Download Host Genetic Control of Incubation Periods of Creutzfeldt

J. gen. Virol. (1989), 70, 1391-1400. Printedin Great Britain
1391
Key words: CJD/mouse/incubationperiods/host genetic control
Host Genetic Control of Incubation Periods of Creutzfeldt-Jakob Disease
in Mice
By S H I R O U M O H R I 1. A N D J U N T A T E I S H I 2
1Laboratory Animal Center, Faculty of Medicine and ZDepartment of Neuropathology,
Neurological Institute, Faculty of Medicine, Kyushu University 60, Fukuoka 812, Japan
(Accepted 13 February 1989)
SUMMARY
Host genetic control of the incubation period of Creutzfeldt-Jakob disease (CJD)
was studied using various inbred strains of mice, including B10 congenic strains.
Various incubation periods were found in mice injected either intracerebrally or
intraperitoneally with the Fukuoka 1 strain of the CJD agent; NZW/Sea and A/JJms
had the shortest, and BI0.AKM/OIa and C57BL/6J the longest, incubation periods.
Length of the CJD incubation period did not correlate with the genetic markers tested,
i.e. the murine major histocompatibility (H-2) complex (which has previously been
reported to be linked to a gene influencing CJD incubation period in mice), coat colour
or sex genes. In NZW/Sea × C57BL/6J F 1 hybrid mice the CJD incubation periods
were similar to that of the parent with the longest incubation period. Incubation
periods of the backcross progeny from F1 and NZW/Sea were intermediate between
those of the parental mice and had a unimodal distribution pattern. A similar
observation was made on the progeny of the A/JJms x C57BL/6J mating. On the other
hand, the length of incubation period for the NZW/Sea x B10. AKM/Ola F1 hybrid
fell between those for the two parents and the NZW/Sea x A/JJms F~ hybrid had a
significantly longer incubation period than those of the two parents. These results
suggest that polygenes probably control the length of the CJD incubation period in
mice.
INTRODUCTION
Creutzfeldt-Jakob disease (CJD) is caused by a slow infectious agent, also referred to as an
'unconventional virus' (Gajdusek, 1977), 'virino' (Dickinson & Outram, 1979), 'prion' (Prusiner,
1982) and by other terms. It has a devastating effect on the central nervous system (CNS), in the
absence of any inflammatory response, and the resulting syndrome is similar to that seen in
scrapie (Manuelidis et al., 1978). Although the disease often occurs sporadically, an autosomal
dominant inheritance has been observed in several families; hence, genetic factors may control
susceptibility to CJD (Masters et al., 1981; Asher et al., 1983). It has been reported that the
susceptive gene for CJD might be linked to that of the human leukocyte antigen (HLA) DQw3
(Kuroda et al., 1985).
The susceptibility of different strains of mice to CJD and/or scrapie has been determined by
measuring the incubation period. Three genes that influence the incubation period have been
identified. First, Dickinson et al. (1968) identified a single autosomal gene designated Sinc
(scrapie incubation) and postulated the existence of two alleles only. Subsequently, VM mice
were found to possess the prolonged incubation allele p7 and other strains such as C57BL/6 mice
had the short incubation s7 allele. Secondly, Pid-1 (prion incubation determinant) which had a
significant influence on the incubation period for the experimental mouse CJD model (Fukuoka
1 strain) is linked to the H-2 complex on chromosome 17, corresponding to HLA in
humans (Kingsbury et al., 1983). The q allele at the D subregion of H-2 coded for shorter
incubation periods whereas the d allele coded for longer ones. Thirdly, a single gene, Prn-i (prion
0000-8757 © 1989 SGM
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s. MOHRI AND J. TATEISHI
incubation), with a profound effect on the incubation period of scruple was identified in mice
after injection of the Chandler scrapie agent (Carlson et al., 1986). A study on the correlation
between the murine prion protein sequence and length of scrapie incubation period suggested
that the Prn-i gene was linked to or congruent with the murine prion protein gene (Prn-p) which
encoded the prion protein. These genes from the prion gene complex were located on
chromosome 2 (Sparkes et al., 1986). Studies of the nucleotide sequence of the Prn-p gene of
inbred mouse strains revealed substitutions at codons 108 and 189 (Westaway et al., 1987). On
scruple infection, N Z W , C57BL/6J and m a n y other inbred strains of mice having the same
amino acids at codons 108 and 189, Prn-p ~, had short incubation periods, whereas I/Ln, IM, P/J
and BDP/J mice that have one or two substitutions at codons 108 and 189, Prn-p b, had longer
incubation periods. Recently, it has been shown that the Sinc and Prn-p genes are linked and
could even be the same gene (Hunter et al., 1987).
