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-Mediated Inhibition
Laboratory of Intracellular Parasites, Immunology Section, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rocky Mountain Laboratory, Hamilton, MT 59840
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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and
TNF-
. The relative contribution of IFN- is controversial,
however, due to variation in results presented by different
laboratories. To determine whether C. trachomatis strain
differences contributed to this apparent conflict, the relative
resistance of IFN--deficient mice to murine and human strains of
C. trachomatis was compared. All human serovars were
much more sensitive to the direct inhibitory actions of IFN- than
the MoPn strain. Furthermore, genital clearance of human serovar D in
the C57BL/6 mouse was mediated by class II-independent mechanisms that
probably involved local production of IFN- by cells of the innate
immune system. TNF- also contributed indirectly to host resistance
against all strains tested. The differential susceptibility of distinct
C. trachomatis strains to effector cytokines such as
IFN- could not have been predicted by interstrain biologic variation
or by the profile of cytokines stimulated during infection. These
findings indicate that strain variation should be considered in
situations where related isolates of a given parasite produce
conflicting data in models of infection and immunity. They also suggest
that stimulation of mucosal IFN- activity is a relevant goal for a
human chlamydial vaccine. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNF-, and other proinflammatory cytokines
3, 10 .
The potential contributions of IFN- and/or TNF- to chlamydial
resistance have been analyzed in vivo and in vitro in an effort to
identify the molecular mechanisms of cytokine action. Monoclonal
Ab-mediated neutralization of IFN- enhanced host susceptibility to
chlamydial respiratory infection 21, 22, 23 , although resistance could
not consistently be restored by passive administration of recombinant
cytokine 21 . In vitro, IFN- inhibited the growth of C.
psittaci 24 and C. trachomatis LGV 25 by an
oxygen-independent process 26 that reduced the replication of
intracellular reticulate bodies 27, 28 . Two IFN--inducible,
oxygen-independent pathways to be considered in this regard are the
indoleamine 2,3-dioxygenase (IDO) pathway, which involves IDO-driven
conversion of tryptophan to N-formylkynurenine to limit
tryptophan availability 29, 30 , and the inducible nitric oxide
synthase (iNOS) pathway for generating toxic nitrogen radicals lethal
to a variety of intracellular pathogens 31, 32, 33, 34, 35 . The IDO-driven,
tryptophan reversible pathway was implicated in IFN--mediated
inhibition of C. psittaci replication in human cells 36, 37 , whereas the iNOS effector pathway was credited with
IFN--mediated, nonreversible inhibition of C. trachomatis
L2 growth in murine fibroblasts 38, 39 , consistent with the species
distribution of these effector pathways. The relevant action of TNF-
has been more difficult to localize, its contribution being more
readily demonstrable in vivo 11, 40 than in vitro 41 . Further
evaluation of its relevance to host resistance is warranted.
The notion that IFN-- and/or TNF--driven pathways mediated
similar levels of resistance to all chlamydial strains was recently
challenged by publication of conflicting reports on the recovery
profiles of IFN--deficient 42 or IFN- receptor-deficient mice
43 . Johansson et al. 44 determined that IFN- receptor gene
knockout mice (IFN-R-/-) developed more severe primary
genital tract infections than control animals and displayed no acquired
resistance to rechallenge. At the same time, Perry et al. 3 and
Cotter et al. 4 reported minimal effects of an IFN- deficiency on
the resolution of genital infections, despite macrophage-mediated
dissemination of bacteria to systemic organs. One critical difference
between these experimental systems was the use of C.
trachomatis serovar D by one lab 44 and C.
