located?
Plasma membrane, endosomal membrane and other intracellular compartments of our cells
How does V-ATPase favors Influenza viral infection?
By keeping an acidic pH within the endosome which favors viral release
What does V-ATPase do inside the cells?
Binds ATP –> Hydrolysis + tranports protons from cytoplasm –> lumen of endosomes/organelles –> lowers pH inside these intracellular compartments which is necessary for multiple cellular processes
What are the domains of V-ATPase?
Peripheral V1 –> subunits A,B,C,D,E,F,G
Integral V0 subcomplex –> subunits a,c,d,e
How is V-ATPase activity regulated?
Through disassembly of V1 and V0 domains to regulate pH levels of endosomes/organelles
What causes disassembly of V-ATPase?
GLUCOSE DEPLETION –> decreased glycolysis –> decreased ATP levels
What causes assembly of V-ATPase?
GLUCOSE REPLETION –> increased glycolysis –> sufficient ATP levels (V-ATPase is ATP dependent) –> pump activated –> + acidification
How does glucose stimulates V-ATPase activity as per recent research?
Via Phosphatidylinositol 3-kinase signaling pathway and direct physical interaction of glycolytic enzymes and subunits of V-ATPase
What glycolytic enzymes interact with subunits of V-ATPase as per recent research?
Phosphofructokinase 1 (PFK-1) (mediates step 3) + a subunit AND Aldolase (mediates step 4) + a,B and E subunits
How does glucose reduction and/or inhibition of glycolysis reduce influenza viral infection?
V-ATPase disassembly –> reduce acidification of endosomes –> inhibits influenza M2 and activities –> inhibits influenza viral REPLICATION
Problem with antiviral drugs for influenza?
Target viral proteins: Neuraminidase (NA) and M2, but they lose effectiveness as the virus mutates
What is the 1st enzyme of glycolysis?
Hexokinase
What is the % of viral infection reduction when inhibiting Glycolysis?
80-90%!
What represents the viral genome of Influenza virus?
viral ribonucleoprotein (vRNP) complexes
What promotes low acidic pH within the endosome?
V-ATPase
Where does the virus containing endosome transported to initially?
Periphery of nucleus
What specific subunits of V-ATPase are involved in Influenza viral infection?
V1 domain: A,B,C
V0 domain: b, c, d1
What subunit seems to have specificity for Influenza virus as per research?
V0d1, Influenza virus seems to manipulate this subunit to stimulate endosome acidification at the nuclear periphery
What is Glycolysis?
Process by which glucose is metabolized to generate a net gain of 2 ATP, 2 NADH+ (nicotinamide adenine dinucleotide), and 2 molecules of pyruvate
What happens to Pyruvate molecules?
They are further metabolized to produce more ATP
What activated V-ATPase?
ATP, which binds to the catalytic sites on the A and B subunits
Is glycolysis absolutely required for V-ATPase activation?
No, pump can still be activated as long as additional ATP is available from other sources
What happens in diabetic patients?
Will likely have more severe viral infections and Influenza symptoms
What happens when cells are changed from a high glucose medium to a low one?
They become LESS SUSCEPTIBLE to infection by Influenza virus!
What is this research proving?
Decreasing glucose and/or inhibiting glycolysis may be a way to reduce influenza viral infection in mammals (and humans too!)
