Candida and Long Covid

Abstract

The pandemic has supercharged growing awareness of the gut microbiome as a critical determinant of human health. Long haulers share microbiomes similar to those seen in myalgic encephalomyelitis/chronic fatigue syndrome and fibromyalgia, all frequently associated with Candida overgrowth (CO). Candida has a unique relationship with IDO and altered tryptophan metabolism (ATM), mediated by IFN-γ. Zonulin, a circulating protein that increases intestinal and endothelial permeability, has emerged as a central player. This protein can be activated by proteases secreted by Candida and mast cells, enabling myriad autoimmune and other chronic diseases. Many of these are seen in long Covid (LC). Candida hyphal walls express proteins that are analogous to gliadin/gluten (celiac disease antibodies) or that are GPCRs, e.g., Crohn’s disease antibodies present only in eukaryotes, that may trigger antigliadin and anti-GPCR autoantibodies respectively. These latter include the Saccharomyces/Candida hyphal GPCR seen in CrD and the Candida hyphal Rrp9 muscarinic GPCR seen in POTS. These two autoantibody producing pathways both activate zonulin and may encompass the broad spectrum of autoimmune diseases seen in LC. IFN-γ, a marker for LC, can activate not only IDO but also zonulin. The spike protein S on SARS CoV2 can attach to both the ACE2 receptor (required for tryptophan absorption) and Toll-like receptor4 (TLR4) bearing cells (endothelial cells and enterocytes). Spike protein S is persistent in LC and, as a ligand for TLR4, can also activate zonulin. S can also activate the nucleotide-binding domain, leucine-rich repeat, and pyrin domain-containing protein 3 (NLRP3) inflammasome, as can candidalysin. This inflammasome is directly connected to dementia, cancer, autoimmunity and obesity. A hypothetical pathophysiologic model is proposed implicating pre-existing CO, aggravated by Covid-19, in not only the genesis of LC but also that of autoimmune disease, dementia, cancer, many chronic diseases, and aging. Candida may accomplish this directly or through IFN-γ induced upregulation of both IDO and zonulin.