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Infection and Immunity, July 1999, p. 3686-3689, Vol. 67, No. 7
0019-9567/99/$04.00+0
Chlamydial Colonization of Multiple Mucosae
following Infection by Any Mucosal Route
Linda L.
Perry,* and
Scott
Hughes
Laboratory of Intracellular Parasites, Rocky
Mountain Laboratories, National Institute of Allergy and Infectious
Diseases, National Institutes of Health, Hamilton, Montana 59840
Received 12 February 1999/Returned for modification 12 March
1999/Accepted 20 April 1999
 |
ABSTRACT |
Chlamydia trachomatis inoculated by any mucosal route
colonized multiple murine mucosae and, in most cases, the spleen,
liver, and kidneys. Cell-to-cell transmission, systemic dissemination, and autoinoculation of infectious fluids may have contributed to
chlamydial spread. Intermucosal trafficking of protective T cells
cannot be accurately evaluated by using live chlamydial challenges.
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TEXT |
Chlamydia trachomatis is
an obligate intracellular bacterium with a tropism for mucosal
epithelial cells. The clinical consequences of infection vary according
to the site of colonization and may be associated with the development
of blindness, pneumonia, infertility, and/or proctitis (28).
Once introduced to a susceptible mucosa, Chlamydia spreads
canalicularly along adjacent epithelia by a process that is undoubtedly
facilitated by the entry and exit of chlamydial elementary bodies from
the apical surface of mucosal epithelial cells (8). In most
cases, Chlamydia is cleared through the action of
neutrophils and mononuclear leukocytes recruited to the site of
infection, with a predominant role for type 1 CD4+ T cells
and the proinflammatory cytokines that they secrete (4, 9, 11, 16,
22, 30). Unfortunately, Chlamydia-induced inflammation may also contribute to the development of residual tissue
pathology and associated infertility (2, 20, 21, 33, 34).
For these reasons, limiting the extent and severity of infection
remains a primary vaccine goal.
Induction of immunity to epithelial pathogens such as C. trachomatis has relied heavily upon delivery of vaccine antigens to a mucosal surface, particularly the intestinal mucosa, which serves
as an inductive site for the common mucosal immune system. This system
was defined initially by the ability of enterically introduced antigens
to trigger antibody secretion not only locally but also at distant,
unrelated mucosae (13-15), a phenomenon attributed to the
directed trafficking of reactive B lymphocytes from the gastrointestinal tract to pulmonary and genital tissues
(13). In contrast, antigens administered parenterally
induced systemic but not mucosal antibody secretion (15),
suggesting separation of systemic and mucosal lymphocyte trafficking
pathways. Molecular support for this distinction came from the
identification of vascular cell adhesion molecule (VCAM) on endothelial
cells of the systemic vasculature and mucosal addressin cell adhesion
molecule (MAdCAM) on endothelial cells of the intestinal lamina
propria. Lymphocytes infiltrating each of these sites expressed
distinct profiles of complementary membrane integrins, represented as
4
1 at VCAM+ tissues and 47 at
MAdCAM+ mucosae (3). These findings strengthened
the notion that induction of mucosal immunity required a mucosal
immunization strategy, even though direct evidence for intermucosal
trafficking by antigen-specific T cells was lacking.
Vaccine trials against C. trachomatis have focused upon
immunization with the homotypic major outer membrane protein (MOMP) or
with MOMP-expressing bacteria. Oral administration of UV-inactivated Chlamydia (10) or purified or recombinant MOMP
induced weak antibody reactivity but failed to alter the course of a
subsequent ocular (31) or genital (32) chlamydial
infection. Direct inoculation of the Peyer's patches with recombinant
MOMP was equally ineffective in providing protection against
Chlamydia-associated salpingitis and infertility
(32). However, oral (6, 7, 17) or intranasal (18) administration of live C. trachomatis
stimulated widespread immune reactivity at both the T- and B-cell
levels and induced effective protection against a subsequent
respiratory or genital Chlamydia challenge. It has been
suggested that these data support the idea that the gastrointestinal
tract is an induction site for Chlamydia-specific T-cell
immunity (6), but the apparent requirement for a live rather
than killed antigenic stimulus remained unexplained. Given the
propensity of C. trachomatis to ascend from the vagina to
the ovary in normal mice or to the kidneys in immunodeficient mice
(22), the possibility that Chlamydia does not
remain confined to the site of inoculation but spreads to adjacent,
nontargeted mucosae to induce protective immunity at each site must
also be considered. The current experiments were undertaken to evaluate
that possibility.
