Mucosal vaccination delays or prevents prion infection via an oral route

doi:10.1016/j.neuroscience.2005.02.031

Neuroscience

Volume 133, Issue 2, 2005, Pages 413-421

https://doi.org/10.1016/j.neuroscience.2005.02.031 Get rights and content

Abstract

In recent years major outbreaks of prion disease linked to oral exposure of the prion agent have occurred in animal and human populations. These disorders are associated with a conformational change of a normal protein, PrP^C (prion protein cellular), to a toxic and infectious form, PrP^Sc (prion protein scrapie). None of the prionoses currently have an effective treatment. A limited number of active immunization approaches have been shown to slightly prolong the incubation period of prion infection. Active immunization in wild-type animals is hampered by auto-tolerance to PrP and potential toxicity. Here we report that mucosal vaccination with an attenuated Salmonella vaccine strain expressing the mouse PrP, is effective at overcoming tolerance to PrP and leads to a significant delay or prevention of prion disease in mice later exposed orally to the 139A scrapie strain. This mucosal vaccine induced gut anti-PrP immunoglobulin (Ig)A and systemic anti-PrP IgG. No toxicity was evident with this vaccination approach. This promising finding suggests that mucosal vaccination may be a useful method for overcoming tolerance to PrP and preventing prion infection among animal and potentially human populations at risk.

Section snippets

Construction of a recombinant Salmonella vaccine strain expressing tandem copies of PrP

The construction of the S. typhimurium aroC LVR01 has been previously described (Chabalgoity et al., 2000). The construction of the PrP expression vector was as follows: plasmid pTECH2 (kindly provided by Dr. C. M. Anjam Khan, Institute for Cell and Molecular Biosciences & School of Biomedical Sciences, University of Newcastle, UK) allows the expression of multiple tandem copies of a foreign antigen as a C-terminal fusion to the non-toxic fragment C of tetanus toxin (TetC) (Khan et al., 1994).

Expression of PrP by mouse-adapted Salmonella typhimurium LVR01

The expression of recPrP by S. typhimurium LVR01 vaccine strain was assessed by SDS-PAGE and Western blotting using anti-PrP antibody 7F9 (Liu et al., 2001). Fig. 1 shows the Western blot, in which 5μg of bacterial suspension was run in each lane. In lane 1 only S. typhimurium without the PrP insert was run, while in lanes 2 and 3 LVR01 expressing either one or two copies of mouse PrP, respectively, was electrophoresed. The arrow indicates the PrP band. As can be seen, the strain encoding the

Discussion

Historically, vaccination has been one of the most successful medical interventions. Recent studies have expanded the conditions where vaccination may be used, including neurodegenerative conformational disorders. These conditions include prion disease and AD. They are characterized by the accumulation of a constitutively expressed protein in an abnormal, pathology associated conformation. Numerous recent reports, including from our laboratories, as well as from many others, (reviewed in

Acknowledgments

This work was supported by NIH grants: NS47433, AG20197, AR2594 and the Alzheimer’s Disease Association.

