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Review
. 2021 Mar 12:15:648629.
doi: 10.3389/fnins.2021.648629. eCollection 2021.

Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases

Christine Römer  1
Affiliations
Review

Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases

Christine Römer. Front Neurosci. .

Abstract

Many neurodegenerative diseases are associated with chronic inflammation in the brain and periphery giving rise to a continuous imbalance of immune processes. Next to inflammation markers, activation of transposable elements, including long intrespersed nuclear elements (LINE) elements and endogenous retroviruses (ERVs), has been identified during neurodegenerative disease progression and even correlated with the clinical severity of the disease. ERVs are remnants of viral infections in the human genome acquired during evolution. Upon activation, they produce transcripts and the phylogenetically youngest ones are still able to produce viral-like particles. In addition, ERVs can bind transcription factors and modulate immune response. Being between own and foreign, ERVs are reviewed in the context of viral infections of the central nervous system, in aging and neurodegenerative diseases. Moreover, this review tests the hypothesis that viral infection may be a trigger at the onset of neuroinflammation and that ERVs sustain the inflammatory imbalance by summarizing existing data of neurodegenerative diseases associated with viruses and/or ERVs.

Keywords: HERV; LINE; neurodegeneration; neuroinflammation; virus.

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Conflict of interest statement

The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.

Figures

FIGURE 1
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
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, can lead to sustained neuroinflammation via antibodies against ERVs, superantigen formation, demyelination, and neuronal death. In parallel, IFN-mediated innate immune response can further activate ERVs which contain IFN response elements (such as HERV-K), thereby creating an IFN loop. Next to the danger of chronic neuroinflammation, this additionally carries mutational burden for the host, collectively leading to the CNS damage. The probability and scope of the CNS damage is further determined by facilitating factors, including comorbidities and environmental triggers as well as age. Abbreviations: cGAS, cyclic GMP-AMP synthase; CNS, central nervous system; ERV, endogenous retrovirus; IFN, interferon; MDA5, melanoma differentiated associated gene 5; PAMP, pathogen-associated molecular pattern; RIG-I, retinoic acid inducible gene I; TLR, toll-like receptor; ZBP-1, Z-DNA binding protein 1.
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