However, differences in incubation period have been observed in mouse strains of the same
Sinc s7 and/or Prn-p ~ genotype (Outram, 1976; Kingsbury et al., 1983; Westaway et al., 1987).
This suggests the presence of another factor that influences the incubation period of scrapie and
CJD in mice.
We investigated the susceptibility of different strains of inbred mice, including B 10 congenic
strains, to CJD infection by measuring incubation periods. To determine the genetic basis for
control of the incubation period, we compared various crosses and backcrosses between the
inbred strains. The evidence obtained suggests that additional genes, albeit perhaps minor ones,
probably influence the incubation period of C J D in mice.
METHODS
Animals. Inbred strains of B10 congenic B10.AKM/OIa mice were provided by Dr K. Moriwaki, National
Institute of Genetics, Mishima, Japan and B10.A/SgSnSlc, B10.BR/SgSnSIc and B10.D2/nSnSlc mice were
obtained from Shizuoka Laboratory Animal Center, Hamamatsu, Japan. B10.A(3R)/Jms, A.AL/Jms and
A/JJms mice were provided by Dr K. Sudoh, Laboratory Animal Research Center, Institute of Medical Science,
University of Tokyo, Japan and SJL/N and C57BL/6J mice were from Dr K. Esaki, Central Institute for
Experimental Animals, Kawasaki, Japan. BALB/cSea, DBA/1JSea, DBA/2Sea, NZB/Sea and NZW/Sea mice
were obtained from Seiwa Experimental Animals, Yoshitomi, Japan, and SWR/J were from the Jackson
Laboratory, Bar Harbor, Me., U.S.A. Mice were maintained in rooms with a controlled temperature (23 to 27 °C)
and humidity (55 to 65 %), with a 12 h on and 12 h off cycleof artificial light. Food and water were given ad libitum.
The mice were bred and kept under specific pathogen-flee conditions, either in barrier systems or in isolators.
Test crosses. Reciprocal first filial (F1) hybrid progenies from mating of various inbred strains were used, as
follows: NZW/Sea x C57BL/6J Fl, A/JJms x C57BL/6J F1, NZW/Sea x B10.AKM/Ola F 1 and
NZW/Sea x A/JJms F1. The following backcrosses were also used: (NZW/Sea x C57BL/6J F1) x C57BL/6J,
(NZW/Sea x C57BL/6J F1) x NZW/Sea, (A/JJms x C57BL/6J Fi) x C57BL/6J and (A/JJms x C57BL/6J
F1) x A/JJms. All these crosses and backcrosses were done in our laboratory.
CJD agent. The CJD agent strain Fukuoka 1, isolated from the brain of a patient with CJD (Tateishi et al.,
1979), was used. The mouse brain inoculum was obtained from B10. D2/nSnSlc mice with advanced clinical CJD.
The brains were homogenized in phosphate-buffered saline and centrifuged at 2000g for 10 rain. The titre of the
inoculum was 10TM LDs0 NZW/Sea mouse intracerebral (i.c.) wet weight units/g, as determined by endpoint
titration, using the method of K/irber (1931). The 1~ (w/v) supernatant was stored at - 70 °C until use. Twenty p.1
of the inoculum was injected into the right parietal lobe in the case of the i.c. route, and 50 pl was injected in the
case of the intraperitoneal (i.p.) route, as described by Mohri et al. (1987).
Measurement of incubationperiods. Mice were examined two or three times a week for the clinical assessment of
CJD, as described in Results. The mice were anaesthetized with ether and decapitated when they were in a poor
condition or exhibited severe clinical signs of CJD. Incubation periods were calculated as the number of days
between inoculation and death.
Pathology. To confirm the diagnosis of CJD, the brains were immediately removed and placed in 10~ formalin.
Paraffin sections (6 ~tm) of these tissues were stained with haematoxylin and eosin.
Statistics. Student's paired t-test was used to determine the statistical significance of results.
RESULTS
Clinical signs of C J D in mice began with uncoordinated movements, ruffled fur, arched back,
generalized tremor, tail rigidity, slow righting reflex and bradykinesia followed by ataxia and
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Host control o f CJD in mice
1393
paraplegia in the hind legs. The disorders progressed rapidly and the mice died within 2 to 4
weeks after the onset of the illness (Mohri et al., 1987). The signs were much the same in each
strain. Some SJL/N mice were sensitive to sound and touch stimulation and staggered while
running in the cage.
