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Journal of Clinical Microbiology, June 1998, p. 1700-1703, Vol. 36, No. 6
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
Proliferative Enterocolitis Associated with Dual
Infection with Enteropathogenic Escherichia coli
and Lawsonia intracellularis in Rabbits
David B.
Schauer,1,2,*
Sonya N.
McCathey,1
Barbara M.
Daft,3
Sharda S.
Jha,2
Lisa E.
Tatterson,2
Nancy S.
Taylor,1 and
James G.
Fox1,2
Divisions of Comparative
Medicine1 and
Toxicology,2 Massachusetts Institute of
Technology, Cambridge, Massachusetts 02139, and
California
Veterinary Diagnostic Laboratory System, University of California,
San Bernardino Branch, San Bernardino, California
924123
Received 1 October 1997/Returned for modification 19 February
1998/Accepted 26 February 1998
 |
ABSTRACT |
Both enteropathogenic Escherichia coli (EPEC) and an
obligate intracellular bacterium, previously referred to as an
intracellular Campylobacter-like organism and now
designated Lawsonia intracellularis, have been reported as
causes of enterocolitis in rabbits. An outbreak of enterocolitis in a
group of rabbits, characterized by an unusually high rate of mortality,
was found to be associated with dual infection with EPEC and L. intracellularis. The EPEC strain was found to have
eaeA gene homology but was negative for afrA
homology. The absence of the afrA gene, which encodes the
structural subunit for the AF/R1 pilus, indicates that this rabbit EPEC
strain is distinct from the prototypic RDEC-1 strain. This finding
suggests that rabbit EPEC strains widely reported in Western Europe,
which lack AF/R1 pili, are also present in rabbits in the United
States. Dual infection with these two pathogens in rabbits has not been previously reported and may have contributed to the unusually high
mortality observed in this outbreak.
| |
INTRODUCTION |
Enterocolitis is a significant cause
of morbidity and mortality in rabbits, and infection with
Escherichia coli is perhaps the most important cause of
rabbit enterocolitis. The severity of disease presentation in
colibacillosis is variable and is dependent on the particular strain of
E. coli (19) as well as on the presence of
concurrent infectious agents (25). In cases of severe
morbidity and mortality, treatment is often not effective and entire
rabbit herds must be depopulated and restocked. Therefore, a better
understanding of the factors which control disease expression in rabbit
colibacillosis is needed. The purpose of this study was to ascertain
the etiology of an outbreak of enterocolitis in a group of rabbits,
characterized by an unusually high rate of mortality.
The prototypic diarrheagenic E. coli strain of rabbits,
designated RDEC-1, was isolated 20 years ago from an outbreak of
diarrhea in a rabbit colony (3). This strain is considered
an attaching and effacing E. coli (AEEC) strain because it
causes attaching and effacing (AE) lesions (24). These
lesions are characterized by intimate bacterial adherence to the apical
cytoplasmic membrane of intestinal epithelial cells, often with
pedestal or cup formation, destruction of the microvillus brush border,
and rearrangement of the enterocyte cytoskeleton at the site of
bacterial attachment (18). AEEC strains include both
enteropathogenic E. coli (EPEC) and certain strains of
enterohemorrhagic E. coli (EHEC). EPEC strains do not
express the high levels of Shiga toxin which are characteristic of EHEC
strains, but all AEEC strains, as well as certain Hafnia
alvei strains (1) and Citrobacter rodentium strains (22), appear to have a common 35-kb pathogenicity
island located on the chromosome (13), which encodes all of
the gene products necessary for production of AE lesions
(14). This pathogenicity island is called the locus for
enterocyte effacement (LEE). The presence of the LEE-encoded AE genes,
and of eaeA in particular, has been used to identify AEEC.
In addition to the AE gene products of the LEE, RDEC-1 expresses
plasmid-encoded AF/R1 pili which promote adherence to rabbit intestinal
epithelial cells (27). The structural subunit of the AF/R1
pilus is encoded by the afrA gene (28). Although
most, if not all, EPEC strains from rabbits have AE genes, including eaeA, few, if any, rabbit EPEC isolates from Western Europe
express AF/R1 pili (2, 20). Indeed, a distinct fimbrial
adhesin, called AF/R2, has been identified in some of these rabbit EPEC strains (4). The plasmid pRKB35, which is pUC18 containing a
400-bp KpnI fragment from the afrA gene, provides
a convenient gene probe for the identification of the RDEC-1 rabbit
EPEC strain.
