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in the Innate Resistance to Infection with Chlamydia pneumoniae1
Microbiology and Tumorbiology Center, Karolinska Institutet, Stockholm, Sweden
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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R, IL-12, perforin, and
recombination-activating gene-1 (RAG-1), we analyzed the regulation and
importance of IFN- in the control of infection with
Chlamydia pneumoniae. IL-12 participates
in resistance of mice to C. pneumoniae, probably by
regulating the protective levels of IFN- mRNA. In turn, IFN- is
necessary for the increased IL-12p40 mRNA accumulation that occurs in
lungs during infection with C. pneumoniae, suggesting a
positive feedback regulation between these two cytokines. In
experiments including RAG-1-/-/IFN-R-/-
mice we showed that IFN- produced by innate cells controls the
bacterial load and is necessary for the increased accumulation of
transcripts for enzymes controlling high output NO release (inducible
NO synthase), superoxide production (gp-91 NADPH oxidase), and
catalyzis of tryptophan (indoleamine 2,3-dioxygenase (IDO)), mechanisms
probably related to bacterial killing. Adaptive immune reponses
diminish the levels of IFN- and IL-12 mRNA and thereby the levels of
inducible NO synthase, IDO, and gp91 NADPH oxidase trancripts. By using
RAG-1-/-/perforin-/- mice, we excluded the
overt participation of NK cell cytotoxicity in the control of C.
pneumoniae. However, NK cells and probably other innate immune
cells release IFN- during the bacterial
infection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C. pneumoniae provokes a similar lung pathology in humans
and rodents (5). A mouse model of infection has been used
to study the immunological mechanisms of immunity. Immunity to C.
pneumoniae proceeds in two stages: 1) an early response requiring
IFN- to limit the growth of the bacteria, and 2) a later adaptive
immune response that involves CD4+ and
CD8+ T cells in protection (6).
Still, the role that cellular and soluble components play during
chlamydial infection is not fully elucidated, nor is the relative
importance of the adaptive vs the innate arms of the immune system
early after infection.
IFN- can be induced by IL-12 but also by other cytokines such as
IL-2, IL-18, and IFN-
ß (7). The relative prevalence
of these different stimuli seems to depend on the nature of the
infecting/immunizing agent (8). IFN- can be released by
cells from both the innate and acquired immune system.
IFN-R-deficient mice show much higher susceptibility to C.
pneumoniae compared with SCID or RAG-1-/-
mice or with wild-type
(WT)3 controls,
suggesting major involvement of innate cells in the release of IFN-
(6).
Chlamydia is internalized by macrophages as well as by
"nonprofessional" phagocytes, where it survives and replicates. In
such cells, IFN- synergizes with bacterial products to activate
various bactericidal or bacteriostatic mechanisms (9, 10, 11).
IFN- is a strong activator of indoleamine 2,3-dioxygenase (IDO),
which catalyzes decyclization of L-tryptophan,
thereby limiting the availability of this amino acid to intracellular
microorganisms (12, 13, 14). Induction of IDO has been
positively correlated with inhibition of chlamydial growth in vitro
(15, 16, 17, 18, 19). IFN- can also activate inducible nitric oxide
synthase (iNOS), which catalyzes production of NO from
L-arginine (20). Inhibition of
chlamydial growth through induction of iNOS has also been reported
(9, 21, 22, 23). Stimulation of neutrophils or monocytes with
IFN- leads to induced transcription of the gp91 component of NADPH
oxidase (ox) mRNA (24, 25). Activation of this
multicomponent NADPH ox drives the respiratory burst of phagocytic
cells catalyzing the release of
O2-. The relative importance of
these effector mechanisms in the control of C. pneumoniae
infection in vivo is unknown.
We have studied in detail the involvement of IFN- in the control of
infection with C. pneumoniae. A reciprocal control of
expression between IL-12 and IFN- during C. pneumoniae
infection was found. IFN- also induced in vivo gene expression of
iNOS, IDO, and gp91 NADPH ox, all likely to be involved in destruction
of C. pneumoniae. That IFN- indeed plays this central
role in the innate control of infection with C. pneumoniae
was finally demonstrated by using RAG-1 and IFN-R single- and
double-knockout mice. In contrast, perforin-mediated lysis plays no
overt role in the innate resistance to C. pneumoniae.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mutant mouse strains without IFN-R (26),
perforin (27), recombination-activating gene-1 (RAG-1)
(28), and IL-12p40 (29) were generated by
homologous recombination in embryonic stem cells. Mice
(H-2b) underwent five to nine backcrosses with
C57BL/6 mice, which were used as controls. Mice were bred and kept
under specific pathogen-free conditions and were maintained in
isolation under negative pressure during experiments. They were used
between 6 and 10 wk of age.