Histopathology showed a severe spongy state and proliferation of astrocytes in the white
matter of the cerebrum, especially in the brain stem, cerebellum, internal capsule and ports. The
grey matter of the cerebral cortex, thalamus and brain stem was involved to a milder or lesser
degree, as reported by Tateishi et al. (1980). The histopathological profiles were essentially the
same in all mice, though spongiform change tended to be more severe after i.c. inoculation in
those strains (NZW/Sea, A/JJms and DBA/1JSea) having shorter incubation periods.
No intrinsic male/female differences in the CJD incubation period were seen in any strain,
after i.c. or i.p. inoculation (data not shown).
Table 1 shows the mean incubation periods of each strain after i.c. injection, ranked from
short to long. In order to search for genes influencing the incubation period in mouse CJD, we
recorded coat colour and H-2 haplotypes as the marker loci of each strain of mice. Table 2 shows
the same data for i.p. inoculated mice. The incubation period of CJD differed between the
various strains from 124 days in NZW/Sea mice to 186 days in B10. AKM/Ola mice after i.c.
inoculation and from 243 days in A/JJms mice to 355 days in NZB/Sea mice after i.p.
inoculation. Incubation periods for NZW/Sea and A/JJms mice were significantly shorter than
those for other strains. In contrast, the C57BL/6J, B10.A/SgSnSIc and B10.AKM/Ola mice
had significantly longer incubation periods. Ranking of the incubation periods in i.p. injected
mice almost totally corresponded to that for i.c. injected mice, SWR/J and NZB/Sea being
exceptions.
Mice with the b allele of the coat colour gene tended to have shorter incubation periods than
those with the B allele. Thus, locus b of the coat colour gene on chromosome 4 could modify the
incubation period. Similarly, the c allele on chromosome 7 appeared to result in shorter
incubation periods than the C allele after i.p. injection but not always in the case of i.c. injection.
These observations provide additional evidence that loci b and c of the coat colour genes did not
influence the CJD incubation period in the backcross mice, as shown in Table 3.
No positive correlation between incubation period and the H-2 locus on chromosome 17 was
evident in inbred strains of mice (Tables 1 and 2). In congenic strains of B10 mice, no differences
in incubation period between the q allele (B 10. AKM/Ola mice) and the d allele (B 10. A/SgSnSlc)
in the D subregion were observed (Table 4). A significant difference, however, was seen
between BI0.A(3R)/Jms and B10.A/SgSnSIc, with the same d allele. These observations
suggest that the D subregion of the H-2 complex does not play a significant role in controlling the
length of the incubation period.
The mean length and distribution of incubation periods in progeny from the crosses and/or
backcrosses are shown in Fig. 1 and 2. Reciprocal crosses and backcrosses of maternal and
paternal strains represented mixed groups; there were no significant differences in incubation
periods between the progeny of reciprocal matings, e.g. of the NZW/Sea x C57BL/6J F1 mice,
the progeny of the NZW/Sea mother and the C57BL/6J mother had mean incubation periods of
163 and 168 days, respectively. This phenomenon was common in other combinations of strains
(data not shown).
In the F~ hybrid mice from the NZW/Sea × C57BL/6J mating and those backcrossed with
C57BL/6J, the mean incubation periods were 166 and 175 days, respectively (Fig. 1c and d). The
length and unimodal pattern of the incubation periods were similar to those of C57BL/6J mice,
173 days (Fig. 1 b). On the other hand, the Fx backcross to NZW/Sea had an incubation period,
155 days (Fig. 1 e), intermediate between those of the two parental mice, 124 days and 173 days,
respectively (Fig. 1a and b). The pattern of distribution was unimodal. Lengths and distribution
patterns of the incubation periods (Fig. 1 h to j) of the F1 hybrid and backcross mice from mating
A/JJms x C57BL/6J were similar to those from NZW/Sea x C57BL/6J.
Similar results were obtained with i.c. or i.p. routes of inoculation for A/JJms, C57BL/6J and
their F~ hybrid offspring, though the distribution of the incubation periods varied widely for i.p.
but not i.c. inoculated mice (Fig. 2g to i).
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* Strains linked by vertical lines do not differ significantly in incubation period by Student's t-test (P > o.ool).
~"Incubation period (mean + S.D.) following i.p. inoculation.