trachomatis MoPn by the other two 3, 4 . The possibility that
distinct chlamydial isolates might exhibit differential sensitivities
to IFN- or other type 1 cytokines implicated in host resistance
formed the basis for the present studies, where strain-specific
susceptibilities were directly compared in vivo and in vitro.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal C57BL/6 mice were purchased from The Jackson Laboratory
(Bar Harbor, ME). MHC class II-deficient
(Abß-/-) mice on a C57BL/6
background were purchased from Taconic Farms (Germantown, NY). Breeding
pairs of iNOS-deficient mice on a 129/J x C57BL/6 background were
obtained from Carl Nathan (Cornell University Medical College, New
York, NY). Breeding pairs of IFN--deficient mice 42 were
obtained through the courtesy of Tim Stewart (Genentech, San Francisco,
CA). TNFRp55-deficient mice (TNFR-/-) 45 were
obtained through the generosity of Werner Lesslauer (Hoffmann-LaRoche,
Basel, Switzerland) and acquired from the colony of David Erle
(University of California at San Francisco, San Francisco, CA).
IL-12p40-deficient mice 46 were obtained through the kindness of
Jeanne Magram (Hoffmann-LaRoche, Nutley, NJ). Animals were bred in an
Association for Assessment and Accreditation of Laboratory Animal Care
accredited facility in filter-top cages and maintained using standard
precautions for immunodeficient mouse strains. Experiments utilizing
IFN--/- and TNFR-/- knockout mice were
performed twice, and experiments using iNOS-/-,
Abß-/-, and
IL-12p40-/- mice performed once using eight to ten
animals per group. Only female mice were used in the reported
experiments.
Growth of Chlamydia and infection protocol
C. trachomatis strains serovar D, serovar L2, and MoPn were grown in HeLa 229 cells, and elementary bodies (EB) were purified by discontinuous density centrifugation as previously described 47 . Infection of the uterine mucosa could be readily achieved by either vaginal or intrauterine inoculation with MoPn but only by intrauterine inoculation with human chlamydial strains. Therefore, mice pretreated with progesterone were infected vaginally with 1.5 x 103 inclusion-forming units (IFU) MoPn in 5 µl of a sucrose-sodium phosphate-glutamic acid buffer (SPG) as previously described 3 or by direct intrauterine inoculation of 105 IFU serovar D or serovar L2 in 30 µl of SPG by midline celiotomy under methoxyflurane anesthesia (Metofane; Mallinckrodt Veterinary, Mundelein, IL), followed by closure with surgical staples (9-mm Autoclips; Roboz, Rockville, MD). Infections were monitored by enumerating IFUs recovered from swabbing the vaginal vault with Calgiswabs (Spectrum Medical Industries, Los Angeles, CA) on HeLa cell monolayers using indirect immunofluorescence as described previously 10 .
Ab and cytokine assays
Serum and vaginal washes collected 18 days postinfection were isotyped by ELISA against homologous heat-killed EBs (56°C for 30 min) using alkaline phosphatase-conjugated anti-mouse Ig sera (Southern Biotechnology Associates, Birmingham, AL) as described previously 10 . Cytokines produced by splenic mononuclear cells after 72-h in vitro restimulation with homologous heat-killed EBs were also assayed by ELISA using capture and detection mAbs from PharMingen (San Diego, CA) as previously described 3 . Local cytokine production was measured by primer-directed RT-PCR amplification of Trizol-extracted (Life Technologies, Grand Island, NY) genital tract RNA followed by agarose gel analysis of PCR products as described previously 3 .
Effects of exogenous IFN- on chlamydial growth in vitro
Duplicate cultures of murine L-929 fibroblast cells or
intestinal epithelial cells (IEC4.1) 48 were established in 96-well
plates (5 x 104 cells/well) in Eagle’s MEM or
modified Ham’s medium, respectively, supplemented with 10% FCS and 10
µg/ml gentamicin sulfate. Cells were cultured for 24 h in
varying concentrations of murine rIFN- or TNF- (Genzyme,
Cambridge, MA) and then washed and infected with C.