Generation of RAG-1-/-/IFN-R-/- and
RAG-1-/-/ perforin-/- mice
Mice homozygous for the RAG-1-/- were
crossed with animals homozygous for either IFN-R or perforin
deficiency. The progeny was intercrossed and F2
was screened for the homozygous disrupted perforin or IFN-R genes
by PCR analysis of tail DNA lysate according to standard protocols
(26, 27) using the following primers: sense IFNR,
5'-CCC ATT TAG ATC CTA CAT ACG AAA CAT ACG G-3'; antisense IFNR,
5'-TTT CTG TCA TCA TGG AAA GGA GGG ATA CAG-3'; sense perforin, 5'-CCG
GTC CTG AAC TCC TGG CCA C-3'; antisense perforin, 5'-CCC CTG CAC ACA
TTA CTG GAA G-3'. RAG-1-/- homozygosity was
determined by absence of IgG3 in sera and by absence of peripheral
blood CD4+ cells in F2
mice.
Infection and infectivity assay
Mycoplasma-free C. pneumoniae isolate Kajaani was propagated in HL cells. Infected cells were sonicated, cell remnants were removed by centrifugation, and the bacteria were stored in small aliquots in sucrose-phosphate-glutamate solution at -70°C until used. The infectivity as measured by inclusion-forming units (IFU) of bacterial preparation was determined in HL cell culture. Mice were mildly sedated with metofane and were infected intranasally (i.n.) with 106 IFU diluted in 40 µl of PBS.
Animals were sacrificed, and right lungs were removed, minced, and mechanically homogenized in 2 ml of sucrose-phosphate-glutamate solution. Homogenates were centrifuged for 10 min at 500 x g to remove coarse tissue debris. Lysates were then diluted 10- and 100-fold in DMEM containing 5% FCS and streptomycin. The infectious titer was assayed by culturing 500 µl of duplicate dilutions of the lysates on confluent Vero cells grown on round 13-mm2 coverslides in a shell vial. Inoculated cells were centrifuged for 1 h at 1600 rpm. Thereafter, supernatant was removed and DMEM containing cycloheximide and streptomycin was added. Cells were incubated at 35°C for 72 h, fixed with methanol, and stained with a FITC-conjugated Chlamydia genus-specific mAb (Pathfinder Chlamydia Confirmation System; Kallestad Diagnostics, Chaska, MN). Inclusion bodies were counted by fluorescence microscopy. The infectivity was expressed as IFU/lung.
Competitive RT-PCR assay
The accumulation of IFN-, IL-12p40, iNOS, gp91 NADPH ox, and
ß-actin mRNA in freshly extracted left lungs from infected mice was
measured by competitive PCR assays as previously described
(30). Competitor fragments with a different length but
using the same primers as the target DNA were constructed using
composite primers (31) and an exogenous DNA fragment or by
subcloning of mutated (deleted or ligated) cytokine cDNA. Competitors
were amplified by PCR, purified (Qiagen, Studio City, CA), and
quantified in a spectrophotometer.
The primer sequences for the amplification of the cDNA were as follows:
sense iNOS, 5'-CCC TTC CGA AGT TTC TGG CAG CAG CAG C-3'; antisense
iNOS, 5'-GGC TGT CAG AGC CTC GTG GCT TTG G-3'; sense gp91 NADPH ox,
5'-CTT TGT CAT TCT GGT GTG GTT GG-3'; antisense gp91 NADPH ox, 5'-CCC
CAT TCT TCG ATT TTG TCT GC-3'; sense IFN-, 5'-TGG ACC TGT GGG TTG
TTG ACC TCA AAC TTG GC-3'; antisense IFN-, 5'-TCG ATC TTG GCT TTG
CAG CTC TTC CTC ATG GC-3'; sense IL-12p40, 5'-CGT GCT CAT GGC TGG TGC
AAA G-3'; antisense IL-12p40, 5'-CTT CAT CTG CAA GTT CTT GGG C-3';
sense ß-actin, 5'-GTG GGC CGC TCT AGG CAC CAA3'; antisense
ß-actin, 5'-CTC TTT GAT GTC ACG CAC GAT TTC-3'.
Ten- or 3-fold serial dilutions of the competitor were amplified in the presence of a constant amount of cDNA. Reactions were conducted for 28–45 cycles in a thermal cycler (Perkin-Elmer/Cetus, Norwalk, CT) using an annealing step at 60°C (except at 65°C for IL-12).