Mice.
C57BL/6J female mice 8 to 12 weeks of age were obtained
from Jackson Laboratories, Bar Harbor, Maine. Animals were housed in an
American Association for Accreditation of Laboratory Animal Care-accredited facility in filter-top cages under standard
environmental conditions and were provided food and water ad libitum.
C. trachomatis.
The C. trachomatis strain
mouse pneumonitis (MoPn) was grown in HeLa 229 cells, and elementary
bodies were purified by discontinuous density gradient centrifugation
as previously described (5).
Infection of mice.
Preliminary experiments revealed that the
spread of Chlamydia was dependent upon the success of
infection over a wide range of challenge doses. Therefore, mice were
infected with Chlamydia at doses that provided reproducible
infections without causing overt clinical disease. Gastrointestinal
infections were performed by depositing 50 µl of 250 mM sucrose-10
mM sodium phosphate-5 mM L-glutamic acid (pH 7.2) (SPG)
containing 104 inclusion-forming units (IFU) of C. trachomatis MoPn into the stomach with a Jorgensen feeding needle
under methoxyflurane anesthesia. Intranasal and intratracheal
infections with 400 IFU of MoPn in 30 µl of SPG were also performed
under anesthesia. A midline incision over the trachea with a no. 10 scalpel blade followed by blunt tissue dissection aided exposure of the
trachea at the level of the thoracic inlet. Vaginal infection of mice
pretreated with 2.5 mg of medroxy-progesterone acetate (Depo-Provera;
Upjohn) on day 
5 was performed by depositing 5 µl of SPG containing
1.5 × 103 IFU of MoPn into the vaginal vault. The
presence of infectious MoPn in relevant tissues was determined by
sacrificing mice at 7 or 10 days postinfection and enumerating
chlamydial organisms recovered from weighed, minced tissue fragments by
IFU formation on HeLa cell monolayers using indirect immunofluorescence
as described previously (16). Chlamydial shedding from the
genital mucosa was monitored by swabbing the vaginal vault twice weekly
with Calgiswabs (Spectrum Medical Laboratories, Los Angeles, Calif.) as
previously described (22). In certain experiments, mice were outfitted with 3.5-cm-diameter padded Elizabethan collars cut from
exposed X-ray film to prevent self-grooming and autoinoculation of
genital and/or intestinal secretions. Continued presence of the collars
was monitored daily and animals that lost their collars were excluded
from that group.
The ability of a primary chlamydial infection to induce immunity at a
distant mucosal site was assessed initially between noncontiguous
mucosae of the respiratory and genital tracts. Female mice were
infected vaginally with C. trachomatis and monitored for
bacterial shedding until immune-mediated clearance was complete by 28 days postinoculation (p.i.) (data not shown). Four weeks later,
these genitally immune mice as well as naive control animals were
rechallenged with a potentially lethal dose of C. trachomatis by direct intratracheal injection. Several logs of
Chlamydia were recovered from the lungs of naive control
mice on day 11 p.i., but none were detected in the lungs of immune
mice (Table 1). These data were
consistent with previous reports and suggested that T cells primed in
the genital tract may have trafficked to the pulmonary mucosa in
response to a chlamydial challenge. Since the potential usefulness of
this model to evaluate mucosal T-cell trafficking patterns depended
upon containment of infections to the targeted mucosa, spread from the
trachea to adjacent epithelia of the gastrointestinal tract was also
assessed. High levels of infectious Chlamydia were detected
in the small intestines of normal as well as
Chlamydia-immune mice (Table 1), indicating that pulmonary
containment had not occurred. Instead it appeared that chlamydial
spread to contiguous mucosae may be a complicating factor in in vivo
analyses of mucosal trafficking and protection by
Chlamydia-specific T cells.
The extent to which
Chlamydia deposited at the genital,
pulmonary, or gastrointestinal mucosae was capable of colonizing
nontargeted
mucosal tissues was addressed more thoroughly in mice
infected
by three commonly used mucosal routes, i.e., intranasal, oral,
and vaginal. It was found that
Chlamydia deposited
intranasally
or orally colonized both the pulmonary and
gastrointestinal tracts
(Fig.
1), as
might be predicted by the continuity of epithelia
lining these tissues.