Intracellular Campylobacter-like organisms (ICLOs) have been
most frequently recognized in pigs (21) and in hamsters
(26), but they have also been reported in other animal
species, including rabbits (10, 17, 23) and ferrets (6,
7). These intracellular organisms are gram-negative, curved- to
spiral-shaped bacteria which exist free in the apical cytoplasm of
intestinal epithelial cells. They cause proliferative ileitis and/or
proliferative colitis characterized by epithelial cell hyperplasia and
mucosal inflammation. Although the ICLOs have not been cultured on
cell-free media, nucleotide sequence determination of the 16S rRNA gene
of ICLOs isolated from pigs (15) and from ferrets
(5) has shown that the organisms are related to
Desulfovibrio desulfuricans but are sufficiently distinct
from the Desulfovibrio spp. to warrant placing them in a
separate genus, where they comprise a single species called
Lawsonia intracellularis (15).
| |
MATERIALS AND METHODS |
Animals.
In late 1995, a closed, Pasteurella-free
production colony of barn-housed New Zealand White rabbits experienced
an outbreak of diarrhea associated with approximately 70% mortality in
which over 400 animals died. Clinical signs of disease included acute diarrhea, dehydration, and weight loss in animals from 2 to 4 months of
age. Prior to this outbreak, fecal flotation revealed the presence of
coccidia in the colony but the rabbits did not have clinical signs of
disease and did not suffer significant mortality.
Histologic examination.
Segments of visibly thickened ileum
were collected at necropsy from four affected rabbits and were fixed in
10% neutral-buffered formalin. Fixed tissues were processed, paraffin
embedded, and sectioned routinely at 5 µm. Sections were stained with
hematoxylin and eosin or with a modified Warthin-Starry silver
impregnation stain.
Bacterial culture and isolation.
Samples of ileal contents
from the four affected rabbits were plated on hektoen enteric agar and
on xylose-lysine-deoxycholate agar for enteric pathogens, on
cefoxitin-cycloserine-fructose modified agar for Clostridium
spp., and on brucella agar supplemented with 5% defibrinated sheep
erythrocytes and with cefoperazone (20 mg/liter), vancomycin (10 mg/liter), and amphotericin B (2 mg/liter) (Campy CVA agar; Becton
Dickinson Microbiology Systems, Cockeysville, Md.) for
Campylobacter spp. and for Helicobacter spp.
Enteric media were incubated at 37°C in ambient O2, media for Clostridium spp. were incubated at 37°C in an
anaerobic atmosphere (Anaerogen; Oxoid Ltd., Basingstoke, England), and
media for Campylobacter spp. and Helicobacter
spp. were incubated at 37°C in a microaerobic atmosphere (90%
N2, 5% CO2, and 5% H2). E. coli strains were biotyped with a commercial identification system
(API 20E; bioMérieux Vitek Inc., St. Louis, Mo.).
DNA isolation.
DNA was isolated from E. coli
using Qiagen genomic tips according to the recommendations of the
manufacturer (Qiagen Inc., Chatsworth, Calif.).
Southern blot analysis.
Southern blot analysis for E. coli virulence factors was performed with an ECL Direct Kit
(Amersham Corp., Arlington Heights, Ill.). Briefly, genomic DNA was
digested with HindIII (New England Biolabs, Beverly,
Mass.) and separated by electrophoresis. The DNA was then transferred
to a nylon membrane by the capillary transfer method and was UV
cross-linked. The probe for the eaeA gene was a 1-kb
internal restriction fragment from the eaeA gene of a human
EPEC strain (12). The probe for the afrA gene, a gift from J. Robert Canty, was a 400-bp internal restriction fragment from the rabbit EPEC strain RDEC-1 (28). These fragments
were labeled by using an ECL Direct Kit (Amersham) according to the recommendations of the manufacturer. After hybridization with the probe
overnight at 42°C, the membranes were washed twice for 20 min at
42°C in 6 M urea-0.4% sodium dodecyl sulfate-0.1× SSC (1× SSC is
0.15 M NaCl plus 0.015 M sodium citrate). For low-stringency washes,
the final concentration of SSC in the primary wash solution was
increased from 0.1× to 2×. These washes were followed by two additional 5-min washes at room temperature in 20× SSC. The detection reagents included with the kit were used as directed, and positive signals were detected by exposure to radiographic film (Hyperfilm-ECL; Amersham).
Clostridial toxin assay.
