By Taylor Woetzel
In our rapidly evolving medical landscape, elucidation of many causal disease factors has declassed a myriad of diseases from heralds of death to minor inconveniences, easily treated by modern medicine. Once life-threatening diseases like smallpox and poliomyelitis have been virtually eradicated, owing to insights in virology that led to the production of highly effective vaccines. Moreover, contracting potentially fatal tuberculosis in our medically sophisticated landscape almost always leads to mitigation through antibiotic treatment (1). Nevertheless, extensive advances in medicine have yet to yield cures, treatments, or comprehensive explanations for the development of debilitating neurodegenerative diseases like Alzheimer’s and Parkinson’s disease.
Neurodegenerative diseases are age-dependent diseases that affect the central and peripheral nervous system, causing a variety of severe symptoms impacting mobility, cognition, sensation, coordination, and strength. As the nervous system experiences progressive damage over time, symptoms worsen until the patient’s physical and mental functions decline to the point of requiring day-to-day intensive professional care (2). Although causes and symptoms can overlap between different neurodegenerative diseases, they differ in notable ways. A common thread amongst neurodegenerative diseases is the abnormal processing of neuronal proteins, leading to protein-specific diseases. (3). These aberrant proteins often misfold to form cross- amyloid-like fibrils, a stable alternative protein structure that enables intracellular and extracellular aggregation through hydrophobic interactions or hydrogen-bonding. However, the direct pathogenic involvement of such protein aggregates in neurodegenerative disease is somewhat confounded due to lack of a strong correlation between aggregate load and symptom severity (4). While protein aggregates are known to be prevalent in neurodegenerative diseases, another avenue has more recently been explored in attempts to unravel the underlying causes of neurodegeneration: viral infection of the central nervous system (CNS) and its associated immune response (5).
Immune elements have limited access to brain tissues due to the blood-brain barrier (BBB), which encapsulates the brain and tightly regulates entry, and the immune privilege of the CNS – a set of active mechanisms that limit the types and quantities of immune elements granted access to the CNS parenchyma. This functions to limit the potentially harmful immune responses elicited in brain tissues (5). Nonetheless, certain immune cells like microglia have access to the brain and act as sentinels, surveilling for damage (5). Microglia are the resident immune cells of the CNS that activate in response to tissue perturbations (6). They are associated with aggregate formation found in diseased brains and are thought to limit the continued formation of aggregates at an early stage, although the mechanisms for such action are unclear. Among immune CNS cells like microglia, the presence and development of Toll-like receptors (TLRs) can enable an innate immune response, although TLRs are also found on non-immune cells. TLRs recognise and bind to highly conserved structural regions of pathogens (pathogen-associated molecular patterns – PAMPs) or to damaged and stressed tissues (danger-associated molecular patterns – DAMPs), which triggers an immune response to act on them. As such, it follows that TLRs are adapter proteins on microglia, aiding in damage-detecting sentinel activity. However, because TLRs typically induce an inflammatory response involving the production of pro-inflammatory cytokines, they can cause neuronal damage if inadequately managed. This is particularly pertinent when PAMPs and DAMPs are encountered by microglia in the CNS, as the immune response aggressively attempting to eliminate the threats via inflammatory responses can cause extensive neuronal damage and cell death (5). In mouse models, it was shown that recovery from traumatic brain injury had greater success and milder clinical disease when TLRs were not present and thus did not contribute to high pro-inflammatory cytokine production (5).
Viral infections are included in PAMPs that are recognized by TLRs associated with microglia in the CNS. Viral elements can enter the CNS via infected macrophages, transcytosis across the BBB, or through intraneuronal transfer from peripheral neurons (7). Upon detection by microglial TLRs, such viruses trigger a pro-inflammatory immune response which, when in excess, cause neuronal damage that contributes to the development of neurodegenerative disease. This excessive response occurs when immune privilege mechanisms fail to adequately restrain immune elements, spurred by TLR recognition of viruses, from flooding the CNS parenchyma.
A study conducted on the link between the highly pathogenic H5N1 influenza virus and neurodegenerative conditions found that in mice infected with H5N1 influenza, significantly higher levels of protein aggregates associated with Alzheimer’s and Parkinson’s disease were found in various virally infected areas of the brain in comparison to that of the controls. Active microglia were also found to be associated with these aggregates, indicating an association of protein aggregates and an inflammatory immune response. Moreover, microgliosis, the vigorous inflammatory response of CNS microglia to pathogens, persisted far longer than the acute H5N1 infection; patients with various types of Parkinson’s disease experience a very similar response (8). A different population-wide study identified hepatitis C infection as a risk factor for the development of Parkinson’s disease – an association based on findings that both hepatitis C and Parkinson’s disease prompt upregulation of an inflammatory immune response, which then leads to cell death and the development of neurodegenerative symptoms (9). The connection between viral infection of the CNS and the subsequent development of neurodegenerative disease extends to a multitude of neurotropic viruses beyond just influenza and hepatitis C – Coxsackie, Japanese encephalitis B, western equine encephalitis, herpes, and HIV infections have all been associated with neurodegeneration as well, and are likely to promote neurological symptoms through similar immune inflammatory pathways (10).
While further research to elucidate the causal factors of specific neurodegenerative diseases is necessary to make ground-breaking medical advances, it has become clear that viral infections of the CNS are a risk-factor in the development of such devastating neurodegenerative diseases. Through an overzealous upregulated inflammatory immune response launched largely by viral recognition through microglial TLRs, a defensive mechanism detrimentally harms that which it was supposed to protect.
References:
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