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Prions are unconventional infectious agents that cause lethal transmissible neurodegenerative diseases in human and animals. Prions can be distinguished from other known pathogens by their lack of nucleic acids. The most essential process for prion propagation is conversion from normal cellular prion protein on the cell membrane to insoluble, limited protease digestion-resistant, pathogenic scrapie prion protein. For dozens of years, many pharmacological tools and interventions targeting different stages of disease progression have been developed and evaluated, and a few have been entered clinical trials. However, no approved prophylactic or therapeutic drugs for prion diseases are available. In this review, we summarize the current concepts in prion research and discuss advances in the research and development of drugs for the prevention and treatment of prion disease.
The role of prion strain diversity in the development of successful therapeutic treatments
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Prions are a self-propagating misfolded conformation of a cellular protein. Prions are found in several eukaryotic organisms with mammalian prion diseases encompassing a wide range of disorders. The first recognized prion disease, the transmissible spongiform encephalopathies (TSEs), affect several species including humans. Alzheimer's disease, synucleinopathies, and tauopathies share a similar mechanism of self-propagation of the prion form of the disease-specific protein reminiscent of the infection process of TSEs. Strain diversity in prion disease is characterized by differences in the phenotype of disease that is hypothesized to be encoded by strain-specific conformations of the prion form of the disease-specific protein. Prion therapeutics that target the prion form of the disease-specific protein can lead to the emergence of drug-resistant strains of prions, consistent with the hypothesis that prion strains exist as a dynamic mixture of a dominant strain in combination with minor substrains. To overcome this obstacle, therapies that reduce or eliminate the template of conversion are efficacious, may reverse neuropathology, and do not result in the emergence of drug resistance. Recent advancements in preclinical diagnosis of prion infection may allow for a combinational approach that treats the prion form and the precursor protein to effectively treat prion diseases.
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Currently all prion diseases are without effective treatment and are universally fatal. It is increasingly being recognized that the pathogenesis of many neurodegenerative diseases, such as Alzheimer disease (AD), includes “prion-like” properties. Hence, any effective therapeutic intervention for prion disease could have significant implications for other neurodegenerative diseases. Conversely, therapies that are effective in AD might also be therapeutically beneficial for prion disease. AD-like prion disease has no effective therapy. However, various vaccine and immunomodulatory approaches have shown great success in animal models of AD, with numerous ongoing clinical trials of these potential immunotherapies. More limited evidence suggests that immunotherapies may be effective in prion models and in naturally occurring prion disease. In particular, experimental data suggest that mucosal vaccination against prions can be effective for protection against orally acquired prion infection. Many prion diseases, including natural sheep scrapie, bovine spongiform encephalopathy, chronic wasting disease, and variant Creutzfeldt–Jakob disease, are thought to be acquired peripherally, mainly by oral exposure. Mucosal vaccination would be most applicable to this form of transmission. In this chapter we review various immunologically based strategies which are under development for prion infection.
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Prion diseases are subacute neurodegenerative diseases that affect humans and certain domestic and free-ranging animals. The infectious prion agent is considered to comprise solely of abnormally folded isoforms of the cellular prion protein. Pathology during prion disease is restricted to the central nervous system where it causes extensive neurodegeneration and ultimately leads to the death of the host. Many natural prion diseases are acquired peripherally, such as by oral exposure, lesions to skin or mucous membranes, and possibly also via the nasal cavity. Following peripheral exposure, some prions accumulate to high levels within the secondary lymphoid tissues as they make their journey from the site of infection to the brain. The replication of these prions within secondary lymphoid tissues is important for the efficient spread of disease to the brain. This article provides an account of the key tissues, cells, and molecules involved in the propagation of prions from peripheral sites of exposure (such as the lumen of the intestine) to the brain, and describes how additional factors such as inflammation and aging may influence susceptibility to peripherally acquired prion diseases.
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Citation Excerpt :
A potential means to prevent some prion infections is by mucosal immunization [14], since the alimentary tract is the major route of entry for prion diseases such as CWD, BSE and vCJD [9]. We reported the first successful use of mucosal vaccination in prion infection using a Salmonella delivery system [15]. Live attenuated strains of Salmonella enterica have been used for many years as mucosal vaccines against salmonellosis and as delivery systems for the construction of multivalent vaccines with broad applications in human and veterinary medicine [16].
Prion disease is a unique category of illness, affecting both animals and humans, in which the underlying pathogenesis is related to a conformational change of a normal, self-protein called PrP^C (C for cellular) to a pathological and infectious conformer known as PrP^Sc (Sc for scrapie). Bovine spongiform encephalopathy (BSE), a prion disease believed to have arisen from feeding cattle with prion contaminated meat and bone meal products, crossed the species barrier to infect humans. Chronic wasting disease (CWD) infects large numbers of deer and elk, with the potential to infect humans. Currently no prionosis has an effective treatment. Previously, we have demonstrated we could prevent transmission of prions in a proportion of susceptible mice with a mucosal vaccine. In the current study, white-tailed deer were orally inoculated with attenuated Salmonella expressing PrP, while control deer were orally inoculated with vehicle attenuated Salmonella. Once a mucosal response was established, the vaccinated animals were boosted orally and locally by application of polymerized recombinant PrP onto the tonsils and rectal mucosa. The vaccinated and control animals were then challenged orally with CWD-infected brain homogenate. Three years post CWD oral challenge all control deer developed clinical CWD (median survival 602 days), while among the vaccinated there was a significant prolongation of the incubation period (median survival 909 days; p = 0.012 by Weibull regression analysis) and one deer has remained CWD free both clinically and by RAMALT and tonsil biopsies. This negative vaccinate has the highest titers of IgA in saliva and systemic IgG against PrP. Western blots showed that immunoglobulins from this vaccinate react to PrP^CWD. We document the first partially successful vaccination for a prion disease in a species naturally at risk.
Food Safety Implications of Prion Disease
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In the last decade of the twentieth century, a new degenerative neurological disease in humans was linked to the consumption of bovine products derived from cattle suffering from a prion disease. Prions are a unique class of infectious agents, as they are resistant to most disinfection procedures that eliminate viral and bacterial contamination and may effectively cross species barriers. The prion agent consists of a conformationally distinct form of a normal cellular protein, which is capable of converting the normal protein into the diseased form. Studies on the pathogenesis of the bovine prion disease called bovine spongiform encephalopathy have demonstrated that certain cattle tissues represent a greater risk for infection of food products and feed materials, and removal of these tissues from bovine products destined for the human food chain has greatly reduced the risk of human infection. A current challenge is to further limit disease through development of live animal diagnostics capable of detecting disease prior to appearance of clinical signs.