trachomatis strains MoPn, D, or L2 at multiplicities of infection
(MOIs) that resulted in 
20% of the cells being infected (equivalent
to an MOI of 0.25). Monolayers were refed with medium containing the
homologous cytokine for an additional 24–48 h and then fixed in
absolute methanol, stained with chlamydial specific Ab, and IFU
determined 49 . Alternatively, cell monolayers were removed with
trypsin, and the cells were washed, lysed, and assayed for chlamydial
growth by titration of IFU from clarified supernatants on HeLa 229 cell
monolayers. In certain experiments, the reversibility of
IFN--mediated inhibition was examined by washing infected cultures
after 24 h of incubation in IFN- and either refeeding with
IFN--free medium or adding 0.0125–3.2 mM of the iNOS competitive
inhibitor NG-monomethyl-L-arginine
(MLA) (Calbiochem, San Diego, CA). Cells were fixed and stained 24–72
h later by immunofluorescence for IFU determination. The effect of
IFN- was considered to be chlamydiacidal if inhibition was
nonreversible or chlamydiastatic if inhibition was reversible.
Statistical analyses
Differences between groups were analyzed for statistical significance using Student’s two-tailed t test.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Normal C57BL/6 mice were infected genitally with doses of C.
trachomatis MoPn or serovar D chosen to maximize the
respective infections. Systemic and local immune responses were
measured 18 days postinfection. Serum Abs were predominately of the
IgG2 and IgG3 isotypes with little to no detectable IgG1, a profile
consistent with stimulation of type 1 immune responses (Fig. 1
A). Systemic (Fig. 1B) and local (Fig. 1C) cytokine responses were
also Th1-biased as reflected by the production of proinflammatory
cytokines IFN- and TNF-, but not traditional Th2 cytokines IL-4
and IL-5, consistent with previous reports in MoPn-infected mice 3 .
IL-10, a Th2-derived regulatory cytokine that is produced simultaneous
with IFN- in certain parasitic infections 50 , was also expressed.
Thus, host immune responses induced following infection of the genital
mucosa with C. trachomatis MoPn or serovar D were markedly
similar and reflected a strong bias toward type 1 T cell-mediated
immunity.
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and TNF- on chlamydial
clearance in vivo
The relative contributions of two prominent proinflammatory
cytokines, IFN- and TNF-, to immune-mediated clearance of murine
and human chlamydial strains from the genital mucosa was directly
compared in groups of normal and gene-deficient mice. Shedding of MoPn
from genital epithelial cells diminished at a similar rate in normal
and IFN--deficient mice (Fig. 2),
indicating the relative IFN- insensitivity of this murine strain. In
contrast, genital clearance of the human serovar D strain was severely
compromised in IFN--/- mice (Fig. 2). Normal mice
resolved serovar D genital infections within 7–10 days, while
IFN--/- mice required nearly 50 days. Similar results
were obtained following infection with the L2 serovar of LGV (data not
shown), indicating a critical role for IFN- in the clearance of
infections with human but not the murine C. trachomatis
strain. Documentation of such distinct differences in strain
susceptibility to IFN--mediated immunity in vivo was unexpected and,
to our knowledge, not previously reported in the field of parasite
immunity.
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on the resolution of genital infections
with human and murine chlamydial strains was evaluated in similar
experiments using mice bearing targeted mutations in the TNF- p55
receptor molecule. Infection of these mice or their immunologically
competent counterparts with serovar D or MoPn revealed a marginal but
statistically significant reduction in the rate of chlamydial clearance
from TNFR-/- mice (Fig. 2
, lower panels).
Since IFN- and TNF- exhibit some functional overlap, the ability
to detect the loss of either cytokine alone suggests that
cytokine-specific as well as shared mechanistic pathways may be
operative in mediating chlamydial clearance from the genitourinary
tract.