Southern blot of RT-PCR-amplified IDO transcripts
IDO transcripts were amplified from lung cDNA from individual
mice containing similar titers of ß-actin transcripts as measured in
a competitive PCR assay. The primer sequences for amplification of IDO
cDNA were as follows: sense IDO, 5'-CTG CCT CCT ATT CTG TCT TAT GC-3';
anti sense IDO, 5'-AGA CCA GAC CAT TCA CAC ACT CG-3'. After
amplification (45 cycles, annealing step at 56°C), PCR products were
subjected to electrophoresis in 1.5% agarose gels. The gels were
denatured and neutralized, and a semidry transfer onto nylon membranes
(Hybond-N; Amersham, Buckinghamshire, U.K.) was performed overnight at
room temperature as described. After baking and prehybridization in a
buffer containing 2x standard saline citrate phosphate/EDTA (SSPE),
5x Denhart’s, and 0.5% SDS for 2 h at 62°C, membranes were
hybridized with 5 x 106 cpm/membrane of
[-32P]5'-IDO probe (5'-TCT GGG AAT AAA ACA
CGA GGC TGG CAA-3') in prehybridization buffer overnight at 62°C.
After hybridization, the membranes were washed twice with 0.2x
SSPE and 0.5% SDS for 15 min at 62°C. Signal intensity of
Southern blots was scanned using a PhosphorImager (Molecular Dynamics,
Sunnyvale, CA).
NO release and measurement
NO was measured by the concentration of nitrite, the stable end product of NO synthase-generated reactive nitrogen intermediates. Peritoneal cells were adjusted to 106/ml in DMEM without phenol red. Cells were distributed in triplicate in V-shaped 96-well plates. A total of 0.5 mM L-NG-monomethyl-L-arginine (Sigma, St. Louis, MO) was then added to some of the cultures. Supernatants were sampled after 48 h for the determination of nitrite concentration using the Griess assay.
Cytotoxic assay
A total of 5 x 103 51Cr-labeled yeast artificial chromosome-1 (YAC-1), RMA, or RMA-s target cells were added to 96-well V-bottom microtiter plates containing appropriate numbers of effector cells. The plates were incubated for 4 h at 37°C. After incubation, the plates were centrifuged, and the released 51Cr in the supernatant was measured in a gamma counter. The percentage of specific lysis was calculated as follows: [(experimental release - spontaneous release)/(maximum release - spontaneous release)] cpm x 100.
Ab determinations
Outer membrane protein-2 is an abundant immunogenic protein of
C. pneumoniae. The contents of anti-outer major
protein-2 (anti-OMP-2) Abs in the sera from infected mice were
measured by ELISA. The plates were coated overnight with 0.7 µg/ml
Trx-albumin-binding protein-OMP fusion protein (6). After
blocking with 1% BSA in PBS, sera from individual mice were then added
at 1:100 or 1:400 dilutions. The plates were subsequently developed
with alkaline phosphatase-conjugated rabbit anti-mouse IgG2a or
anti-mouse IgG1 (The Jackson Laboratory, Bar Harbor, ME). The assay
was standardized between plates by including the titration of a
positive serum pool from C. pneumoniae-infected
IFN-R-/- mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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in the resistance of mice
against C. pneumoniae. IL-12 is one of the cytokines that
triggers production of IFN-, and it is believed to be important in
specific immunity by promoting Th1 cell differentiation. IFN- and
IL-12 both play a relevant role in control of C. pneumoniae
infection because lungs from IFN-R-/- or
IL-12-/- mice contained higher numbers of
bacteria than WT controls (Fig. 1
A). Lungs from C.
pneumoniae-infected IL-12-/- mice
contained lower levels of IFN- mRNA transcripts than WT controls did
(Fig. 1B). This indicates that IL-12 enhances the level of
IFN- during infection. However, IL-12-/-
mice displayed lower bacterial load than
IFN-R-/- mice did, probably due to the
remaining low, IL-12-independent IFN- release (Fig. 1A).
IFN- is the main cytokine enhancing IgG2a switching. Sera from
IL-12-/--infected mice do have diminished
levels of IgG2a but normal IgG1 (isotype regulated by IL-4)
anti-chlamydial OMP-2 Abs compared with WT mice, suggesting that
diminished levels of IFN- during infection of
IL-12-/- mice were not paralleled by an
enhanced Th2 response (Fig. 1C).
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in the innate
resistance to C. pneumoniae,
RAG-1-/-/IFN-R-/-
double knockouts were generated. The deletion of RAG-1 gene was
confirmed by the absence of IgG3 in sera and by the absence of
CD4+ cells in peripheral blood (data not shown).
The disruption of IFN-R gene was detected by PCR and confirmed by
the lack of detectable nitrite levels in supernatants of
IFN--stimulated macrophages (Fig. 2A).
RAG-1-/-/IFN-R-/-
mice showed dramatically increased bacterial load during infection with
C. pneumoniae compared with RAG-1-/-
controls. All
RAG-1-/-/IFN-R-/-
mice died within a month after infection (Fig. 2B). Deaths
were seldom recorded during infection of
IFN-R-/- mice (data not shown).