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Cellular neuroscienceMucosal vaccination delays or prevents prion infection via an oral route

Abstract

Section snippets

Construction of a recombinant Salmonella vaccine strain expressing tandem copies of PrP

Expression of PrP by mouse-adapted Salmonella typhimurium LVR01

Discussion

Acknowledgments

Med Hypotheses

Vaccine

Neurobiol Aging

Brain Res

Vet J

Clin Immunol

Vaccine

Neurosci Lett

J Biol Chem

Am J Pathol

Neurobiol Aging

Am J Pathol

Neurosci Lett

Vet Immunol Immunopathol

Clin Immunol Immunopathol

Neurobiol Dis

Progress and problems in the biology, diagnostics, and therapeutics of prion diseases

J Clin Invest

Early accumulation of PrP(Sc) in gut-associated lymphoid and nervous tissues of susceptible sheep from a Romanov flock with natural scrapie

J Gen Virol

Infected dendritic cells are sufficient for prion transmission to the CNS in mouse scrapie

J Clin Invest

Prion diseasesinfectious and lethal doses following oral challenge

J Gen Virol

Rapid prion neuroinvasion following tongue infection

J Virol

Chronic wasting disease and potential transmission to humans

Emerg Infect Dis

Induction of autoimmune diabetes by oral administration of autoantigen

Science

Prion protein expression modulates neuronal copper content

J Neurochem

Transmission to mice indicate that “new variant” CJD is caused by the BSE agent

Nature

Preclinical changes in weight of scrapie-infected mice as a function of scrapie agent-mouse strain combination

Intervirology

A Salmonella typhimurium htrA live vaccine expressing multiple copies of a peptide comprising amino acids 8–23 of herpes simplex virus glycoprotein D as a genetic fusion to tetanus toxin fragment C protects mice from herpes simplex virus infection

Mol Microbiol

Cellular neuroscience
Mucosal vaccination delays or prevents prion infection via an oral route