Natural Products as Tools for Defining How Cellular Metabolism Influences Cellular Immune and Inflammatory Function during Chronic Infection

Abstract

Chronic viral infections like those caused by hepatitis C virus (HCV) and human immunodeficiency virus (HIV) cause disease that establishes an ongoing state of chronic inflammation. While there have been tremendous improvements towards curing HCV with directly acting antiviral agents (DAA) and keeping HIV viral loads below detection with antiretroviral therapy (ART), there is still a need to control inflammation in these diseases. Recent studies indicate that many natural products like curcumin, resveratrol and silymarin alter cellular metabolism and signal transduction pathways via enzymes such as adenosine monophosphate kinase (AMPK) and mechanistic target of rapamycin (mTOR), and these pathways directly influence cellular inflammatory status (such as NF-κB) and immune function. Natural products represent a vast toolkit to dissect and define how cellular metabolism controls cellular immune and inflammatory function.

Keywords: AMPK; HCV; HIV; NF-κB; inflammation; mTOR; natural product.

Figure 1

Structures of silybin A and silybin B, resveratrol, and curcumin. Note that silybin A and silybin B comprise the two major flavonolignans in the extract known as silymarin. Silibinin is an equimolar mix of silybin A and silybin B. Not shown are the other 5 flavonolignans that comprise the extract silymarin [44]. The structures share the features of containing multiple phenol groups. Hence, these compounds are all polyphenol-containing natural products.

Figure 2

Metabolic Rules of Engagement of Natural Products with Cells. Some of the earliest cellular responses to natural product exposure include the alteration of mitochondrial function which increases the AMP:ATP ratio, leading to activation of AMPK by phosphorylation (1); Natural products like salicylate can also directly bind to and activate AMPK (2); AMPK activation suppresses Rheb, an upstream activator of mTOR signaling. Thus, AMPK activation by natural products can lead to mTOR inhibition. Natural products like rapamycin can also directly bind to and inhibit mTOR signaling (3); The alteration of mitochondrial energetics may be involved in natural product induction of DDIT4, a novel upstream inhibitor of mTOR (4); Finally, activation of AMPK and inhibition of mTOR by natural products may be directly involved in the suppression of pro-inflammatory signaling such as that mediated by NF-κB (5). For mTOR, there is evidence that IKK interacts with mTORC1 to mediate the connection of mTORC1 to NF-κB, while for AMPK, the route to NF-κB is not presently clear. Citations of studies supporting these interactions are provided in text. Note that the tri-molecular complexes of IKK (IKKα, IKKβ, and IKKγ), and the bimolecular complex of NF-κB are simplified as single proteins. Moreover, only the mTORC1 and canonical NF-κB pathways are shown.