The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis

Donaldson, David S.; Mabbott, Neil A.

doi:10.1099/jgv.0.000507

Cited by 15 publications

(17 citation statements)

References 131 publications

(155 reference statements)

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“…Disturbances to the gut microbiota can contribute to the pathogenesis of several human neurodegenerative diseases [ 30 ]. Microglial activation is a prominent feature of CNS prion disease [ 4, 10 ], but whether the commensal gut microbiota influence the progression of CNS disease is uncertain [ 29, 31, 32 ]. Data in the current study clearly demonstrate that prion disease pathogenesis and susceptibility after exposure by either the IP or IC routes is not influenced by the absence of the commensal gut microbiota in germ-free mice.…”

Section: Discussionmentioning

confidence: 99%

“…Furthermore, the functional maturation of the microglia was compromised in germ-free mice and coincided with their significantly reduced responses to LPS-stimulation or virus infection in the CNS [ 28 ]. The nature of the microglial activation status during CNS prion disease is considered to influence the severity of neurodegeneration [ 5 ], but whether the commensal gut microbiota also influence prion disease pathogenesis is uncertain [ 29 ]. Modifications to the gut microbiota can contribute to the pathogenesis of anxiety and depression, and certain neurodegenerative disorders such as Alzheimer’s disease and Parkinson’s disease [ 30 ].…”

Section: Introductionmentioning

confidence: 99%

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Prion disease pathogenesis in the absence of the commensal microbiota

Bradford

Tetlow

Mabbott

2017

Journal of General Virology

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Prion diseases are a unique group of transmissible, typically sub-acute, neurodegenerative disorders. During central nervous system (CNS) prion disease, the microglia become activated and are thought to provide a protective response by scavenging and clearing prions. The mammalian intestine is host to a large burden of commensal micro-organisms, especially bacteria, termed the microbiota. The commensal microbiota has beneficial effects on host health, including through the metabolism of essential nutrients, regulation of host development and protection against pathogens. The commensal gut microbiota also constitutively regulates the functional maturation of microglia in the CNS, and microglial function is impaired when it is absent in germ-free mice. In the current study, we determined whether the absence of the commensal gut microbiota might also affect prion disease pathogenesis. Our data clearly show that the absence of the commensal microbiota in germ-free mice did not affect prion disease duration or susceptibility after exposure to prions by intraperitoneal or intracerebral injection. Furthermore, the magnitude and distribution of the characteristic neuropathological hallmarks of terminal prion disease in the CNS, including the development of spongiform pathology, accumulation of prion disease-specific protein (PrP), astrogliosis and microglial activation, were similar in conventionally housed and germ-free mice. Thus, although the commensal gut microbiota constitutively promotes the maintenance of the microglia in the CNS under steady-state conditions in naïve mice, our data suggest that dramatic changes to the abundance or complexity of the commensal gut microbiota are unlikely to influence CNS prion disease pathogenesis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Prion disease pathogenesis in the absence of the commensal microbiota

Bradford

Tetlow

Mabbott

2017

Journal of General Virology

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“…As in most natural occurring prion diseases, CWD of cervids is acquired peripherally, mainly after oral exposure, after which prions replicate in GALT. The importance of GALT in the pathogenesis of prion diseases is well documented by several studies that revealed impaired neuroinvasion in the absence of Peyer's patches [137][138][139][140].…”

Section: Pathogenesis Of Cwd: the Interaction Of Prions And Immune Symentioning

confidence: 98%

“…As it was already mentioned, FDC in the Peyer's patches are major sites of early prion replication in orally infected animals, both experimentally [137][138][139][140]174] and in the natural forms of the disease. The study of natural scrapie cases in sheep showed that GALT of the upper gastrointestinal tract exhibited early accumulation of prions when compared to the large intestinal GALT, such as the cecal patches [175][176][177][178].…”

Section: Follicular Dendritic Cells (Fdc) and B And T Lymphocytesmentioning

confidence: 98%

TSE Monitoring in Wildlife Epidemiology, Transmission, Diagnosis, Genetics and Control

Machado¹,

Orge²,

Pires³

et al. 2019

Wildlife Population Monitoring

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Among the transmissible spongiform encephalopathies (TSEs), chronic wasting disease (CWD) in cervids is now the rising concern within Europe. CWD will be outlined in this chapter gathering its epidemiology, transmission, diagnosis, genetics, and control. Prion diseases are fatal neurodegenerative diseases characterized by the accumulation of an abnormal isoform of the prion protein (PrP c), usually designated by PrP sc or prion. CWD is a prion disease of natural transmission affecting cervids detected mainly in North America. The first European case was detected in Norway, in 2016, in a wild reindeer; until April 2018, a total of 23 cases were described. The definite diagnosis is postmortem, performed in target areas of the brain and lymph nodes. Samples are first screened using a rapid test and, if positive, confirmed by immunohistochemistry and Western immunoblotting. It is not possible to establish a culling plan based on the genotype, once affected animals appear with all genotypes. However, some polymorphisms seem to result in longer incubation periods or confer a reduced risk. The control is not easy in captive cervids and even more in the wildlife; some recommendations have been proposed in order to understand the danger and impact of CWD on animal and public health.

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“…However, despite the prominent activation and involvement of the microglia in the brain during prion disease, the absence of the commensal microbiota does not affect the development of the neurodegeneration in the steady state [ 195 , 196 ]. Whether the microglia in the brains of prion-infected germ-free mice are less sensitive to subsequent neurotoxic activation by pro-inflammatory stimuli remains to be determined.…”

Section: Cns Prion Diseasementioning

confidence: 99%

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

Mabbott

Bradford

Pal

et al. 2020

IJMS

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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.

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The influence of the commensal and pathogenic gut microbiota on prion disease pathogenesis

Cited by 15 publications

References 131 publications

Prion disease pathogenesis in the absence of the commensal microbiota

Prion disease pathogenesis in the absence of the commensal microbiota

TSE Monitoring in Wildlife Epidemiology, Transmission, Diagnosis, Genetics and Control

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

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