Viruses and amyloids - a vicious liaison

Figures & data

Figure 1. Organs and tissues affected by systemic and localized amyloidosis are in many instances overlapping with those afflicted by acute COVID-19 and PASC.

Table 1. Human amyloid fibril proteins and their precursors. Table is modified from [29]. Proteins are listed in groups as full-length protein in fibril, fragments in fibril, and endoproteolytic products from precursor proteins.

Fibril protein	Precursor protein	Tropism	Target organs	Full length functional protein in fibril	Fragments of functional protein in fibril	Endo-proteolytic processing required for amyloidogenesis*
Aβ2 M	β2-microglobulin, wild type	Systemic	WT: Musculoskeletal system; Mut: ANS, tongue, heart	X
AApoAII	Apolipoprotein A II, variants	Systemic	Kidney	X
AApoCII	Apolipoprotein C II, variants	Systemic	Kidney	X
AApoCIII	Apolipoprotein C III, variants	Systemic	Kidney	X
ALECT2	Leukocyte chemotactic factor-2	Systemic	Kidney, primarily	X
ACys	Cystatin C, variants	Neurologic	CNS, skin	X
ALac	Lactoferrin	Localized	Cornea	X
AL	Immunoglobulin light chain	Systemic	All organs, usually except CNS	X	X
AH	Immunoglobulin heavy chain	Systemic	All organs except CNS	X	X
ATTR	Transthyretin, wild type and variants	Systemic	WT: Heart mainly in males, lung, ligaments, tenosynovium; Mut:PNS, ANS, heart, eye, kidneys, leptomeninges	X	X
AApoAI	Apolipoprotein A I, variants	Systemic	Heart, liver, kidney, PNS, testis, larynx (C-terminal variants), skin (C-terminal variants)	X	X
ALys	Lysozyme, variants	Systemic	Kidney, Gastrointestinal	X	X
AαSyn	α-Synuclein wild type and variants	Neurologic	CNS, ANS	X	X
ATau	Tau wild type and variants	Neurologic	CNS	X	X
APrP	Prion protein, wild type and variants	Neurologic	WT: CJD, fatal insomnia; Mut: CJD, GSS syndrome, fatal insomnia, PNS	X	X
AKer	Kerato-epithelin TGFB1	Localized	Cornea, hereditary	X	X
AA	(Apo) Serum amyloid A	Systemic	All organs except CNS		X	X
AApoAIV	Apolipoprotein A IV, wild type	Systemic	Kidney medulla and systemic		X	X
AGel	Gelsolin, variants	Systemic	PNS, cornea, Kidney		X	X
AFib	Fibrinogen, α, variants	Systemic	Kidney, primarily		X	X
ABri	ABriPP, variants	Neurologic	CNS		X	X
ADanb	ADanPP, variants	Neurologic	CNS		X	X
Aβ	Aβ protein precursor, wild type and variants	Neurologic	CNS		X	X
ATMEM106B	Transmembrane 106B (TMEM106B)	Neurologic	CNS		X	X
AMed	Lactadherin (MFG-E8)	Localized	Ageing aorta, media, elastic arteries		X	X
ACal	(Pro)calcitonin	Localized	C-cell thyroid tumours, Kidney			X
AIAPP	Islet amyloid polypeptide	Localized	Islets of Langerhans, insulinomas			X
AANP	Atrial natriuretic peptide	Localized	Cardiac atria			X
APro	Prolactin	Localized	Pituitary prolactinomas, ageing pituitary			X
ASom	(Pro)somatostatin	Localized	Somatostatinomas			X
AGluc	Glucagon	Localized	Glucagonomas			X
APTH	Parathyroid hormone	Localized	Parathyroid tumours, Ageing parathyroid glands			X
ASPC	Lung surfactant protein	Localized	Lung			X
ACor	Corneodesmosin	Localized	Cornified epithelia, hair follicles			X
AOAAP	Odontogenic ameloblast-associated protein	Localized	Odontogenic tumours			X
ASem1	Semenogelin 1	Localized	Vesicula seminalis			X
ACatK	Cathepsin K	Localized	Tumour associated			X
AEFEMP1	EGF-containing fibulin-like extracellular matrix protein 1 (EFEMP1)	Localized	Veins, Aging associated			X
Ains**	Insulin	Localized	Iatrogenic, local injection			X**
Aenf**	Enfurvitide	Localized	Iatrogenic, local injection			X**
AGLP1**	Glucagon-like peptide 1 analog	Localized	Iatrogenic, local injection			X**
AIL1RAP**	Interleukin-1 receptor antagonist protein	Localized	Iatrogenic, local injection			X**

*not including signal peptide processing.

**iatrogenic provided by injection of medical products.

Figure 2. Endoproteolysis is a common and often required pathway for amyloid formation of natively folded and functional proteins.

Note: Top: The amyloidogenic Aβ peptide, a part of the trans-membrane domain of Amyloid-β precursor protein (AβPP), is cleaved by membrane bound β- and γ-secretase and exported to the extracellular space where it accumulates, deposits as amyloid fibrils and form senile plaques and CAA abundant in Alzheimer’s disease.

Middle: Serum amyloid A (SAA) is a globular, α-helix rich acute phase protein that is highly elevated during inflammation. Inflammatory cells such as macrophages and neutrophils release proteases that cleaves the helical protein into smaller peptides, enabling it to expose amyloidogenic sequences that form amyloid fibrils found as deposits in kidney as well as other organs.

Bottom: SARS-CoV-2 Spike-protein expressed during COVID-19 infection and mRNA vaccination. When cleaved by neutrophil elastase, it will expose amyloidogenic sequences and form fibrils with the potential to inhibit fibrinolysis of formed clots and potentially cause endothelial damage and/or cross-seed amyloidogenic host protein.

Figure 3. TEM micrographs of (on top) full length Spike-protein (Wuhan strain) after co-incubation with neutrophil elastase at 37°C for 24 h. The in silico predicted peptide 192–211 of SARS-CoV-2 Spike-protein, incubated at 37°C for 24 h. The resulting fibrils are straight, twisted and rod-like [81].

Figure 4. There are several mechanisms by which amyloids and viruses co-operate.

Amyloid formation of host encoded protein can be catalyzed on the surface of the virion [112]. Host amyloid coating the surface of the virion can activate macrophages and induce phagocytosis that in turn mediates the generation of amyloid seeds by macrophage proteolytic activity and further amyloid spreading [122]. Virus-derived vesicles (SVPs) can be loaded with amyloid content and target cell receptors leading to efficient and specific release of amyloid protein cargo to nascent host cells [131].

Figure 5. Blood clots formed by thrombin processing of fibrinogen to fibrin recruiting blood platelets in a polymerizing fibrous web. The process of fibrinolysis is regulated by several proteins ultimately affording active plasmin as the proteolytic enzyme to digest insoluble fibrin and, hence resolving the clot. The normal process is shown on the left side of the clot in the figure. If fibrin on the other hand is generated from fibrinogen by thrombin (possibly even without thrombin) in the presence of amyloid seeds the fibrin can form misfolded fibrin (fibrinaloid) which cannot be digested by plasmin (right side of the figure). In addition to seeding misfolding of fibrin, amyloid fibrils are inactivating and activating proteins involved in fibrinolysis: tPA, vitronectin, α2-antiplasmin, and plasmin. Hence, there are many associations between fibrinolysis and amyloid disease as discussed in the main text.

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