Bacterial Colitis Increases Susceptibility to Oral Prion Disease

Abstract

Dietary exposure to prion-contaminated materials has caused kuru and variant Creutzfeldt-Jakob disease in humans, and transmissible spongiform encephalopathies (TSEs) of cattle, mink, and felines. The epidemiology of dietary prion infections suggest that host genetic modifiers, and possibly exogenous cofactors, may play a decisive role in determining disease susceptibility. However, few cofactors influencing prion susceptibility have been identified. Here we investigated whether colitis might represent one such cofactor. We report that moderate colitis caused by an attenuated strain of Salmonella more than doubles the susceptibility of mice to oral prion infection, and modestly accelerates the development of disease after prion challenge. The prion protein was upregulated in intestines and mesenteric lymph nodes of mice with colitis, providing a possible mechanism for the impact of colitis onto prion pathogenesis. Therefore, moderate intestinal inflammation at the time of prion exposure may constitute one of the elusive risk factors underlying the development of TSE.

Endogenous Prion Protein Attenuates Experimentally Induced Colitis

“…In contrast, mice lacking this molecule demonstrated marked elevations in several proinflammatory cytokine transcripts and pro-apoptotic regulatory proteins, factors predicted to exacerbate colitis. As reported by Sigurdson et al,30 who demonstrated increased PrP C expression in the inflamed colons of Salmonella-infected mice, we observed that DSS-induced colitis increased PrP C expression from the endogenous locus. Expression of PrP C from the Tga20 transgene was also up-regulated, which suggests that the necessary regulatory elements were present in the Prnp promoter fragment used in the vector.…”

“…Although acute colitis can accelerate the onset of disease after oral challenge with infectious prions, 30 a physiologic role for PrP C in colitis has not been reported. We, therefore, examined the role of PrP C in mice either lacking or overexpressing this protein in the dextran sulfate sodium (DSS)-induced model of experimental colitis.…”

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

“…An independent study has reported that congruent infection with Salmonella typhimurium exacerbated oral prion disease (Sigurdson et al, 2009). In this study, the effects on prion disease pathogenesis were attributed to the acute inflammation that infection with the bacterium causes in the colon.…”

“…For example, lesions to the mucosa can enhance the oral transmission of prions (Denkers et al, 2011). Pathogen exposure can also modify the expression of PrP C and innate immunity genes in the gut mucosa (Dervishi et al, 2015;Sigurdson et al, 2009). Therefore, gastrointestinal pathogen-mediated damage to the gut mucosa may exacerbate disease pathogenesis by enhancing prion uptake from the lumen.…”

The Immune System in the Pathogenesis and Prevention of Prion Diseases

“…Ultimately, this could lead to accelerated PrP Sc replication during immune responses. Interestingly, the presence of bacterial colitis has recently been shown to increase susceptibility to oral prion infection [80]. It is important to note, however, that several studies appear to directly refute this conclusion.…”