No effects without causes: the Iron Dysregulation and Dormant Microbes hypothesis for chronic, inflammatory diseases

Abstract

Since the successful conquest of many acute, communicable (infectious) diseases through the use of vaccines and antibiotics, the currently most prevalent diseases are chronic and progressive in nature, and are all accompanied by inflammation. These diseases include neurodegenerative (e.g. Alzheimer's, Parkinson's), vascular (e.g. atherosclerosis, pre-eclampsia, type 2 diabetes) and autoimmune (e.g. rheumatoid arthritis and multiple sclerosis) diseases that may appear to have little in common. In fact they all share significant features, in particular chronic inflammation and its attendant inflammatory cytokines. Such effects do not happen without underlying and initially 'external' causes, and it is of interest to seek these causes. Taking a systems approach, we argue that these causes include (i) stress-induced iron dysregulation, and (ii) its ability to awaken dormant, non-replicating microbes with which the host has become infected. Other external causes may be dietary. Such microbes are capable of shedding small, but functionally significant amounts of highly inflammagenic molecules such as lipopolysaccharide and lipoteichoic acid. Sequelae include significant coagulopathies, not least the recently discovered amyloidogenic clotting of blood, leading to cell death and the release of further inflammagens. The extensive evidence discussed here implies, as was found with ulcers, that almost all chronic, infectious diseases do in fact harbour a microbial component. What differs is simply the microbes and the anatomical location from and at which they exert damage. This analysis offers novel avenues for diagnosis and treatment.

Keywords: LPS; amplification; amyloid; blood clotting; inflammation; iron dysregulation.

Figure 1

Overview of the processes involved in the Iron Dysregulation and Dormant Microbes (IDDM) hypothesis of chronic inflammatory diseases. (A) The numbered steps, starting with steps –2a and –2b, that are discussed sequentially in this review. (B) A ‘mind map’ (Buzan, 2002) of this review. LPS, lipopolysaccharide; LTA, lipoteichoic acid; 25(OH)D₃, 25‐hydroxy‐D₃ (vitamin D).

Figure 2

A simplified scheme showing the links between Vitamin D, cytokines and iron metabolism during chronic inflammation. 25(OH)D₃, 25‐hydroxyvitamin D; 1,25(OH)2D₃, calcitriol or 1,25‐dihydroxycholecalciferol; IL, interleukin; LL‐37AMP, antimicrobial peptide LL‐37; LPS, lipopolysaccharide; NRAMP, natural resistance‐associated macrophage proteins; VDR, vitamin D receptor.

Figure 3

Examples of eryptotic red blood cells (RBCs) in inflammation. (A) Healthy RBCs with a platelet; (B) Type 2 diabetes (Pretorius et al., 2015); (C, D) Parkinson's disease (Pretorius et al., 2014b); (E) Rheumatoid arthritis (Olumuyiwa‐Akeredolu et al., 2017); (F) healthy whole blood exposed to interleukin‐8 (Bester & Pretorius, 2016).

Figure 4

Lipopolysaccharide (LPS)‐ and serum amyloid A (SAA)‐mediated cellular production of inflammatory cytokines. Canonical pathway of LPS‐mediated release and nuclear translocation of nuclear factor‐kappa B (NF‐ κB) (based on O'Neill et al., 2009). IKK, IκB kinase complex; INF, interferon; IRF3, interferon regulatory factor 3; MyD88, myeloid differentiation primary response 88; NEMO, NF‐κB essential modulator; p50, NF‐κB subunit, p50; p65, transcription factor p65 also known as nuclear factor NF‐kappa‐B p65 subunit; RANTES, hemokine (C‐C motif) ligand 5; SAA, Serum amyloid A; TBK1, TANK‐binding kinase 1; TIRF, TIR‐domain‐containing adapter‐inducing interferon‐β; TLR, Toll‐like receptor; TRAF, TNF receptor associated factor; TRAM, TRIF‐related adaptor molecule.

Figure 5

Intracellular lipopolysaccharide (LPS)‐mediated activation of caspase‐1 leading to interleukin 1β (IL‐1β) production (after Latz et al., 2013). ASC, caspase activation and recruitment domain; IL, interleukin; INF, type 1 interferon; INFAR, interferon receptor; MALT1, mucosa‐associated‐lymphoid‐tissue lymphoma‐translocation gene 1; NTLP3, nucleotide‐binding oligomerization domain‐like receptor family, pyrin domain‐containing‐3; PRR, pattern recognition receptor; SYK, spleen tyrosine kinase; TLR4, Toll‐like receptor 4.

Figure 6

Energy barriers in prion protein formation [based on Cohen & Prusiner (1998) and Kell & Pretorius (2017a)]. Normal cell‐surface glycoprotein: PrP^c; prion protein scrapie associated: PRP^SC; ΔG^† free energy of activation.

Figure 7

(A) The clotting cascade. Clotting can be activated by either the extrinsic or intrinsic pathway, which converge to a common pathway at factor X, and which ultimately leads to the conversion of prothrombin (factor II) to thrombin that catalyses activation and crosslinking (via factor XIII) of fibrinogen into a fibrin fibre meshwork. Rt‐PA, recombinant tissue plasminogen activator. Redrawn from Kell & Pretorius, 2015b, 2017b). (B) Conversion of soluble fibrinogen molecules to insoluble fibrin fibres during the clotting process (adapted from Kell & Pretorius, 2015b). Fibrinopeptide A and B: FpA and FpB.

Figure 8

Confocal micrographs of human plasma with added fluorescent markers: Amytracker 480 (blue), Amytracker 680 (red) and Thioflavin T (ThT, green), followed by thrombin to create a fibrin clot. (A) Healthy plasma, (B) healthy plasma after exposure to 0.4 ng l⁻¹ lipopolysaccharide (LPS) (Pretorius et al., 2016c); (C) plasma from a patient with type 2 diabetes (Pretorius et al., 2017c).

Figure 9

Dysregulation of inflammatory markers, including cytokines and iron, leads to oxidative stress, which in turn causes changes to both fibrin(ogen) and red blood cells (RBCs) visible as amyloidogenesis and eryptosis. Amyloidogenesis and eryptosis both leadsto inflammation but their induction is also enhanced by the presence of inflammation. COX‐2, cyclooxygenase‐2; PGE2, prostaglandin E2; NOS, nitric oxide synthase; TNFα, tumor necrosis factor alpha; thromboxane A2 is a type of thromboxane that is produced by activated platelets.