A/JJms
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SWR/J
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B10. AKM/Ola
NZB/Sea
Strain*
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S. M O H R I A N D
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Fig. 1. Distribution and mean values of incubation periods of CJD agent-infected mice. Parts (a) to (e)
show the parental strains NZW/Sea (a) and C57BL/6J (b), their F1 hybrid (c) and the progeny of
backcrosses with C57BL/6J and NZW/Sea (d and e) respectively. Parts (f) to (j) show the parental
strains A/JJms (f) and C57BL/6J (g), their F 1 hybrid (h) and the progeny of backcrosses with C57BL/6J
and A/JJms (i and j) respectively. The mean incubation periods are given in days + S.D.; n indicates the
total number of mice of each strain examined. There are statistically significant (P < 0.001) differences
between results with different symbols (,, **, *** or t, f~f). P values were determined using Student's ttest. Parts (b) and (g) show that one mouse died at 131 days post-infection with very slight spongiform
changes.
The F 1 hybrid mice from the NZW/Sea x B10. AKM/Ola mating had a short incubation
period, 168 days, compared with 186 days in B10. AKM/Ola mice (Fig. 2a to c). The incubation
period in the NZW/Sea x A/JJms F1, 147 days, was longer than that of either of the two
parents, 124 days and 129 clays respectively (Fig. 2d to f ) .
DISCUSSION
We obtained evidence for a wide variation in the length of the incubation period of CJD
among different inbred strains of mice. Wider ranges of the incubation periods following i.p.
inoculation compared to i.e. inoculation were observed not only with the CJD Fukuoka 1 strain
but also with other CJD strains isolated in our laboratory. In inbred strains of mice, the broad
variation and continuum of incubation periods was similar to that reported by Kingsbury et al.
(1983) for i.e. inoculated mice. They observed that N Z W mice had the shortest incubation
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Host control of CJD in mice
~(d)
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Incubation period (days)
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,
350
Fig. 2. Distribution and m e a n values of incubation periods of C J D agent-infected mice. (a to c)
Parental strains N Z W / S e a (a) and B 1 0 . A K M / O l a (b), and their F1 hybrid (c), following i.c.
inoculation). (d to f ) Parental strains N Z W / S e a (d) and A / J J m s (e), and their F1 hybrid (f) following
i.c. inoculation. (g to 0 Parental strains A / J J m s (g) and C57BL/6J (h), and their F 1 hybrid (/), following
i.p. inoculation. See Table 1 for statistical details.
T a b l e 3.
CJD incubation periods and coat colours in the progeny from (NZW/Sea × C57BL/6J)
F1 × NZW/Sea matings
Mouse no.
Sex
Incubation (days)*
Coat colour
Genotypet
7922
7923
7940
M
M
M
M
M
M
F
F
F
F
F
M
M
M
F
M
M
M
M
F
F
M
F
F
F
M
M
143
143
148
148
148
148
148
148
153
153
153
153
153
153
155
159
159
159
159
159
159
162
167
167
167
174
185
Albino
Agouti
Agouti
Agouti
Agouti
Agouti
Cinnamon
Albino
Agouti
Agouti
Albino
Albino
Albino
Albino
Albino
Albino
Albino
Cinnamon
Cinnamon
Agouti
Albino
Albino
Agouti
Cinnamon
Albino
Agouti
Agouti
....
A- BA- BA- BA- BA- BA- bb
....
A- BA- B....
....
....
....
....
....
....
A- bb
A- bb
A- B....
....
A- BA- bb
....
A- BA- B-
7941
7942
7943
7944
7945
7957
7958
7959
7960
7961
7962
7979
7984
7985
7986
7987
7988
7989
8010
8014
8015
8016
8060
8095
* All mice were inoculated i.c.
I" A hyphen indicates an u n k n o w n gene.
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S. M O H R I
AND
J. TATEISHI
Table 4. CJD incubation periods in BIO congenic strains o f mice
H-2 subregion
)k
Strain*
BI0.D2/nSnSIc
B10.A(3R)/Jms
B10.BR/SgSnSIc
B10.A/SgSnSlc
B10.AKM/OIa
BI0.A(3R)/Jms
B10.D2/nSnSlc
B10.BR/SgSnSlc
B10.A/SgSnSlc
B10.AKM/Ola
Route
No.
Incubation(days)t
I(
Aa
A/~
E/~
J
E~
S
I~
i.c.
i.e.
i.c.
i.c.
i.c.
i.p.
i.p.
i.p.
i.p.
i.p.