Differential influence of IFN- and TNF- on chlamydial growth
in vitro
To determine the extent to which the IFN- susceptibility
displayed by serovars D and L2 extended to other human isolates, an in
vitro system was established to monitor the effects of added cytokines
on intracellular replication and inclusion formation. Inclusion
formation by human serovars D or L2 was inhibited in a dose-dependent
manner by the addition of species-specific IFN- to human HeLa 229
cells, murine L-929 fibroblasts, or murine IEC4.1 epithelial cells
(Fig. 3, A–C). The
remaining human chlamydial serovars (serovars A through K) exhibited
similar levels of inhibition (data not shown). This was shown to
reflect IFN--mediated inhibition of chlamydial growth, as determined
by diminished recovery of infectious EB from clarified lysates of
IFN--treated, serovar D-infected cells (Fig. 3D). Failure
to reverse this inhibition by removal of cytokine-containing medium
indicated that IFN- was microbicidal rather than microbistatic after
20 h of exposure (data not shown). Inclusion formation by the
murine MoPn strain was highly sensitive to inhibition by human rIFN-
in human HeLa 229 cells but was suppressed only 50–60% by murine
rIFN- in murine fibroblasts or epithelial cells (Fig. 3, A–C). Sensitivity of human but not a murine
chlamydial strain to inhibition by murine IFN- correlates with the
differential dependence of these isolates on IFN--mediated clearance
in vivo (Fig. 2). Data also suggest species-specific adaptation of the
MoPn strain to the inhibitory effect of IFN-.
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had no measurable effect on in vitro growth of
MoPn, serovar D, or serovar L2 at concentrations sublethal for the host
IEC4.1 cell line (data not shown). While these data argue against a
direct inhibitory role for TNF- on chlamydial growth, they do not
rule out an indirect contribution in vivo by activation of other cells
and/or factors present in the environment of the genital mucosa.
Role of nitric oxide effector pathway in IFN--mediated
chlamydial inhibition
Resolution of MoPn genital infections was previously shown to
occur very efficiently in the absence of IFN--inducible nitric oxide
synthase 51, 52 , the enzyme required for initiation of the nitric
oxide effector pathway 53 . Unlike MoPn, however, serovar D displayed
a high degree of sensitivity to IFN--induced effector mechanisms,
mechanisms that could involve the generation of toxic nitrogen radicals
within the cytoplasm of infected cells. To test this possibility, in
vivo clearance of serovar D was compared in normal mice and in mice
lacking a functional iNOS gene (Fig. 4A). Resolution of infections
was only slightly delayed in iNOS-/- mice and only during
the final stages of clearance when small numbers of
Chlamydia persisted. The failure of the
L-arginine competitive inhibitor, MLA, to reverse
IFN--mediated inhibition of serovar D growth in vitro confirmed that
activation of the nitric oxide pathway was not the primary mechanism of
IFN- action (Fig. 4B). Since it could be argued that
results obtained using these murine cell lines were not relevant to
IFN--induced pathways in human cells, the capacity of human IFN-
to induce transcription of iNOS in HeLa cells was evaluated by RT-PCR.
No signal was detected (data not shown), however, indicating that
IFN--mediated inhibition of chlamydial growth in human cells also
occurred through an iNOS-independent mechanism.
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required for inhibition of human chlamydial
strains
The rapid clearance of serovar D from the normal genital mucosa,
occurring often within 1 wk of infection, afforded minimal
opportunities for induction, expansion, and recruitment of protective
CD4+ T cells to the genital mucosa. Given strain
differences in chlamydial sensitivity to IFN-, the potential for
differential dependence on MHC class II-restricted, IL-12-driven type 1
T cells as the relevant source of effector cytokines also had to be
considered. The relative role of this pathway was evaluated by
comparing resolution of serovar D infections in normal mice, in MHC
class II deficient mice (which, in the C57BL/6 strain, can be
accomplished by mutation of the Abß gene), or
in IL-12p40-deficient mice (Fig. 5).
