Prions: Protein Aggregation and Infectious Diseases - Physiological ...

1126 ADRIANO AGUZZI AND ANNA MARIA CALELLA
in the future? Although many mathematical models have
been generated (180, 181), the number of cases is still too
small to predict future developments with any certainty. A
30-yr mean incubation time of BSE/vCJD in humans is not
entirely implausible, and therefore, some authors have
predicted a multiphasic BSE endemic with a second increase
in the incidence of vCJD affecting people heterozygous
at codon 129 (119). Others, these authors included,
regard the incidence of vCJD as subsiding (28). It is
important to note, however, that the above considerations
apply primarily to the epidemiology of primary transmission
from cows to humans. Although by now a pool of
preclinically infected humans may have been built, human-to-human
transmission may present with characteristics
very different from those of primary cow-to-human
transmission, including enhanced virulence, shortened incubation
times, disregard of allelic PRNP polymorphisms
(129MM, MV or VV), and heterodox modes of infection
including blood-borne transmission. If we account for the
time it will take to eradicate these secondary transmissions
in the population, vCJD is not likely to disappear
entirely in the coming four decades. Four cases (three
definite and one presumed) of vCJD transmission by
blood transfusions have been reported in the United Kingdom
(303, 387, 528) (see also http://www.cjd.ed.ac.uk/
TMER/TMER.htm). Most worryingly, the Health Protection
Agency of the United Kingdom has reported a case of
a hemophilic patient who has most likely acquired vCJD
prions through factor VIII preparation derived from
plasma donated by a “preclinical” vCJD patient (http://
www.hpa.org.uk).
The fact that preclinical infected individuals can
transmit vCJD underscores the important medical need
for sensitive diagnostic tools, which could be used for
screening blood units prior to transfusion.
V. PERIPHERAL ROUTES OF PRION
INFECTIVITY
The fastest and most efficient method of inducing
spongiform encephalopathy in the laboratory is intracerebral
inoculation with brain homogenate. Inoculation of
10 6 ID 50 infectious units (defined as the amount of infectivity
that will induce TSE with 50% likelihood in a given
host) will yield disease in approximately half a year; a
remarkably strict inverse relationship can be observed
between the logarithm of the inoculated dose and the
incubation time (406).
However, the above situation does not correspond to
what typically happens in the field. There, acquisition of
prion infectivity through any of several peripheral routes
is the rule. Prion infections can be induced by oral challenge
(159) and occur naturally as a result of food-borne
contamination, as has been shown for Kuru, transmissible
mink encephalopathy, BSE, and vCJD (27, 119, 222, 328).
Physiol Rev VOL 89 OCTOBER 2009 www.prv.org
However, prion diseases can also be initiated by
intravenous and intraperitoneal injection (258) as well as
from the eye by conjunctival instillation (445), corneal
grafts (143), and intraocular injection (161). Two routes of
infection have suggested for a long time that immune cells
might be of importance for this phase of prion pathogenesis:
oral challenge and administration by scarification
(7). Therefore, these routes will be discussed in some
detail in the following paragraphs.
A. Pathway of Orally Administered Prions
After oral infection, an early increase in prion infectivity
is observed in the distal ileum. Within 2 wk of prion
ingestion, prions appear to enter peripheral nerves and
proceed by invasion of the dorsal motor nucleus of the
vagus in the brain, as has been shown in mouse and
hamster scrapie studies (336). Gastrointestinal infections
caused by viruses, bacteria, and parasites, as well as
idiopathic inflammatory diseases, could alter the dynamics
of prion entry and systemic spread. It has been recently
reported that moderate colitis, caused by an attenuated
Salmonella strain, more than doubles the susceptibility
of mice to oral prion infection and modestly
accelerates the development of disease after prion challenge
(459).
How do prions reach the peripheral nerves after having
entered the gastrointestinal tract? Following exposure,
many acquired TSE agents accumulate in lymphoid
tissue, in the case of oral exposure, the gut-associated
lymphatic tissue (GALT), which includes Peyer’s patches
(PPs) and membranous epithelial cells (M cells), and
mesenteric lymph nodes. Following experimental intragastric
or oral exposure of rodents to scrapie, or nonhuman
primates and sheep to BSE, protease-resistant
prion protein accumulates rapidly in the GALT, PPs, and
ganglia of the enteric nervous system (41, 57, 156, 259),
long before they are detected in the CNS.
Recruitment of activated B lymphocytes to PPs requires
4 7 integrin as an essential homing receptor; PPs
of mice that lack 7 integrin are normal in number, but
are atrophic and almost entirely devoid of B cells (507).
Therefore, it seemed interesting to investigate the susceptibility
to orally administered prions of 7-deficient mice.
Surprisingly, minimal infectious dose and disease incubation
after oral exposure to logarithmic dilutions of prion
inoculum were similar in 7-deficient and wild-type mice
(399). Despite their atrophy, PPs of both 7-knockout and
wild-type mice contained 3–4 log LD 50/g prion infectivity
at 125 or more days after challenge.
Why does reduced mucosal lymphocyte trafficking
not impair, as expected, the susceptibility to orally initiated
prion disease? One possible reason may relate to the
fact that, despite marked reduction of B cells, M cells