Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases

FIGURE 1. Entry routes of exogenous viruses into the central nervous system (CNS). Virus can enter the CNS via (A) Peripheral nerve terminals (in this example of the olfactory nerve) and retrograde axonal transport. (B) Infection of and damage to endothelial cells of the blood brain barrier (BBB). (C) Infection of circulating immune cells that travel across the BBB. (D) Modulation of tight junction molecules of the BBB, increasing BBB permeability. A specific entry route can be typical for a specific virus, however, often more than one route is used. Entry route may vary during the course of infection (e.g., BBB damage in conditions of high viremia) and new CNS entry mechanisms can follow when the viral genome sustains mutational changes. A neurotrophic virus often infects specific cell types within the CNS. Reaching the CNS enables the virus to circumvent the peripheral immune response. To evade also the CNS immune response, viruses may enter a dormant state forming a viral episome or integrating into the host cell DNA.

FIGURE 2. Model of the role of exogenous virus and endogenous retrovirus (ERV) in initiating neuropathologies, illustrating the entry of viruses into the body (“house”) and the presence of ERVs, the physiological immune response on the first level and continuous imbalance on the second, thus leading to damage of the CNS (“roof”). Infections with exogenous viruses often activate the transcription of endogenous retroviruses which are already present in the mammalian genome. This results from disruption of the host-control over ERVs, bordering between own and foreign. Separately and together, activated exogenous viruses and ERVs produce PAMPs, such as viral nucleic acids, viral-like particles, fused transcripts between exogenous virus, and ERV, which are sensed by PAMP sensors (TLR, cGAS, ZBP-1, MDA5, and RIG-I). Collectively, PAMP activation alarms the immune system by initiating innate immune response involving mainly IFN signaling which will trigger the adaptive (humoral and cellular) immunity. Viral infections are generally limited in time as they are combated by the immune system. However, the activation of ERVs and neurotrophic viruses which remain silent yet present within the body,…