Fifty microliters of fecal filtrate
from each intestinal sample was analyzed for Clostridium
difficile toxin by using a C. difficile toxin B human
foreskin tissue culture assay as outlined by the manufacturer (TechLab,
Blacksburg, Va.). The cells were observed for rounding, which indicates
a cytotoxic effect, at 24 and at 48 h.
| |
RESULTS AND DISCUSSION |
Gross necropsy.
Upon gross examination, the affected animals
had thickening of the ileum and the colon as well as mesenteric
lymphadenopathy. No other abnormalities were noted.
Histologic examination.
Evaluation of slides stained with
hematoxylin and eosin revealed intestinal epithelial cell hyperplasia
with blunting of the villi. A moderate inflammatory cell infiltrate was
seen in the majority of the sections which exhibited marked epithelial
cell hyperplasia. A decrease in the number of goblet cells was also observed (Fig. 1). A histologic diagnosis
of proliferative enterocolitis was made. Under high-power
magnification, numerous bacterial organisms were found to be closely
associated with the surface of differentiated intestinal epithelial
cells (Fig. 2). The appearance of these organisms was consistent with that of AEEC. High-power magnification of
slides stained with the modified Warthin-Starry silver stain revealed
numerous curved- to spiral-shaped intracellular organisms in the apical
cytoplasm of intestinal epithelial cells (Fig.
3). The appearance of these organisms was
consistent with that of the obligate intracellular bacterium L. intracellularis.
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FIG. 1.
Photomicrograph of a section of small intestine from a
rabbit with proliferative enterocolitis. The mucosa of the intestine
has blunted villi, a moderate inflammatory cell infiltrate, and a
decreased number of goblet cells. The crypt epithelial cells are
markedly hyperplastic. Hematoxylin and eosin stain was used
(magnification, ×40).
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FIG. 2.
Photomicrograph of mucosal detail of a section of small
intestine from a rabbit with proliferative enterocolitis, demonstrating
typical AE lesions on surface intestinal epithelial cells. Hematoxylin
and eosin stain was used (magnification, ×1,000).
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FIG. 3.
Photomicrograph of a section of small intestine from a
rabbit with proliferative enterocolitis, demonstrating numerous curved-
to spiral-shaped bacteria in the apical cytoplasm of the intestinal
epithelial cells. Modified Warthin-Starry silver stain was used
(magnification, ×1,000).
|
|
Pathogenic synergism, related to the severity of disease in weanling
rabbits, has been reported between EPEC and rotavirus
(
25).
Experimental inoculation of weanling rabbits with >10
6 CFU
of RDEC-1 in conjunction with rotavirus resulted in increased
morbidity
and mortality compared to inoculation with RDEC-1 alone.
There was no
histologic evidence of rotavirus infection in these
rabbits, but
specific assays were not performed. It may be that
dual infection with
EPEC and
L. intracellularis in these rabbits
also resulted
in pathogenic synergism, leading to increased morbidity
and mortality
compared to infection with either agent alone.
A similar pathogenic synergism in hamsters was reported by Frisk and
Wagner (
8). In that study, animals were inoculated
with
ileal suspensions from naturally infected hamsters suffering
from
proliferative ileitis, resulting in dual infection with an
organism
indistinguishable from
L. intracellularis and with an
E. coli strain. The
E. coli organism, which
produced histologic
changes suggestive of an enteroinvasive
E. coli, was also found
intracellularly, and in some cases the two
bacterial species were
found within the same intestinal epithelial
cell. In general,
the
E. coli strain was more frequently
observed in areas of nonhyperplastic,
acute enteritis, whereas the
L. intracellularis organisms were
consistently associated
with areas of hyperplasia. The authors
hypothesized that infection with
the
E. coli strain preceded,
and might facilitate subsequent
infection with, the
L. intracellularis organism
(
8). It may be that infection with EPEC also increases
the
susceptibility of rabbits to infection with
L. intracellularis.
However,
L. intracellularis infection
can occur independent of
EPEC infection in rabbits (
10,
23).
Bacterial culture.
No Clostridium spp. were
recovered from anaerobic cultures of the ileal contents from the
rabbits, and no clostridial toxins were detected. Aerobic culture of
the ileal contents from the rabbits yielded E. coli. The
E. coli isolates were clonal as judged by the API 20E
biochemistry profile (Table 1). The
strain was positive for fermentation of mannitol, sorbitol, rhamnose,
melibiose, and arabinose and negative for fermentation of inositol,
sucrose, and amygdalin. These isolates are nonmotile biotype 3 (biotype 3
) in the simplified biotyping scheme of Peeters et al.
