Unraveling the Connection of Epstein–Barr Virus and Its Glycoprotein M_146–157 Peptide with Neurological Ailments

Abstract

Epstein−Barr virus (EBV) is known to be associated with several cancers along with neurological modalities like Alzheimer's disease (AD) and multiple sclerosis (MS). Previous study from our group revealed that a 12 amino acid peptide fragment ( 146 SYKHVFLSAFVY 157 ) of EBV glycoprotein M (gM) exhibits amyloid-like self-aggregative properties. In the current study, we have investigated its effect on Aβ 42 aggregation along with its effect on neural cell immunology and disease markers. EBV virion was also considered for the above-mentioned investigation. An increase in the aggregation of Aβ 42 peptide was observed upon incubation with gM 146−157 . Further, the exposure of EBV and gM 146−157 onto neuronal cells indicated the upregulation of inflammatory molecules like IL-1β, IL-6, TNF-α, and TGF-β that suggested neuroinflammation. Besides, host cell factors like mitochondrial potential and calcium ion signaling play a crucial role in cellular homeostasis and alterations in these factors aid in neurodegeneration. Changes in mitochondrial membrane potential manifested a decrease while elevation in the level of total Ca 2+ ions was observed. Amelioration of Ca 2+ ions triggers excitotoxicity in neurons. Subsequently, neurological disease-associated genes APP, ApoE4, and MBP were found to be increased at the protein level. Additionally, demyelination of neurons is a hallmark of MS and the myelin sheath consists of ∼70% of lipid/cholesterol-associated moieties. Hereby, genes associated with cholesterol metabolism indicated changes at the mRNA level. Enhanced expression of neurotropic factors like NGF and BDNF was discerned postexposure to EBV and gM 146−157 . Altogether, this study delineates a direct connection of EBV and its peptide gM 146−157 with neurological illnesses.

Deciphering the Association of Epstein–Barr Virus and Its Glycoprotein M Peptide with Neuropathologies in Mice

“…IL-6 showed changes only in the G4 ( p < 0.05) of brain tissue samples compared to G1, whereas no changes were observed in the serum samples (Figure Ic). Consistent with our previously reported in vitro results, the exposure of EBV/gM 146–157 to mice instigated the expression of inflammatory moieties, namely, IL-6 and TNF-α . Similarly, mice infected with Japanese encephalitis virus (JEV) have shown an increased level of chemokines and cytokines like IL-6, TNF-α, and TGF-β.…”

“…Furthermore, an in silico report from our group has suggested that a 12-amino acid peptide of EBV glycoprotein M (EBV-gM) ( 146 SYKHVFLSAFVY 157 ) has comparable aggregative properties like amyloid-β 42 (Aβ 42 ) and exhibited cytotoxicity toward neurons . Subsequently, the presence of the above-mentioned peptide showed association with elevation in inflammatory as well as neurodegenerative disease markers like amyloid precursor protein (APP) and MBP in the cell line . Therefore, in the current study, we validated the connection of EBV/gM 146–157 with neuropathologies in the mouse model.…”

“…Precisely, a total of four groups (each having six mice) were made, namely, the immunosuppressed control, IMR-32 cell-exposed, EBV-infected IMR-32, and gM 146–157 -exposed IMR-32 subjected with one neat control group (negative control). For immunosuppression, mice were subjected to peritoneal cyclosporin (working concentration: 10 mg/kg) on alternate days for 10 days, and then, a xenograft of IMR-32 prior exposed with EBV (as mentioned previously) or gM 146–157 for 24 h was administered intranasally . Three doses were given for the cell mentioned above every 5 days.…”

Understanding the Neurotrophic Virus Mechanisms and Their Potential Effect on Systemic Lupus Erythematosus Development

“…An in silico analysis determined that EBV infection is associated with AD development due to the formation of peptide aggregates, specifically a 12-amino acid peptide derived from the glycoprotein gM (Figure 1A) [80]. Additionally, it has been observed that neuronal cells exposed to EBV and gM induce an environment that promotes neuroinflammation due to the positive upregulation of specific inflammatory cytokines such as IL-1β, IL-6, and TNF-α [31]. On the other hand, Parkinson's disease has also been associated with EBV infection because it is caused by a molecular mimetism between the C-terminal region of α-synuclein and a repeat region in the latent membrane protein 1 (LMP1) protein from EBV [81].…”

“…All this results in a complex structure that denies microorganisms access to the CNS from the nasal epithelium, cerebrospinal fluid (CSF), or via hematogenous spread [27][28][29]. Neurotropic viruses have mechanisms that allow them to invade the CNS, infect local cells, and induce a pro-inflammatory immune response that alters normal function [30][31][32].…”