30
14
16
21
21
18
20
17
17
19
160 + 6
165 + 7
168 + 4
174 + 10
186 + 12
291 + 17
294 +__18
302 + 15
323 + 18
329 + 19
d
b
k
k
k
b
d
k
k
k
d
b
k
k
k
b
d
k
k
k
d
b
k
k
k
b
d
k
k
k
d
b
k
k
k
b
d
k
k
k
d
b
k
k
k
b
d
k
k
k
d
k
k
k
k
k
d
k
k
k
d
d
k
d
k
d
d
k
d
k
d
d
k
d
q
d
d
k
d
q
* Strains linked by vertical lines do not differ significantlyin incubation period by Student's t-test (P > 0.001).
t Incubation period (mean + S.D.).
period for scrapie and that C57BL/6J mice infected with scrapie or the CJD agent had a longer
incubation period. Similar results for CJD were obtained in our study but we observed that
B 10. AKM/Ola mice had the longest incubation period after i.c. or i.p. inoculation in contrast to
Kingsbury et al. (1983) who found this strain to have the shortest incubation period. This
disagreement may relate to mutation or cloning of the CJD agent (Fukuoka 1 strain) during
passage in B10. D2/nSnSlc mice rather than in BALB/c mice (Kingsbury et al., 1983). It is clear
that mutation of scrapie strains is not rare (Bruce & Dickinson, 1987; Kimberlin et al., 1987). In
addition, mutations occurring within mouse genes would contribute to changes in the control of
the incubation period of CJD.
The D subregion of the-H-2 complex was identified as a control element in determining the
length of the CJD, Fukuoka 1, incubation period by Kingsbury et al. (1983), who noted that in
experimental CJD in mice, the q allele in the D subregion was associated with short incubation
periods while the d allele related to long incubation periods. However, in our studies on the
relationship between incubation period and H-2 haplotypes, there was no positive correlation. It
should be stressed that the H-2 complex has no apparent influence on the incubation period of
CJD, as noted with scrapie in mice (Bruce & Dickinson, 1985; Carlson et al., 1986).
In both F1 progenies from the N Z W / S e a x C57BL/6J cross and those from the
A/JJms × C57BL/6J cross, the incubation periods were virtually identical to those of the parent
with the longest incubation period. This suggests that the C57BL/6J genes which code for a long
incubation period are dominant over those of NZW/Sea and A/JJms which code for a short
incubation. This finding is in keeping with data in reports on human familial cases of CJD
(Masters et al., 1981) and host genotypes related to the scrapie incubation period (Dickinson &
Meikle, 1971; Kingsbury et al., 1983; Carlson et al., 1986). However, the mean length of
incubation period for NZW/Sea × B10. AKM/OIa F1 fell between those for the two parents. It
appears that the B 10. AKM/Ola genes coding for a long incubation period show no dominance.
These different results lead to speculation on the host gene action in controlling the incubation
period. If a single gene had been implicated in host control it would be possible to propose a
pleiotropic or quantitative effect. In those cases where the inheritance is polygenetic, the gene
products may act at various stages during the incubation period as agent-binding receptors,
factors active in agent replication, spread of infection, developing clinical disease and so on.
However, in the NZW/Sea x A/JJms F1 hybrids derived from two short incubation period
strains, the incubation period was significantly longer than those of either parent. This
phenomenon, considered as 'hybrid vigour', was recognized in scrapie-infected mice
(Dickinson, 1975; Bruce & Dickinson, 1985) and was termed 'overdominance'.
The genetic basis of the differences in incubation period between the various inbred strains of
mice has only been partially clarified by backcrossing experiments (Fig. 1). If only one gene with
two alleles had been involved, a bimodal distribution of incubation periods would be expected in
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Host control o f CJD in mice
1399
these backcross groups, yet there was no evidence of this. Thus, there are probably polygenetic
factors capable of influencing the length of the CJD incubation period in mice. Since all strains
surveyed here with the short incubation period are Sinc s7 and/or Prn-p a (Dickinson & Meikle,
1971; Carlson et al., 1986; Hunter et al., 1987; Westaway et al., 1987), the related genes are
probably minor ones. The relatively large differences in CJD incubation period between mouse
strains and the result of backcross progeny tests suggest that multifactorial host genes are
involved in the pathogenesis of CJD.
It remains to be seen whether these genes are dependent on the Sinc and/or Prn-p genes and
whether they are dependent on the combination of mouse genotype and agent stain as has been
noted for scrapie (Dickinson & Fraser, 1977; Bruce & Dickinson, 1979; Carp et al., 1987).
Further investigations on experimental CJD in mice using specific inbred strains such as I/Ln
and on the properties of some CJD agents isolated from patients with CJD and GerstmannStriiussler syndrome (Tateishi et al., 1987) are under way, and are expected to show relationships
between these genes and the prion gene complex.
We thank Dr A. T a k e n a k a and Dr S. H a n d a for advice and encouragement, Miss K. H a t a n a k a and Miss C.
K a n e k o for excellent technical assistance, and Mr S. Y a m a g a t a and M r Y. Ogawa for animal care. M. O h a r a
provided comments on the manuscript.
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