Viruses and Endogenous Retroviruses as Roots for Neuroinflammation and Neurodegenerative Diseases

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.

The enigma and implications of brain hemispheric asymmetry in neurodegenerative diseases

“…Although this mechanism has been most well-studied in the context of Parkinson’s disease and α-syn, the vagal nerve could also theoretically serve as a pathway for the asymmetric arrival of other neurodegenerative triggers such as viruses. 188 …”

“… 161 Whether this asymmetry in BBB breakdown exists in human is unknown. Asymmetries in the blood–CSF barrier are also possible given the early lateralization seen in the CP (see ‘Asymmetry in Cytoarchitecture’), and since some viruses implicated in neurodegeneration use a ‘trojan horse’ method to enter the brain within immune cells, 188 , 194 the CP may be an asymmetric entry point.…”

Predicted Cellular Interactors of the Endogenous Retrovirus-K Integrase Enzyme

“…Endogenous retrovirus-K (ERVK/HERV-K) is a biomedically-relevant symbiont within the primate lineage [ 6 , 7 ]. Its expression has been associated with a variety of cancers [ 8 ], neurological conditions [ 9 , 10 , 11 , 12 , 13 ], autoimmune diseases [ 14 ], and infections [ 13 , 15 ]. A common thread that weaves through ERVK-associated disease is genomic instability.…”

The Influence of Virus Infection on Microglia and Accelerated Brain Aging

“…Once neurotropic viruses have entered the central nervous system, they need to bind with their surface ligand proteins to corresponding receptors on the target cells enabling them to enter and infect the cells, as reviewed by Schweighardt and Atwood (2001) [ 104 ]. However, virus infection of the brain may induce neuroinflammation and neurodegeneration as recently reviewed by Römer (2021) [ 105 ]. Certain viruses may specifically target neural or neuronal precursor cells that are needed for neuronal turn-over in certain brain systems, including the hippocampus and the olfactory system [ 106 , 107 ].…”

“…For avoiding acute and severe encephalitis, the virus and its interplay with the immune system should keep the interference with the brain structure and function to a low level [ 110 ]. In that respect, one needs to consider that viral infections of the brain may be “asymptomatic” with no short-term effects [ 111 ], but viruses may persist in brain cells over a longer period of time [ 105 , 110 , 112 ]. Accordingly, possible neuroprotective mechanisms for neuronal survival in the course of virus infection may play a role in neuronal persistence of the virus [ 113 ].…”