While slight enhancement of infection was observed in either of these
gene knockout mice as compared with control animals, effects were much
less dramatic than were previously noted with the MoPn strain. MHC
class II knockout mice maintained high level genital tract infections
with MoPn for the entire 70-day observation period 10 , and
IL-12p40-deficient mice displayed extended MoPn infections lasting up
to 50 days (results obtained by mAb-mediated cytokine depletion 3
were similar to those obtained using these IL-12p40 knockout mice (data
not shown)). Yet the effect of these deletions on clearance of serovar
D was marginal. The absence of class II-associated functions in
Abß-/- mice was confirmed by
the failure to detect T cell-dependent switching of serum Ig isotypes
and the absence of systemic IFN- responses following infection.
Nevertheless, Abß-/- mice
generated a local IFN- response that was detected by RT-PCR
amplification of genital tract RNA (Fig. 6) and that presumably mediated host
resistance to epithelial infection. The local cellular source of
IFN- in these mice has not yet been identified.
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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are
distinct; human C. trachomatis serovars D and L2 were highly
sensitive and the mouse MoPn relatively resistant to IFN--mediated
inhibition in vitro and in vivo in the murine host. The
IFN--sensitivity defined for the D and L2 strains extended to all
human serovars, rendering MoPn somewhat unique among C.
trachomatis isolates in its diminished sensitivity to this
pleiotropic mediator. Much less variation was observed in strain
sensitivity to TNF- since genital clearance was marginally delayed
in TNF--deficient mice, regardless of the infecting strain.
TNF--mediated inhibition of chlamydial growth and/or clearance could
not be demonstrated in vitro, however, suggesting that the relevant
action of this cytokine was indirect and required additional cells or
mediators not present in the in vitro culture system. Collectively, it
appeared that both IFN- and TNF- contribute to chlamydial
resistance in vivo with the relative contribution of IFN- being
strain-dependent.
Differential susceptibilities of human vs murine C.
trachomatis strains to inhibition by murine IFN- could not have
been predicted from the spectrum of immunological responses evoked
during infection with either organism. In both cases, the distribution
of serum Ig isotypes and the panel of cytokines produced locally and
systemically were similar and differed only in magnitude, most likely
as a reflection of the abbreviated course of human C.
trachomatis infections in the murine host. The capacity of
Chlamydia or any pathogen to induce a wide array of T and B
cell responses does not necessarily imply equal susceptibility to their
action, however. This can now be appreciated in the
Chlamydia system where human but not murine isolates are
highly sensitive to murine IFN-, a finding that resolves the
conflict between the results of Johansson et al. 44 and those
of Perry et al. 3 and Cotter et al. 4 .
The sensitivity of C. trachomatis serovar D to
IFN--mediated inhibition may explain the rapid clearance of this
strain from the urogenital mucosa of normal as well as immunodeficient
mice. Animals carrying targeted mutations in MHC class II or IL-12p40
genes resolved serovar D infections at nearly the same rate as intact
control mice, presumably due to IFN- produced locally by NK or other
cells of the innate immune system. This contrasts sharply with the
clearance of MoPn, which is strictly CD4+ T cell-dependent
10 . The implications of these differences for continued use of the
MoPn murine system as a model for human urogenital infection are
unclear since the immunological parameters of human infections have not
been defined. The fact that human C. trachomatis strains
have retained sensitivity to human IFN- suggests that IFN- may
participate in the resolution of human urogenital infections, but
whether it is derived from cells of the innate or acquired immune
systems is unknown. Given these uncertainties, the murine MoPn model of
urogenital infection may be appropriate for analyses of cellular events
leading to induction and expression of a type 1 T cell response, but it
is poorly suited to investigations of IFN--driven effector
pathway(s). Similarly, MoPn would be a poor choice of strains to test
the efficacy of vaccines designed to stimulate a protective IFN-
response.
These data predict that IFN- may play a major role in the
elimination of C. trachomatis from the human genital mucosa
in vivo. If so, the relative ability of each individual to mount an
efficacious IFN- response through either innate or acquired pathways
could have a profound influence on the clinical outcome of infection.
