COVID-19: Proposing a Ketone-Based Metabolic Therapy as a Treatment to Blunt the Cytokine Storm

Figure 8

Proinflammatory signaling that occurs during viral infection and mechanisms through which R-BHB inhibits this signaling. (a) The ACE system. (b) The mechanism by which R-BHB inhibits the NLRP3 inflammasome is unknown. Four possible mechanisms are shown. (c) The hexosamine biosynthesis pathway is required to initiate an effective antiviral innate immune response, but its increased activity can also stimulate a cytokine storm. Abbreviations: 6PGDL: 6-phosphonoglocono-D-lactone; 6PG: 6-phosphogluconate; ACE2: angiotensin-converting enzyme 2; ACE: angiotensin-converting enzyme; ANG (1-9): angiotensin (1-9); ANG (1-7): angiotensin (1-7), a vasodilator; ANG II: angiotensin II, a vasoconstrictor; ANG III: angiotensin III, a metabolite of ANG II; BRCC3: Lys-63-specific deubiquitinase BRCC36; CARD: caspase recruitment domain; CLIC: chloride intracellular channel protein; F1,6BP: fructose 1,6-bisphosphate; F6P: fructose 6-phosphate; FADD: fas-associated protein with death domain; GlcNAc: G,N-acetylglucosamine; G3P: glyceraldehyde 3-phosphate; G6P: glucose 6-phosphate; GlcN-6P: glucosamine-6-phosphate; GlcNAc-6P: N-acetyl glucosamine-6-phosphate; GlcNAc-1p: N-acetyl glucosamine-1-phosphate; HBP: hexosamine biosynthesis pathway; IKK_ε: IκB kinase ε; IL-1R: interleukin-1 receptor; IRAK-1 and IRAK-4: interleukin-1 receptor kinases 1 and 4; IRF3 and IRF5: IFN-regulatory factors 3 and 5; JNK1: c-Jun N-terminal protein kinase 1; K63-Ub: K63-linked polyubiquitin binding; MasR: Mas receptor; MAVS: mitochondrial antiviral signaling protein; MDA5: melanoma differentiation-associated gene 5; MyD88: myeloid differentiation primary response 88; NF-κB: nuclear factor kappa-light-chain-enhancer of activated B cells; NLRP3: NOD-, LRR-, and pyrin domain-containing protein 3; NOD1 and NOD2: nucleotide-binding oligomerization domain-containing proteins 1 and 2; OGT: O-linked N-acetylglucosamine (GlcNAc) transferase; P2X7: P2X purinoceptor 7; PDPK: phosphoinositide-dependent kinase-1; PPP: pentose phosphate pathway; PTMs: posttranslational modifications; R5P: ribose 5-phosphate; RIG-1: retinoic acid-inducible gene I; S7P: sedoheptulose 7-phosphate; SERCA: sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase; STAT3: signal transducer and activator of transcription 3; TBK-1: TANK-binding kinase 1; TLR: toll-like receptor; TNFR: tumor necrosis factor receptor; TRAF6: tumor necrosis factor receptor- (TNFR-) associated factor 6; TRIF: TIR domain-containing adapter-inducing interferon β; TRX: thioredoxin; TXNIP: thioredoxin-interacting protein; UDP-GlcNAc: uridine diphosphate N-acetylglucosamine.

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