Molecular Mimicry Analyses Unveiled the Human Herpes Simplex and Poxvirus Epitopes as Possible Candidates to Incite Autoimmunity

Abstract

Clinical epidemiological studies have reported that viral infections cause autoimmune pathology in humans. Host-pathogen protein sequences and structure-based molecular mimicry cause autoreactive T cells to cross-activate. The aim of the current study was to implement immunoinformatics approaches to infer sequence- and structure-based molecular mimicry between viral and human proteomic datasets. The protein sequences of all the so far known human-infecting viruses were obtained from the VIPR database, and complete human proteome data were retrieved from the NCBI repository. Based on a predefined, stringent threshold of comparative sequence analyses, 24 viral proteins were identified with significant sequence similarity to human proteins. PathDIP identified the enrichment of these homologous proteins in nine metabolic pathways with a p-value < 0.0001. Several viral and human mimic epitopes from these homologous proteins were predicted as strong binders of human HLA alleles, with IC50 < 50 nM. Downstream molecular docking analyses identified that lead virus-human homologous epitopes feasibly interact with HLA and TLR4 types of immune receptors. The vast majority of these top-hit homolog epitopic peptides belong to the herpes simplex and poxvirus families. These lead epitope biological sequences and 3D structural-based molecular mimicry may be promising for interpreting herpes simplex virus and poxvirus infection-mediated autoimmune disorders in humans.

Molecular Mimicry as a Mechanism of Viral Immune Evasion and Autoimmunity

“…In this study, we evaluated 134 proteomes from all existing human infecting viruses for short linear molecular mimicry to human proteins, comprising one of the largest viral screens to date. These results broaden the current knowledge on the rates of mimicry, as prior studies have primarily focused on limited number of pathogens or mimics predicted to bind to common HLA haplotypes [16][17][18][19] . Furthemore, our research reveals underlying cellular and biological patterns associated with mimicry, highlighting the complexity and molecular consequences of hostpathogen interactions.…”

“…linear sequence) needs to be evaluated to better understand how viral mimicry may be perceived by the adaptive immune system. While prior studies have evaluated linear AA mimicry in limited cohorts of pathogens [16][17][18] or searched specifically for top mimics that may contribute to auto-immunity 19 , it remains unclear how the abundance of linear mimicry differs across a wider range of the human virome.…”

Viruses as a potential environmental trigger of type 1 diabetes mellitus (Review)

“…One of the most commonly discussed possibilities is molecular mimicry which involves cross-reactive immunity against epitopes shared between viruses and human pancreatic β-cells. Thus, molecular mimicry may cause the activation of self-reactive T cells in T1DM, activated by a virus that carries an epitope bearing a strong similarity to certain structures present in human β-cells ( 72 ). This triggers a cross-reactive autoimmune response that eliminates the viral infection and the β-cells of the pancreatic islets.…”

When inflammatory stressors dramatically change, disease phenotypes may transform between autoimmune hematopoietic failure and myeloid neoplasms

“…1) When infected by microbes or inoculated with vaccines, hosts generate high-affinity antibodies or emCTLs through class switching and affinity maturation in the fight against invading pathogens. High-affinity antibodies or emCTLs cross-react with epitopes of autoantigens in certain tissues (molecular mimicry) ( 120 – 123 ). After being trained in response to microbial infections, these autoreactive lymphocytes migrate to remote organs, exert an immunological attack, and induce tissue damage when recognizing cognate autoantigens ( 117 – 119 ).…”