Peptide Sharing Between Viruses and DLX Proteins: A Potential Cross-Reactivity Pathway to Neuropsychiatric Disorders

Abstract

The present study seeks to determine potential associations between viral infections and neuropsychiatric diseases. To address this issue, we investigated the peptide commonalities between viruses that have been related to psychiatric and neurological disorders—such as rubella, human immunodeficiency virus, and herpesviruses—and human distal-less homeobox (DLX) proteins expressed in developing brain—namely, DLX1, DLX2, DLX5, and DLX6. Peptide matching analyses revealed a high degree of pentapeptide sharing. From an immunological perspective, this overlap is relevant because pentapeptides are endowed with immunogenicity and antigenicity—that is, they are immune determinants. Moreover, infection-induced immune cross-reactions might have functional, spatial, and temporal implications related to the functions and expression patterns of DLX1 and DLX5 in the fetal and adult human brain. In sum, our data support the hypothesis that viral infections may be linked to neuropsychiatric diseases through autoimmune cross-reactions caused by molecular mimicry between viral proteins and brain-specific DLX self-antigens.

Viruses and Autoimmunity: A Review on the Potential Interaction and Molecular Mechanisms

“…Pentapeptide similarity between the NMDA 2A receptor and viral proteins have been previously reported [96]. Using the same mechanism, other peptide commonalities with high degree of pentapeptide sharing were found between viral peptides and the human distal-less homeobox (DLX) transcription factors expressed during early fetal neurodevelopment (DLX1, DLX2, DLX5, and DLX6) [94]. Analysis of the brain-specific DLX self-antigens pentapeptide revealed matching with several viruses that have been related to neurological disorders including rubella and herpesviruses [94].…”

“…Several recent studies aimed to explain the contribution of viral infections in CNS disorders. It was suggested that antiviral immune response cross-react with human NMDA receptors (2A subunit) [94], which are responsible for excitatory glutamatergic transmission and are ion channel proteins found in nerve cells [95]. Pentapeptide similarity between the NMDA 2A receptor and viral proteins have been previously reported [96].…”

“…Using the same mechanism, other peptide commonalities with high degree of pentapeptide sharing were found between viral peptides and the human distal-less homeobox (DLX) transcription factors expressed during early fetal neurodevelopment (DLX1, DLX2, DLX5, and DLX6) [94]. Analysis of the brain-specific DLX self-antigens pentapeptide revealed matching with several viruses that have been related to neurological disorders including rubella and herpesviruses [94]. Collectively, these studies support the assumption that viral infections may relate to CNS disorders through autoimmune cross-reactions caused by molecular mimicry.…”

A Peptide Link Between Human Cytomegalovirus Infection, Neuronal Migration, and Psychosis

“…These proteins were examined in the present study in light of their involvement with neuronal migration, while it is highly likely that any alteration of their function or structure may affect higher cognitive processes through impairment of different mechanisms above and beyond migration (i.e., axon guidance, neurotransmission, excitatory-inhibitory balance, oscillatory neuronal firing, and others). Notably, these mechanisms can also be directly affected by cross-reactive targeting of proteins allowing membrane excitability (26)(27)(28)(29)(30), in a complex endotypical scenario that mirrors the phenotypical complexity of mental disorders without the need for a biunivocal match between them.…”

“…Therefore, we here tried to elucidate the associations between HCMV infection, aberrant neuronal migration, and psychosis, building on previous research that had assessed peptide commonality and potential immune cross-reactivity between microbial and human proteins (26)(27)(28)(29)(30)(31). More specifically, we investigated the peptide platform shared by HCMV and human proteins involved in neuronal migration.…”