Immune Cell Regulatory Pathways Unexplored as Host-Directed Therapeutic Targets for Mycobacterium tuberculosis: An Opportunity to Apply Precision Medicine Innovations to Infectious Diseases

Abstract

The lack of novel antimicrobial drugs in development for tuberculosis treatment has provided an impetus for the discovery of adjunctive host-directed therapies (HDTs). Several promising HDT candidates are being evaluated, but major advancement of tuberculosis HDTs will require understanding of the master or "core" cell signaling pathways that control intersecting immunologic and metabolic regulatory mechanisms, collectively described as "immunometabolism." Core regulatory pathways conserved in all eukaryotic cells include poly (ADP-ribose) polymerases (PARPs), sirtuins, AMP-activated protein kinase (AMPK), and mechanistic target of rapamycin (mTOR) signaling. Critical interactions of these signaling pathways with each other and their roles as master regulators of immunometabolic functions will be addressed, as well as how Mycobacterium tuberculosis is already known to influence various other cell signaling pathways interacting with them. Knowledge of these essential mechanisms of cell function regulation has led to breakthrough targeted treatment advances for many diseases, most prominently in oncology. Leveraging these exciting advances in precision medicine for the development of innovative next-generation HDTs may lead to entirely new paradigms for treatment and prevention of tuberculosis and other infectious diseases.

Keywords: host-directed therapy; immunometabolism; precision medicine; signaling pathways; tuberculosis.

Figure 1.

Signaling pathways of immunometabolism and its dysregulation. Growth receptors (including receptor tyrosine kinases) and pattern recognition receptor (PRRs) induce mechanistic target of rapamycin (mTOR) and poly(ADP-ribose) polymerase (PARP) activation through phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT) and c-Jun N-terminal kinase (JNK)/extracellular signal-regulated kinase (ERK) signaling, respectively, to stimulate inflammation, largely by upregulation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kB). Phosphatidylinositol-3, 4, 5,-trisphosphate 3-phosphatase (PTEN) directly inhibits PI3K activation. Sirtuin (SIRT) and AMP-activated protein kinase (AMPK) cross-activate each other. SIRT dampens inflammation by blocking PARP directly. SIRT signaling also downregulates NF-kB activation. AMPK inhibits PARP through suppression of ERK signaling. AMPK stimulates PTEN, blocks mTOR and induces autophagy. Increased reactive oxygen species (ROS)/oxidative cellular stress induces ERK signaling and PARP activation, and endoplasmic reticulum stress (ERS) increases PARP activation. Both types of stress lead to inflammation, cell damage, and death, and damage-associated molecular pattern (DAMP) molecule release. DAMPs further increase these signaling patterns, resulting in a vicious cycle of progressive inflammation and cell death. The stress responses also lead to increased uptake of oxidized low-density lipoprotein (ox-LDL) in macrophages via scavenger receptors. Increased ox-LDL causes lipid droplet formation that may lead to foam cell development. Foamy macrophages are most often M2 polarized, producing a hypoinflammatory response and increasing susceptibility to Mycobacterium tuberculosis infection. β-Adrenergic and some G-protein–coupled receptors can activate adenylate cyclase that in turn increases protein kinase A (PKA) and SIRT activities. SIRT activation can also inhibit cyclic adenosine monophosphate (cAMP) phosphodiesterase (PDE).

Figure 2.

Poly(ADP-ribose) polymerase (PARP) and sirtuin (SIRT) effects on immunometabolism. A, PARP “PARylates” many substrates including RelA for activation of nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) in an oxidized nicotinamide adenine dinucleotide (NAD⁺)–dependent manner, leading to elevated reactive oxygen species (ROS)–oxidative stress/endoplasmic reticulum stress (ERS) and proinflammatory cytokine production. PARP hyperactivity also causes chronic inflammation by depleting NAD⁺ that subsequently decreases SIRT activity and lowers adenosine triphosphate (ATP) concentrations. SIRT can counteract NF-κB activation through deacetylation of the RelA/p65 subunit of NF-kB. Depleted ATP activates AMP-activated protein kinase (AMPK), which in turn increases ATP and NAD⁺ levels, leading to increased SIRT activity and suppressed PARP activity that may bring the cell back to equilibrium. B, SIRT regulates immune cell metabolic activity largely through regulation of hypoxia-inducible factor (HIF1α) and peroxisome proliferator–activated receptor γ coactivator (PGC-1α). Increased phosphatidylinositol 3-kinase (PI3K)/serine-threonine protein kinase (AKT)/mechanistic target of rapamycin (mTOR) signaling activates HIF to convert cell energy production mechanism to aerobic glycolysis during immune activation enhancing T-helper 1 cell differentiation. SIRT, along with AMPK, converts T-cell energy metabolism to fatty acid oxidation by blocking HIF activity and activating PGC-1α to enhance differentiation toward memory T cells and T-regulatory cells.