(19). Peeters et al. found that biotype 3 strains were
highly correlated with severe disease, accounted for 35.5% of the
isolates from weanling rabbits with diarrhea, and were not recovered
from healthy rabbits (19).
Southern blot analysis of E. coli isolates.
Genomic DNA from the E. coli isolates did possess
eaeA gene homology, which was detected under conditions of
high stringency (Fig. 4). Even under
conditions of low stringency, there was no evidence of afrA
gene homology in the DNA from the E. coli isolates (data not
shown). DNA from the positive control, RDEC-1, did possess afrA gene homology, which was detected under conditions of
both high and low stringency.
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FIG. 4.
Southern blot of HindIII-digested genomic
DNA from E. coli strains probed with the eaeA
gene probe under conditions of high stringency. The lanes contain
independent isolates from four rabbits with dual infections with EPEC
and L. intracellularis, RDEC-1, and a nonpathogenic E. coli K-12 strain.
|
|
Rabbit EPEC strains from Western Europe, even those of the same
serogroup as RDEC-1 (O15:H
), do not express AF/R1 pili. Some
serogroup O103 rabbit EPEC strains do express an analogous initial
adhesin, called AF/R2 (
4), but the recovery of these strains
from rabbits in North America has not been reported. The absence
of the
afrA gene in these isolates indicates that rabbit EPEC
strains such as those reported in Western Europe are also present
in
rabbits in the United States. We did not test for the AF/R2
gene, nor
did we serotype the isolates in this study. However,
the fact that
these isolates are biotype 3
suggests that these
strains may also
belong to serogroup O15:H
. The possible existence
of yet another
initial adhesin in the rabbit EPEC O15:H
strains
other than RDEC-1
remains to be determined.
We have demonstrated that the rabbits in this outbreak had a dual
infection with EPEC and
L. intracellularis. The rabbit EPEC
strain was typical of those biotype 3
isolates from Western Europe
which are associated with severe disease and which do not express
AF/R1
pili. While these isolates appear to be of the same biotype
and may
indeed also belong to the same O15:H
serogroup as the
prototypic
RDEC-1 strain, they are distinct from RDEC-1. To our
knowledge, such a
rabbit EPEC isolate has not been previously
reported in rabbits in the
United States. The prevalence of strains
such as these in rabbits in
the United States remains to be determined.
It is also not clear if the
high mortality associated with this
outbreak was attributable to the
virulence of this rabbit EPEC
strain, to pathogenic synergism between
EPEC and
L. intracellularis,
or to both of these factors.
Additional experiments, including
experimental inoculation studies, are
being conducted to address
these questions.
The source of the EPEC and the
L. intracellularis has not
been established. No new rabbits had been introduced into this colony
prior to the outbreak of disease. It is interesting that at
approximately
the time that morbidity and mortality developed in the
rabbits,
a herd of pigs was introduced onto the farm in an adjacent
facility.
It is possible that the rabbits were exposed to fomites
contaminated
with feces from the pig facility. Both EPEC (
9)
and
L. intracellularis (
21) have been reported to
cause disease in pigs, raising the
possibility of cross-species
transmission of these agents from
pigs to rabbits. There are no
experimental data to support this
hypothesis, but cross-species
transmission of
L. intracellularis from pigs to hamsters has
been reported previously (
11,
16).
Also, the zoonotic
cross-species transmission of EHEC from livestock
to humans has a
significant impact on public health. We speculate
that pigs might
indeed be the source of EPEC and/or
L. intracellularis infection for the rabbits in this outbreak. Unfortunately, specimens
from the affected pigs were not available for analysis. Determination
of the host range of these enteric pathogens will require experimental
inoculation studies using naive pigs.
| |
ACKNOWLEDGMENTS |
We thank J. Robert Cantey for the gift of the pRKB35 plasmid and
the RDEC-1 strain.
This work was supported in part by grants CA63112 to D.B.S. and RR07036
to J.G.F. from the National Institutes of Health.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: MIT, Room
56-787B, Cambridge, MA 02139. Phone: (617) 253-8113. Fax: (617)
258-0225. E-mail: schauer{at}mit.edu.
| |
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Journal of Clinical Microbiology, June 1998, p. 1700-1703, Vol. 36, No. 6
0095-1137/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.
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Abstract
Introduction
