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Pathway Description
Immunometabolism Pathway (Viral Activation)
Homo sapiens
Disease Pathway
Created: 2022-07-14
Last Updated: 2022-10-13
The normal response to a virus infection involves viral coat proteins activating the Toll-like receptors TLR4 and TLR2 on the membranes of macrophages, T-cells and dendritic cells. In addition to this protein activation, the viral DNA (or RNA if it is an RNA virus) is taken up by macrophage endosomes. Viral DNA fragments (such as CpG DNA) activates the endosomal TLR9, while viral double-stranded DNA fragments activates the endosomal TLR3 and viral single stranded RNA (if it is an RNA virus) activates endosomal TLR7/8 proteins. Different TRL receptors activate different processes for the innate immune response [1]. The TLR4 activates the production of interferon regulatory factor 3 (IRF3), TIR-domain-containing adapter-inducing interferon-β (TRIF), signal transducer and activator of transcription 1 (STAT1) and nuclear factor kappa B (NF-kB) in the cytoplasm, while TLR9, TRL3 and TLR7/8 activates the production of myeloid differentiation primary response 88 (MyD88), TRIF, interferon regulatory factor 7 (IRF7) and NF-kB in the cytoplasm [1]. The NF-kB protein then goes to nucleus and activates expression of nitric oxide synthase (iNOS) which generates nitric oxide (NO). It also activates aconitate decarboxylase (Irg1), tumor necrosis factor (TNF), interleukin 6 (IL-6) and interleukin 1 beta (IL-1β). These are the pro-inflammatory proteins while nitric oxide (NO) is also a pro-inflammatory molecule that can lead to the production of oxidized tyrosines (i.e., nitrotyrosine). Similarly, the newly expressed IRF3 and IRF7 proteins go to nucleus and activate the production of interferon beta (IFN- β), which is another pro-inflammatory cytokine. The other cytokines, TNF, IL-6, IL-1β and IFN-β move into the bloodstream and head to the brain and into the hypothalamus, leading to release of the hypothalamic corticotropin releasing hormone (CRH) [2]. CRH, in turn, activates the release of pituitary adrenocorticotropic hormone (ACTH), which then moves down through the blood stream towards the adrenal glands (located at the top of the kidneys) to produce cortisol and epinephrine. Cortisol and epinephrine stimulate the ”flight or fight” response, leading to the increased production of glucose from the liver (via glycogen breakdown) and the release of short-chain acylcarnitines (also from the liver) to help support beta-oxidation of fatty acids. These compounds support cell synthesis and growth of the macrophages and neutrophils used in the innate immune response. The liver also produces more IL-6, more TNF and more NO to further stimulate the innate immune response.
Higher nitric oxide (NO) levels lead to blood vessel dilation and reduced blood pressure, which in its most extreme form, can be a major problem in sepsis. Higher iNOS expression in macrophages, neutrophils and dendritic cells consumes the amino acid arginine to produce more NO which disrupts the mitochondrial TCA cycle leading to the accumulation of citrate and the production of fatty acids and acylcarnitines (needed for lipid synthesis). Increased Irg1 (actonitate decarboxylase) expression leads to accumulation of succinate, which results in the succinylation of phosphofructokinase M2 (PKM2) [3]. Succinate also leads to the release of hypoxia inducible factor 1-alpha (HIF-1α) from its PHD-mediated inhibition. HIF-1α interacts with succinylated PKM2 and induces the expression of glycolytic genes such as Glut1 (the glucose transporter) and the pro-inflammatory cytokine IL-1β [3]. As a result of these metabolic changes and the deactivation of the oxidative phosphorylation pathway in their mitochondria, macrophages, neutrophils, T-cells and dendritic cells shift to aerobic glycolysis [4]. This leads to the production of more reactive oxygen species (ROS) which results in the oxidation of certain amino acids, such as methionine. This leads to the increased production of methionine sulfoxide (Met-SO). As the inflammatory response continues, more glucose and arginine in the bloodstream are consumed by dividing white blood cells to produce more lactate and more NO to further push the aerobic glycolytic pathway [4]. This aerobic glycolysis occurs primarily in white blood cells leading to active cell division and rapid white cell propagation (growing by a factor of three to four in a few hours). Hexokinase (HK) along with increased levels of lactate from aerobic glycolysis activate the inflammasome inside macrophages and dendritic cells, leading to the secretion of IL-1β. This cytokine further drives the aerobic glycolysis pathway for these white blood cells. All these signals and effects combine to lead to the rapid and sustained production of large numbers of macrophages, neutrophils, dendritic cells and T-cells to fight the viral infection. This often leads to a reduction in essential amino acids (threonine, lysine, tryptophan, leucine, isoleucine, valine, arginine) and a mild reduction in gluconeogenic acids (glycine, serine) in the bloodstream. The reduction in essential amino acids is intended to “starve” the invading viruses (and other pathogens) of the amino acids they need to reproduce [4]. Some of the reduction in amino acid levels is moderated by the proteolysis of myosin in the muscle and the proteolysis of serum albumin in the blood (the most abundant protein in the blood, which is produced by the liver). These proteins act as amino acid reservoirs to help support rapid immune cell production. The loss of serum albumin in the blood to help support amino acid synthesis elsewhere can lead to hypoalbuminemia, a common feature of infections and inflammation.
As the viruses are cleared, the body goes into the anti-inflammatory response.
References
Immunometabolism Pathway (Viral Activation) References
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