Unraveling the SARS-CoV-2 Spike Protein Long-term Effect on Neuro-PASC

Overview

Journal Front Cell Neurosci

Specialty Cell Biology

Date 2025 Jan 2

PMID 39744674

Authors

Filipe Menezes

Julys da Fonseca Palmeira

Juliana Dos Santos Oliveira

Gustavo Adolfo Arganaraz

Carlos Roberto Jorge Soares

Otavio Toledo Nobrega

Bergmann Morais Ribeiro

Enrique Roberto Arganaraz

Affiliations

Soon will be listed here.

Abstract

The persistence or emergence of long-term symptoms following resolution of primary SARS-CoV-2 infection is referred to as long COVID or post-acute sequelae of COVID-19 (PASC). PASC predominantly affects the cardiovascular, neurological, respiratory, gastrointestinal, reproductive, and immune systems. Among these, the central nervous system (CNS) is significantly impacted, leading to a spectrum of symptoms, including fatigue, headaches, brain fog, cognitive impairment, anosmia, hypogeusia, neuropsychiatric symptoms, and peripheral neuropathy (neuro-PASC). However, the risk factors and pathogenic mechanisms responsible for neuro-PASC remain unclear. This review hypothesis discusses the leading hypotheses regarding the pathophysiological mechanisms involved in long COVID/PASC, focusing on neuro-PASC. We propose vascular dysfunction mediated by activation of astrocytes and pericytes followed by blood-brain barrier (BBB) disruption as underlying pathophysiological mechanisms of neurological manifestations. Additionally, we provide insights into the role of spike protein at the blood-brain interface. Finally, we explore the potential pathogenic mechanisms initiated by the interaction between the spike protein and cellular receptors at the brain endothelial and tissue levels.

References

Rodriguez Y, Rojas M, Beltran S, Polo F, Camacho-Dominguez L, Morales S . Autoimmune and autoinflammatory conditions after COVID-19 vaccination. New case reports and updated literature review. J Autoimmun. 2022; 132:102898. PMC: 9399140. DOI: 10.1016/j.jaut.2022.102898. View

Sommer A, Kordowski F, Buch J, Maretzky T, Evers A, Andra J . Phosphatidylserine exposure is required for ADAM17 sheddase function. Nat Commun. 2016; 7:11523. PMC: 4866515. DOI: 10.1038/ncomms11523. View

Ardestani Zadeh A, Arab D . COVID-19 and male reproductive system: pathogenic features and possible mechanisms. J Mol Histol. 2021; 52(5):869-878. PMC: 8260577. DOI: 10.1007/s10735-021-10003-3. View

Jeong J, Dow S, Young C . Sensory Circumventricular Organs, Neuroendocrine Control, and Metabolic Regulation. Metabolites. 2021; 11(8). PMC: 8402088. DOI: 10.3390/metabo11080494. View

Han Q, Zheng B, Daines L, Sheikh A . Long-Term Sequelae of COVID-19: A Systematic Review and Meta-Analysis of One-Year Follow-Up Studies on Post-COVID Symptoms. Pathogens. 2022; 11(2). PMC: 8875269. DOI: 10.3390/pathogens11020269. View

Crunfli F, Carregari V, Veras F, Silva L, Nogueira M, Antunes A . Morphological, cellular, and molecular basis of brain infection in COVID-19 patients. Proc Natl Acad Sci U S A. 2022; 119(35):e2200960119. PMC: 9436354. DOI: 10.1073/pnas.2200960119. View

Datta G, Miller N, Halcrow P, Khan N, Colwell T, Geiger J . SARS-CoV-2 S1 Protein Induces Endolysosome Dysfunction and Neuritic Dystrophy. Front Cell Neurosci. 2021; 15:777738. PMC: 8579006. DOI: 10.3389/fncel.2021.777738. View

Sunada N, Honda H, Nakano Y, Yamamoto K, Tokumasu K, Sakurada Y . Hormonal trends in patients suffering from long COVID symptoms. Endocr J. 2022; 69(10):1173-1181. DOI: 10.1507/endocrj.EJ22-0093. View

Sauve F, Nampoothiri S, Clarke S, Fernandois D, Ferreira Coelho C, Dewisme J . Long-COVID cognitive impairments and reproductive hormone deficits in men may stem from GnRH neuronal death. EBioMedicine. 2023; 96:104784. PMC: 10507138. DOI: 10.1016/j.ebiom.2023.104784. View

10.