For example, NK cell-derived IFN- may provide a rapid defense
against primary infection that dramatically decreases the infectious
burden of Chlamydia, but the associated reduction in Ag load
could also terminate prematurely the induction of an acquired memory T
cell response capable of protecting the host against reinfection. In
this regard, repeated or persistent chlamydial infections have been
implicated as possible bases for the development of uterine pathology
that leads to infertility and pelvic inflammatory disease 54, 55 . On
the other hand, when innate IFN- sources are insufficient and
clearance depends upon stimulation of Ag-specific T cells, genetic and
environmental factors that influence the induction of type 1 vs type 2
T cell reactivity may dictate the pathological consequences of
infection. Evidence supporting such a dichotomy of clinical responses
has already been provided in individuals suffering from trachoma, an
ocular disease induced by C. trachomatis infection of the
conjunctival mucosa. Individuals with persistent infection and severe
pathological scarring displayed increased production of type 2
cytokines, such as IL-4 56 , whereas the type 1 inducing cytokine,
IL-12, was detected only in patients who presented with inflammation
but no scarring 12 . Evaluation of host cytokine profiles associated
with acute vs chronic stages of sexually transmitted chlamydial
infections may provide similar insights into the immunopathological
basis of human genital disease.
The molecular mechanisms ultimately responsible for elimination
of MoPn or human C. trachomatis strains from the uterine
mucosa have yet to be defined. Unlike other commonly studied
intracellular parasites, C. trachomatis resides within a
parasitophorous vacuole in the cytoplasm of mucosal epithelial cells
rather than macrophages and is, therefore, eliminated by chlamydiacidal
pathways operative in the microenvironment of epithelial cells. To
date, only two IFN--inducible pathways have documented relevance to
the intracellular killing of Chlamydia: induction of nitric
oxide synthase 57 and IDO-driven tryptophan depletion 36 . While
mice infected with either human or murine C. trachomatis
strains synthesized iNOS, in vivo clearance of either infection
proceeded normally in the absence of this pathway (Fig. 4, and 51 . Neither can IFN--mediated inhibition of chlamydial growth be
reversed by addition of an iNOS competitive inhibitor. The IDO pathway
is also an unlikely candidate for consideration since mice lack a
functional IDO gene. Therefore, the possibility that an alternative, as
yet undefined, pathway may represent the lethal step in chlamydial
replication must be considered.
Data presented herein are compatible with the notion that
resistance or susceptibility of C. trachomatis strains to
IFN--mediated effector pathways is not static but has evolved in a
species-specific manner. Thus, the murine strain displays greater
sensitivity to human IFN- than to endogenous murine IFN-, while
human strains are more sensitive to murine IFN- than to human
IFN-, when compared on a quantitative basis (compare Fig. 3, A and B, with Fig. 3C). That human
strains have retained some level of sensitivity to human IFN- may
simply reflect the fact that these isolates have had less time to adapt
to host IFN--driven effector pathways than their rodent
counterparts, but the process is probably ongoing. In preparation for
the possible development of IFN--resistant human strains, it may be
prudent to investigate the IFN--independent mechanism(s) involved in
the clearance of MoPn infections as well as the IFN--dependent
mechanism(s) now active against human strains. It should also be
considered that immune-mediated selection of IFN--resistant variants
may contribute to chlamydial persistence in the human host.
Although this is the first report documenting interstrain
variation in parasite susceptibility to the molecular effector
mechanisms of cell-mediated immunity in vivo, Chlamydia may
not be the only parasite that displays this level of diversity.
Differential susceptibility of Leishmania species to in
vitro killing by lymphokine-activated macrophages has been noted by
Scott et al. 58 . The Neal strain of L. tropica but not the
Maria strain of L. mexicana amazonensis was susceptible to
macrophage microbicidal activity following cellular activation by a
factor later identified as IFN- (P. Scott, unpublished
observations). It was postulated that resistance of the Maria
strain to IFN--mediated killing may underlie the chronic, nonhealing
nature of lesions induced by this organism, while the sensitivity of
L. tropica to IFN--driven effector mechanisms may provide
the molecular basis for the self-healing nature of those lesions 58 .
