The Effects of Immune System Modulation on Prion Disease Susceptibility and Pathogenesis

Abstract

Prion diseases are a unique group of infectious chronic neurodegenerative disorders to which there are no cures. Although prion infections do not stimulate adaptive immune responses in infected individuals, the actions of certain immune cell populations can have a significant impact on disease pathogenesis. After infection, the targeting of peripherally-acquired prions to specific immune cells in the secondary lymphoid organs (SLO), such as the lymph nodes and spleen, is essential for the efficient transmission of disease to the brain. Once the prions reach the brain, interactions with other immune cell populations can provide either host protection or accelerate the neurodegeneration. In this review, we provide a detailed account of how factors such as inflammation, ageing and pathogen co-infection can affect prion disease pathogenesis and susceptibility. For example, we discuss how changes to the abundance, function and activation status of specific immune cell populations can affect the transmission of prion diseases by peripheral routes. We also describe how the effects of systemic inflammation on certain glial cell subsets in the brains of infected individuals can accelerate the neurodegeneration. A detailed understanding of the factors that affect prion disease transmission and pathogenesis is essential for the development of novel intervention strategies.

Neuroinflammatory Markers: Key Indicators in the Pathology of Neurodegenerative Diseases

“…Initially, it was presumed that prion disease (PRD) does not stimulate the immune system due to the lack of a humoral stimulus to protease-resistant prion protein and interferon formation in the infected organism [ 137 ]. Later, it was found that an assortment of pro-inflammatory chemokines and cytokines are elevated in the CNS in response to prion infection.…”

Subclinical infection occurs frequently following low dose exposure to prions by blood transfusion

“…It is also possible that age-related declines in host homeostatic mechanisms, or events such as co-infection with other pathogens, might result in increased prion replication and the late appearance of clinical disease. Whilst these are currently hypothetical possibilities, there is accumulating evidence from experimental models that systemic inflammation or co-infection with various pathogens can accelerate prion pathogenesis 33 .…”

Clinical and Radiological Deterioration in a Case of Creutzfeldt–Jakob Disease following SARS-CoV-2 Infection: Hints to Accelerated Age-Dependent Neurodegeneration

“…An increasing body of evidence indicates that infection with SARS-CoV-2 can affect the CNS and can induce a range of neurological and neuropsychiatric syndromes, either by rare direct invasion or, more often, by secondary immune-mediated mechanisms [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 ]. However, less is known about the influence of SARS-CoV-2 on neurodegenerative diseases, including CJD, and on the underlying neuropathological alterations.…”

“…Similarly in our case, the number of leukocytes began to increase in COVID-19 ICU and were particularly high at the time when neurological deterioration was noticeable. High levels of TNF-α and INF-γ, the cytokines found to correlate with viral loads in SARS-CoV-2 infection, enhance the neurotoxic effects of reactive astrocytes, which mediate neuronal damage and serve as foci for prion protein propagation [ 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 ]. Furthermore, astrocyte and microglial overactivation of cathepsins is a major contributor to neurodegeneration in sporadic CJD [ 29 ], and a recent animal study demonstrated an age-dependent increase in the genetic expression and protein activation of macrophage cathepsins in response to the SARS-CoV-2 spike protein [ 30 ].…”

“…Inflammation and pathogen co-infection may affect the extent of neurodegenerative alterations in sporadic CJD [ 16 ]. Similarly, systemic inflammation associated with a SARS-CoV-2 infection can potentially aggravate the clinical course of sporadic CJD, as suggested in recent reports [ 17 , 18 ].…”