Schultheiss C, Willscher E, Paschold L, Gottschick C, Klee B, Bosurgi L . Liquid biomarkers of macrophage dysregulation and circulating spike protein illustrate the biological heterogeneity in patients with post-acute sequelae of COVID-19. J Med Virol. 2022; 95(1):e28364. PMC: 9878213. DOI: 10.1002/jmv.28364. View

11.

Taquet M, Geddes J, Husain M, Luciano S, Harrison P . 6-month neurological and psychiatric outcomes in 236 379 survivors of COVID-19: a retrospective cohort study using electronic health records. Lancet Psychiatry. 2021; 8(5):416-427. PMC: 8023694. DOI: 10.1016/S2215-0366(21)00084-5. View

12.

Cantuti-Castelvetri L, Ojha R, Pedro L, Djannatian M, Franz J, Kuivanen S . Neuropilin-1 facilitates SARS-CoV-2 cell entry and infectivity. Science. 2020; 370(6518):856-860. PMC: 7857391. DOI: 10.1126/science.abd2985. View

13.

Reynolds J, Mahajan S . SARS-COV2 Alters Blood Brain Barrier Integrity Contributing to Neuro-Inflammation. J Neuroimmune Pharmacol. 2021; 16(1):4-6. PMC: 7786155. DOI: 10.1007/s11481-020-09975-y. View

14.

Cao X, Nguyen V, Tsai J, Gao C, Tian Y, Zhang Y . The SARS-CoV-2 spike protein induces long-term transcriptional perturbations of mitochondrial metabolic genes, causes cardiac fibrosis, and reduces myocardial contractile in obese mice. Mol Metab. 2023; 74:101756. PMC: 10281040. DOI: 10.1016/j.molmet.2023.101756. View

15.

Chen R, Wang K, Yu J, Howard D, French L, Chen Z . The Spatial and Cell-Type Distribution of SARS-CoV-2 Receptor ACE2 in the Human and Mouse Brains. Front Neurol. 2021; 11:573095. PMC: 7855591. DOI: 10.3389/fneur.2020.573095. View

16.

Sudre C, Murray B, Varsavsky T, Graham M, Penfold R, Bowyer R . Attributes and predictors of long COVID. Nat Med. 2021; 27(4):626-631. PMC: 7611399. DOI: 10.1038/s41591-021-01292-y. View

17.

Andrews M, Mukhtar T, Eze U, Simoneau C, Ross J, Parikshak N . Tropism of SARS-CoV-2 for human cortical astrocytes. Proc Natl Acad Sci U S A. 2022; 119(30):e2122236119. PMC: 9335272. DOI: 10.1073/pnas.2122236119. View

18.

Rong Z, Mai H, Ebert G, Kapoor S, Puelles V, Czogalla J . Persistence of spike protein at the skull-meninges-brain axis may contribute to the neurological sequelae of COVID-19. Cell Host Microbe. 2024; 32(12):2112-2130.e10. DOI: 10.1016/j.chom.2024.11.007. View

19.

Parekh R, Sriramula S . Activation of Kinin B1R Upregulates ADAM17 and Results in ACE2 Shedding in Neurons. Int J Mol Sci. 2020; 22(1). PMC: 7795389. DOI: 10.3390/ijms22010145. View

20.

Pretorius E, Vlok M, Venter C, Bezuidenhout J, Laubscher G, Steenkamp J . Persistent clotting protein pathology in Long COVID/Post-Acute Sequelae of COVID-19 (PASC) is accompanied by increased levels of antiplasmin. Cardiovasc Diabetol. 2021; 20(1):172. PMC: 8381139. DOI: 10.1186/s12933-021-01359-7. View