Variation in the in vitro sensitivity of different clinical isolates of
Mycobacteria avium to peroxide-induced killing within human
monocytes has also been reported 59 , as well as strain differences,
in the induction of IFN- by Plasmodium yoelii 60 .
Thus, it may no longer be appropriate to assume that results obtained
using a given strain of bacteria or protozoa are relevant to all
strains within that species, or that animal isolates will behave
similarly to those obtained from human sources in all respects.
Analysis of the molecular basis for IFN--induced growth inhibition
and for the killing of strains resistant to IFN- may also provide
new insights into the array of host-defense mechanisms available
against human pathogens.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Harlan D. Caldwell, Laboratory of Intracellular Parasites, Rocky Mountain Laboratory, 903 South 4th Street, Hamilton, MT 59840. E-mail address:
3 Abbreviations used in this paper: LGV, lymphogranuloma venereum; MoPn, mouse pneumonitis; IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxide synthase; EB, elementary body; IFU, inclusion-forming unit; MLA, NG-monomethyl-L-arginine.
Received for publication July 6, 1998. Accepted for publication December 7, 1998.
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 D. E. Nelson, D. P. Virok, H. Wood, C. Roshick, R. M. Johnson, W. M. Whitmire, D. D. Crane, O. Steele-Mortimer, L. Kari, G. McClarty, et al. Chlamydial IFN-{gamma} immune evasion is linked to host infection tropism PNAS, July 26, 2005; 102(30): 10658 - 10663. [Abstract] [Full Text] [PDF]
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 J M Lyons, J I Ito Jr, A S Pena, and S A Morre Differences in growth characteristics and elementary body associated cytotoxicity between Chlamydia trachomatis oculogenital serovars D and H and Chlamydia muridarum J. Clin. Pathol., April 1, 2005; 58(4): 397 - 401. [Abstract] [Full Text] [PDF]
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 S. Bas and C. Gabay Reply Rheumatology, February 1, 2004; 43(2): 250 - 251. [Full Text] [PDF]
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T. Darville, J. M. O'Neill, C. W. Andrews Jr., U. M. Nagarajan, L. Stahl, and D. M. Ojcius Toll-Like Receptor-2, but Not Toll-Like Receptor-4, Is Essential for Development of Oviduct Pathology in Chlamydial Genital Tract Infection J. Immunol., December 1, 2003; 171(11): 6187 - 6197. [Abstract] [Full Text] [PDF]
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R. P. Morrison and H. D. Caldwell Immunity to Murine Chlamydial Genital Infection Infect. Immun., June 1, 2002; 70(6): 2741 - 2751. [Full Text] [PDF]
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S. Dessus-Babus, T. L. Darville, F. P. Cuozzo, K. Ferguson, and P. B. Wyrick Differences in Innate Immune Responses (In Vitro) to HeLa Cells Infected with Nondisseminating Serovar E and Disseminating Serovar L2 of Chlamydia trachomatis Infect. Immun., June 1, 2002; 70(6): 3234 - 3248. [Abstract] [Full Text] [PDF]
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J.-L. Perfettini, T. Darville, A. Dautry-Varsat, R. G. Rank, and D. M. Ojcius Inhibition of Apoptosis by Gamma Interferon in Cells and Mice Infected with Chlamydia muridarum (the Mouse Pneumonitis Strain of Chlamydia trachomatis) Infect. Immun., May 1, 2002; 70(5): 2559 - 2565. [Abstract] [Full Text] [PDF]
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G. Entrican, S. Wattegedera, M. Chui, L. Oemar, M. Rocchi, and C. McInnes Gamma Interferon Fails To Induce Expression of Indoleamine 2,3-Dioxygenase and Does Not Control the Growth of Chlamydophila abortus in BeWo Trophoblast Cells Infect. Immun., May 1, 2002; 70(5): 2690 - 2693. [Abstract] [Full Text] [PDF]