Surprisingly, however, orally and intranasally
infected mice also
developed chlamydial infections of the genital
tract (Fig.
1),
indicating the spread of infection to a noncontiguous
mucosa.
Transmission of
Chlamydia from the genital tract to the
pulmonary and gastrointestinal mucosae was also detected by 7
days p.i.
(Fig.
1), verifying the capacity of these bacteria to
colonize
nonadjacent mucosal tissues. Anesthetized mice infected
intranasally
occasionally developed infections of the conjunctival
mucosa as well
which was expressed as a mild-to-moderate transient
conjunctivitis
(data not shown). Spread in this case presumably
occurred via ascending
infection of the nasolacrimal ducts. These
data revealed that primary,
experimental
Chlamydia infections
by any route may lead to
colonization of targeted as well as nontargeted
mucosae with no
apparent requirement for continuity between epithelial
surfaces.
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FIG. 1.
Mucosal distribution of C. trachomatis 7 days
after infection by the intranasal, oral, or intravaginal route.
Chlamydia recovered from the lung, small intestine, or
genital tract was enumerated on HeLa cell monolayers as described in
Materials and Methods and is presented as the mean numbers of IFU ± standard errors of the means. Numbers above each bar represent the
fraction of mice displaying chlamydial colonization at each tissue
site.
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|
The mechanism of chlamydial spread between contiguous epithelia of the
nasal, respiratory, and gastrointestinal tracts probably
involved
direct cell-to-cell transmission of infectious elementary
bodies, or at
least it would be difficult to rule out this possibility.
The mechanism
of spread to noncontiguous mucosae was less clear,
however. It was
considered that
Chlamydia penetrating the epithelial
barrier
might disseminate systemically via the vascular or lymphatic
systems to
lodge wherever susceptible target cells were encountered.
Under these
conditions, colonization of distant mucosae requires
that chlamydial
elementary bodies gain access to the epithelial
layer and not just the
submucosal stroma, which may be difficult
to achieve without directed
migration. Nevertheless, dissemination
was monitored by enumerating
bacterial burdens in the internal
organs of mice infected by the oral,
intranasal, or vaginal route.
The majority of orally or intranasally
infected mice developed
significant chlamydial burdens in the liver,
spleen, and/or kidneys
(Fig.
2) but not
in the heart or peripheral blood (data not shown).
Systemic
dissemination was less apparent following vaginal chlamydial
infection
in that organisms were detected primarily in the kidneys
(Fig.
2),
possibly due to retrograde transport of bacteria along
the epithelial
lining of the ureters. Therefore, chlamydial spread
from the lung or
gastrointestinal tract to the genital tract may
occur via cell-to-cell
transmission and/or systemic dissemination
of infectious elementary
bodies, while alternative pathways may
be more relevant to spread from
the genital mucosa.
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FIG. 2.
Internal dissemination of C. trachomatis 7 days after infection by the intranasal, oral, or intravaginal route.
Chlamydia recovered from the spleen, liver, or kidneys of
infected mice was enumerated as described in Fig. 1 and is presented as
the mean numbers of IFU ± standard errors of the means. Numbers
above each bar represent the fraction of mice displaying chlamydial
colonization at each tissue site. Differences between groups were not
statistically significant due to the small size of the intravaginal
group.
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Under conventional group housing conditions, mutual
grooming is a natural behavior in mice.
Chlamydia
present in intestinal
or genital secretions could provide a ready
source of unintentional
oropharyngeal infection that is not usually
considered. The possibility
of transmission by this route was tested by
comparing rates of
chlamydial spread from the genital tract to the
respiratory or
gastrointestinal tracts of mice housed singly and in
groups. Singly
housed mice were further separated into those wearing
restrictive
Elizabethan collars to prevent orovaginal autoinoculation
and
those without. The spread of infection from the genital mucosa
to
unrelated mucosal tissues in all three groups of mice is presented
in
Fig.
3. Animals without restrictive
collars, whether housed
singly or in groups, developed infections of
both the pulmonary
and intestinal mucosae within 10 days of a primary
genital infection.
In contrast, singly housed animals wearing
restrictive collars
to prevent self-grooming showed no evidence of
pulmonary infection,
suggesting that autoinoculation may play a role in
the spread
of
Chlamydia from the genital tract to the lungs.
The presence
of collars did not prevent spread of infection to the
intestinal
tract, however, suggesting that an alternative mechanism was
in
play. External exchange of contaminated fluids between the genital
and rectal ori should be considered in this regard.
