Molecular Mimicry between SARS-CoV-2 Proteins and Human Self-Antigens Related with Autoimmune Central Nervous System (CNS) Disorders

Abstract

SARS-CoV-2 can trigger autoimmune central nervous system (CNS) diseases in genetically susceptible individuals, a mechanism poorly understood. Molecular mimicry (MM) has been identified in other viral diseases as potential triggers of autoimmune CNS events. This study investigated if MM is the process through which SARS-CoV-2 induces the breakdown of immune tolerance. The frequency of autoimmune CNS disorders was evaluated in a prospective cohort with patients admitted to the COVID-19 Intense Care Unity (ICU) in Rio de Janeiro. Then, an in silico analysis was performed to identify the conserved regions that share a high identity between SARS-CoV-2 antigens and human proteins. The sequences with significant identity and antigenic properties were then assessed for their binding capacity to HLA subtypes. Of the 112 patients included, 3 were classified as having an autoimmune disorder. A total of eleven combinations had significant linear and three-dimensional overlap. NMDAR1, MOG, and MPO were the self-antigens with more significant combinations, followed by GAD65. All sequences presented at least one epitope with strong or intermediate binding capacity to the HLA subtypes selected. This study underscores the possibility that CNS autoimmune attacks observed in COVID-19 patients, including those in our population, could be driven by MM in genetically predisposed individuals.

Keywords: COVID-19; SARS-CoV-2; autoimmune disorders; central nervous system; immune tolerance; molecular mimicry.

Figure 1

MRI of patient 1. (A)—axial flair sequence reveals hyperintense lesion near the posterior horn of the right lateral ventricle (red arrows). (B,C)—axial flair and sagittal T2 sequences demonstrate hyperintense lesion in the pons (red arrows). (D–F)—axial and sagittal T1 sequences with contrast demonstrating impregnation of the lesions (yellow arrows).

Figure 2

MRI of patient 2. (A–D)—sagittal and axial flair sequences and sagittal T2, showing multiple lesions (red arrows) with hypersignal, distributed in the periventricular and subcortical regions and in the spinal cord. Some of these lesions are impregnated with contrast (yellow arrows) (E,F).

Figure 3

MRI of patient 3—(A–F)—flair sequence in the axial plane showing multiple lesions in the inferior cerebellar peduncle and the subcortical and periventricular regions, predominantly in the right hemisphere (red arrows).

Figure 4

Models had a significant linear and three-dimensional overlap of autoimmune CNS proteins (in red) and SARS-CoV-2 (in blue) proteins according to TM-align, with their respective amino acid sequences. The arrows indicate the sequence region with three-dimensional overlap. (a) M and NMDAR1 (TM-score: 0.89). (b) M and MPO (TM-Score = 0.73). (c) nsp2 and NMDAR1 (TM-score = 0.69). (d) S and MOG (TM-score = 0.63). (e) ORF7a and MOG (TM-score = 0.62). (f) N and MPO (TM-score = 0.59). (g) nsp13 and GAD65 (TM-score = 0.52). (h) nsp1 and GAD65 (TM-score = 0.52). (i) nsp1 and MOG (TM-score = 0.50). (j) nsp3 and MPO (TM-score = 0.50). (k) S and NMDAR1 (TM-score = 0.50).