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T. Darville, C. W. Andrews Jr., J. D. Sikes, P. L. Fraley, L. Braswell, and R. G. Rank Mouse Strain-Dependent Chemokine Regulation of the Genital Tract T Helper Cell Type 1 Immune Response Infect. Immun., December 1, 2001; 69(12): 7419 - 7424. [Abstract] [Full Text] [PDF]
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L. Del Rio, A. J. Buendia, J. Sanchez, M. C. Gallego, M. R. Caro, N. Ortega, J. Seva, F. J. Pallares, F. Cuello, and J. Salinas Endogenous Interleukin-12 Is Not Required for Resolution of Chlamydophila abortus (Chlamydia psittaci Serotype 1) Infection in Mice Infect. Immun., August 1, 2001; 69(8): 4808 - 4815. [Abstract] [Full Text] [PDF]
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K. H. Ramsey, G. S. Miranpuri, I. M. Sigar, S. Ouellette, and G. I. Byrne Chlamydia trachomatis Persistence in the Female Mouse Genital Tract: Inducible Nitric Oxide Synthase and Infection Outcome Infect. Immun., August 1, 2001; 69(8): 5131 - 5137. [Abstract] [Full Text] [PDF]
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J. U. Igietseme and A. Murdin Induction of Protective Immunity against Chlamydia trachomatis Genital Infection by a Vaccine Based on Major Outer Membrane Protein-Lipophilic Immune Response-Stimulating Complexes Infect. Immun., December 1, 2000; 68(12): 6798 - 6806. [Abstract] [Full Text] [PDF]
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S. G. Morrison, H. Su, H. D. Caldwell, and R. P. Morrison Immunity to Murine Chlamydia trachomatis Genital Tract Reinfection Involves B Cells and CD4+ T Cells but Not CD8+ T Cells Infect. Immun., December 1, 2000; 68(12): 6979 - 6987. [Abstract] [Full Text] [PDF]
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K. H. Ramsey, J. L. DeWolfe, and R. D. Salyer Disease Outcome Subsequent to Primary and Secondary Urogenital Infection with Murine or Human Biovars of Chlamydia trachomatis Infect. Immun., December 1, 2000; 68(12): 7186 - 7189. [Abstract] [Full Text] [PDF]
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S. A. Morre, J. M. Lyons, J. I. Ito Jr., and R. P. Morrison Murine Models of Chlamydia trachomatis Genital Tract Infection: Use of Mouse Pneumonitis Strain versus Human Strains Infect. Immun., December 1, 2000; 68(12): 7209 - 7211. [Full Text] [PDF]
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R. P. Morrison Differential Sensitivities of Chlamydia trachomatis Strains to Inhibitory Effects of Gamma Interferon Infect. Immun., October 1, 2000; 68(10): 6038 - 6040. [Abstract] [Full Text] [PDF]
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T. Darville, C. W. Andrews Jr., and R. G. Rank Does Inhibition of Tumor Necrosis Factor Alpha Affect Chlamydial Genital Tract Infection in Mice and Guinea Pigs? Infect. Immun., September 1, 2000; 68(9): 5299 - 5305. [Abstract] [Full Text] [PDF]
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S. G. Morrison and R. P. Morrison In Situ Analysis of the Evolution of the Primary Immune Response in Murine Chlamydia trachomatis Genital Tract Infection Infect. Immun., May 1, 2000; 68(5): 2870 - 2879. [Abstract] [Full Text] [PDF]
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J. U. Igietseme, G. A. Ananaba, J. Bolier, S. Bowers, T. Moore, T. Belay, F. O. Eko, D. Lyn, and C. M. Black Suppression of Endogenous IL-10 Gene Expression in Dendritic Cells Enhances Antigen Presentation for Specific Th1 Induction: Potential for Cellular Vaccine Development J. Immunol., April 15, 2000; 164(8): 4212 - 4219. [Abstract] [Full Text] [PDF]
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