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FIG. 3.
Mucosal distribution of C. trachomatis in
vaginally infected mice housed under various conditions. Tissue burdens
of Chlamydia from tissues recovered 10 days postinfection
were enumerated as described in Fig. 1 and are presented as the mean
numbers of IFU ± standard errors of the means. Numbers above each
bar represent the fraction of mice displaying chlamydial colonization
at each site. Chlamydia were not recovered from lung tissues
of singly housed mice wearing restrictive Elizabethan collars.
Differences between groups were not statistically significant due to
the small size of the single, collared group.
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|
The propensity of
Chlamydia to infect contiguous as well as
noncontiguous mucosae by any of several pathways suggests that
experimental containment of infections to a single mucosal site
may be
an unrealistic goal. Indeed,
Chlamydia-infected children
from areas where trachoma is endemic also display involvement
of
multiple mucosal tissues (
12,
29), suggesting a similar
potential for bacterial spread during human infection. Further
investigations will be required to determine the relevance of
these
observations to the course of human disease. For example,
the fact that
enterically infected mice maintain approximately
4 logs of
Chlamydia per gram of large intestine for over 8 months
p.i.
with no clinical or histological evidence of disease (
23a)
raises the possibility that the intestine may act as a reservoir
for
chronic reinfection of other mucosal tissues. The degree of
mucosal
cross-protection afforded by T cells primed at a distant
mucosal site
is also poorly understood. In the present experiments,
C57BL/6 mice
infected intratracheally with 400 IFU of
C. trachomatis MoPn
consistently developed clinical signs of pneumonia that included
dyspnea, tachypnea, lethargy, and wasting. In contrast, mice infected
orally or vaginally who developed pulmonary infections as a result
of
chlamydial spread showed no clinical signs of pulmonary disease,
even
given additional time for bacterial replication to occur
(data not
shown).
The ability of
Chlamydia to spread to multiple mucosae
complicates attempts to define the inductive sites for mucosally
protective
CD4
+ T cells. However, based upon the relative
efficacies of
Chlamydia-specific
vaccines administered by
distinct mucosal routes, nonenteric mucosae
may be most important in
this regard. Thus, enteral exposure to
UV-inactivated or subunit
vaccines (
10,
32) failed to provide
significant protection
against the pathologic consequences of
a subsequent genital challenge,
even though type 1 T-cell immunity
was successfully induced
(
10). In contrast, the use of a parenteral
immunization
scheme achieved a measurable level of host protection
(
19,
32). The relative success of a nonenteric immunization
strategy
may be related to the stimulation of a population of
T cells capable of
migrating between systemic and mucosal sites
due to the shared
expression of lymphocyte-homing molecules. In
this regard, we have
shown that T cells homing to the
Chlamydia-infected
genital
mucosa express predominantly the
4
1 integrin that exhibits
binding specificity for the VCAM addressin that is expressed
systemically
as well as in the genital mucosa. In contrast, intestinal
T cells
express predominantly the
4
7 integrin, which allows
binding
to the locally expressed MAdCAM
+ addressin
(
23). Use of a VCAM-dominated homing pathway at the
genital
mucosa suggests that genital T cells may be capable of
migrating to
other VCAM-dominated tissues, such as the liver and
lung (
1,
23a-27), but not to the VCAM
, MAdCAM
+
mucosa of the gastrointestinal tract. In return,
4
1
+
T cells primed in response to systemic immunization may be capable
of
trafficking to VCAM
+ mucosae of the genital tract and lung
but not to the VCAM
intestine. Sharing of
lymphocyte-homing markers between systemic
tissues and nonenteric
mucosae suggests that the common mucosal
immune system defined for B
lymphocytes may be more complex at
the T-cell level. Further
investigations are required to address
the precise pathways of mucosal
T-cell trafficking and the potential
for inducing protection by
systemic versus mucosal vaccination
with nonreplicating
C. trachomatis immunogens.
| |
FOOTNOTES |
*
Corresponding author. Mailing address: Laboratory of
Intracellular Parasites, Rocky Mountain Laboratories, National
Institute of Allergy and Infectious Diseases, National Institutes of
Health, 903 S. 4th St., Hamilton, MT 59840. Phone: (406) 363-9272. Fax: (406) 363-9380.
Editor:
J. R. McGhee
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