Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19

Charnley, Mirren; Islam, Saba; Bindra, Guneet K.; Engwirda, Jeremy; Ratcliffe, Julian; Zhou, Jiangtao; Mezzenga, Raffaele; Hulett, Mark D.; Han, Kyunghoon; Berryman, Joshua T.; Reynolds, Nicholas P.

doi:10.1038/s41467-022-30932-1

Cited by 55 publications

(106 citation statements)

References 64 publications

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“…to have amyloidogenic potential (35,36). Similar findings have been previously demonstrated for HSV-1, where HSV-1 reactivation was shown to increase AD risk (37), and HSV-1 infection was shown to induce amyloid aggregation in animal models (20,38,39).…”

Section: Discussionsupporting

confidence: 80%

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion

Christ

Kapell

Mermelekas

et al. 2022

Preprint

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The corona virus (SARS-CoV-2) pandemic and the resulting long-term neurological complications in patients, known as long COVID, have renewed the interest in the correlation between viral infections and neurodegenerative brain disorders. While many viruses can reach the central nervous system (CNS) causing acute or chronic infections (such as herpes simplex virus 1, HSV-1), the lack of a clear mechanistic link between viruses and protein aggregation into amyloids, a characteristic of several neurodegenerative diseases, has rendered such a connection elusive. Recently, we showed that viruses can induce aggregation of purified amyloidogenic proteins via the direct physicochemical mechanism of heterogenous nucleation (HEN). In the current study, we show that the incubation of HSV-1 and SARS-CoV-2 with human cerebrospinal fluid (CSF) leads to the amyloid aggregation of several proteins known to be involved in neurodegenerative diseases, such as: APLP1 (amyloid beta precursor like protein 1), ApoE, clusterin, α2-macroglobulin, PGK-1 (phosphoglycerate kinase 1), ceruloplasmin, nucleolin, 14-3-3, transthyretin and vitronectin. Importantly, UV-inactivation of SARS-CoV-2 does not affect its ability to induce amyloid aggregation, as amyloid formation is dependent on viral surface catalysis via HEN and not its ability to replicate. Our results show that viruses can physically induce amyloid aggregation of proteins in human CSF, and thus providing a potential mechanism that may account for the association between persistent and latent/reactivating brain infections and neurodegenerative diseases.

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Section: Discussionsupporting

confidence: 80%

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion

Christ

Kapell

Mermelekas

et al. 2022

Preprint

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“…In ME/CFS (Myalgic Encephalomyelitis/Chronic Fatigue Syndrome), autoimmunity is well described [ 94 ]; and might also play an important role in long COVID because some autoantibodies share elements of epitope with the SARS-CoV-2 virus [ 99 ]. It has also been suggested that some of the viral sequences are amyloidogenic [ 100 , 101 ]. Viral persistence may play a key role in patients suffering from long COVID [ 102 ], and therefore driving an ongoing immune response or the development of autoimmunity (see Fig.…”

Section: Discussionmentioning

confidence: 99%

Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system

Kruger

Vlok

Turner

et al. 2022

Cardiovasc Diabetol

131

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Background Post-acute sequelae of COVID-19 (PASC), also now known as long COVID, has become a major global health and economic burden. Previously, we provided evidence that there is a significant insoluble fibrin amyloid microclot load in the circulation of individuals with long COVID, and that these microclots entrap a substantial number of inflammatory molecules, including those that might prevent clot breakdown. Scientifically, the most challenging aspect of this debilitating condition is that traditional pathology tests such as a serum CRP (C-reactive protein) may not show any significant abnormal inflammatory markers, albeit these tests measure only the soluble inflammatory molecules. Elevated, or abnormal soluble biomarkers such as IL-6, D-Dimer or fibrinogen indicate an increased risk for thrombosis or a host immune response in COVID-19. The absence of biomarkers in standard pathology tests, result in a significant amount of confusion for patients and clinicians, as patients are extremely sick or even bed-ridden but with no regular identifiable reason for their disease. Biomarkers that are currently available cannot detect the molecules present in the microclots we identified and are therefore unable to confirm their presence or the mechanisms that drive their formation. Methods Here we analysed the protein content of double-digested microclots of 99 long COVID patients and 29 healthy controls. The patients suffering from long COVID reported their symptoms through a questionnaire completed by themselves or their attending physician. Results Our long COVID cohort’s symptoms were found to be in line with global findings, where the most prevalent symptoms were constant fatigue (74%,) cognitive impairment (71%) and depression and anxiety (30%). Our most noteworthy findings were a reduced level of plasma Kallikrein compared to our controls, an increased level of platelet factor 4 (PF4) von Willebrand factor (VWF), and a marginally increased level of α-2 antiplasmin (α-2-AP). We also found a significant presence of antibodies entrapped inside these microclots. Conclusion Our results confirm the presence of pro-inflammatory molecules that may also contribute to a failed fibrinolysis phenomenon, which could possibly explain why individuals with long COVID suffer from chronic fatigue, dyspnoea, or cognitive impairment. In addition, significant platelet hyperactivation was noted. Hyperactivation will result in the granular content of platelets being shed into the circulation, including PF4. Overall, our results provide further evidence of both a failed fibrinolytic system in long COVID/PASC and the entrapment of many proteins whose presence might otherwise go unrecorded. These findings might have significant implications for individuals with pre-existing comorbidities, including cardiovascular disease and type 2 diabetes.

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“…A propensity to develop microthrombi in PASC has obvious implications for the pathogenesis of cardiovascular problems discussed above. Intriguingly, it has been suggested that the SARS-CoV-2 proteome includes amyloidogeneic peptides which may contribute to neurological symptoms [ 82 ].…”

Section: Pathogenesis and Biomarkersmentioning

confidence: 99%

Long Covid: where we stand and challenges ahead

et al. 2022

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Post-acute sequelae of SARS-CoV-2 (PASC), also known as Post-Covid Syndrome, and colloquially as Long Covid, has been defined as a constellation of signs and symptoms which persist for weeks or months after the initial SARS-CoV-2 infection. PASC affects a wide range of diverse organs and systems, with manifestations involving lungs, brain, the cardiovascular system and other organs such as kidney and the neuromuscular system. The pathogenesis of PASC is complex and multifactorial. Evidence suggests that seeding and persistence of SARS-CoV-2 in different organs, reactivation, and response to unrelated viruses such as EBV, autoimmunity, and uncontrolled inflammation are major drivers of PASC. The relative importance of pathogenetic pathways may differ in different tissue and organ contexts. Evidence suggests that vaccination, in addition to protecting against disease, reduces PASC after breakthrough infection although its actual impact remains to be defined. PASC represents a formidable challenge for health care systems and dissecting pathogenetic mechanisms may pave the way to targeted preventive and therapeutic approaches.

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Neurotoxic amyloidogenic peptides in the proteome of SARS-COV2: potential implications for neurological symptoms in COVID-19

Cited by 55 publications

References 64 publications

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion

SARS-CoV-2 and HSV-1 Induce Amyloid Aggregation in Human CSF Resulting in Drastic Soluble Protein Depletion

Proteomics of fibrin amyloid microclots in long COVID/post-acute sequelae of COVID-19 (PASC) shows many entrapped pro-inflammatory molecules that may also contribute to a failed fibrinolytic system

Long Covid: where we stand and challenges ahead

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