The enhanced susceptibility of
RAG-1-/-/IFN-R-/-
mice was associated with diminished levels of iNOS, gp91 NADPH ox, and
IDO mRNA compared with those of
RAG-1-/--infected controls (Fig. 3). IL-12p40 mRNA accumulation was
also dramatically diminished in lungs from
RAG-1-/-/IFN-R-/-
mice 2 and 14 days after infection with C. pneumonaie
compared with that of RAG-1-/--infected
controls, indicating that IFN- is a major inducer of IL-12p40
expression during infection with C. pneumoniae (Fig. 4).
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A). We next asked whether the
early efficient control of infection by
RAG-1-/- mice reflected a dominating
participation of innate immune responses in the WT mouse or
compensatory increases of the innate mechanims in the
RAG-1-/- mice due to the lack of the adaptive
part of the protective immune responses. IFN- and IL-12p40 mRNA
accumulations were increased in lungs from infected
RAG-1-/- mice compared with those of WT
infected controls (Fig. 5, B and C). The levels
of iNOS, gp91 NADPH ox, and IDO mRNA in lungs from
RAG-1-/- mice were also dramatically elevated
compared with those of WT infected animals (Fig. 6). Thus, the relative resistance of
RAG-1 mice early after infection is likely to be the result of an
increase of IFN- and IL-12 mRNA levels that compensates for the
absence of adaptive immune responses. Furthermore, this increase was
positively correlated with transcripts levels of IFN--inducible
effector enzymes. The data suggest the presence of protective T and
B cell-dependent immune responses early during infection of WT mice. At
later time points after infection, when T and B cells are necessary for
the control of infection, higher bacterial levels directly activating
innate immune responses could also account for the increased titers of
cytokine transcripts in RAG-1-/- mice.
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in
several protozoan and bacterial infections and might also mediate
control of infection due to their cytotoxic ability. To study the
involvement of NK cell cytotoxicity in the control of C.
pneu-moniae infection,
RAG-1-/-/perforin-/-
mice were generated and infected with the bacteria. Perforin
deficiency was confirmed by the lack of YAC-1 and RMA cytotoxicity
(Fig. 7, A and B).
Lungs from
RAG-1-/-/perforin-/-
mice contained numbers of bacteria similar to those in
RAG-1-/- controls during infection with
C. pneumoniae (Fig. 7C).
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release contributed to
control of infection with C. pneumoniae. For this purpose,
mice were i.v. administered with anti-asialo GM-1 Abs (Fig. 8, A and B).
Spleens from anti-asialo GM-1-administered mice showed a
drastically diminished NK cytotoxic activity. Susceptibility to
C. pneumoniae of RAG-1-/- mice was
not altered by anti-asialo GM-1 administration (Fig. 8C). However, lungs from anti-asialo GM-1-treated and
infected mice contained lower levels of IFN- mRNA in lungs compared
with those of normal rabbit serum-infected controls (Fig. 8D).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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.
IL-12 has been shown to participate in the control of Chlamydia
psitacci and Chlamydia trachomatis through
IFN--independent mechanisms (32, 33, 34). In the present
study, IL-12-/- mice did also display increased
susceptibility to infection with C. pneumoniae. This
increase was paralleled by diminished levels of IFN- mRNA. In
agreement, IgG2a-specific Abs were lower in
IL-12-/- infected mice compared with WT mice.
No compensatory increase of IgG1 Abs took place, thus no shift to a Th2
response was noted. The susceptibility of
IL-12-/- mice to infection with C.
pneumoniae was not as severe as that displayed by
IFNR-/- mice. Our data suggest that this
might be due to a low, IL-12-independent IFN- expression, like
during antiviral immunity (8, 35).
IFN- is known to enhance activation of IL-12p40 and p35 promoters
(36). In our study, levels of IL-12p40 mRNA are
dramatically diminished in
RAG-1-/-/IFN-R-/-
mice at 2 and 14 days after infection with C. pneumoniae
compared with RAG-1-/- controls, suggesting
that IFN- regulates IL-12 production during infection with C.
pneumoniae. Taken together, our data suggest that a positive
feedback loop controls IL-12p40 and IFN- mRNA levels during
infection with C. pneumoniae. It remains to be demonstrated
which of these cytokines acts as initiator of expression of the
counterpart during infection with C. pneumoniae.
We demonstrate that IFN- is necessary for innate resistance against
infection with C. pneumoniae. The difference in
susceptibility of IFN-R-/- mice compared
with that of
RAG-1-/-/IFN-R-/-
mice suggests that IFN--independent adaptive immune mechanisms also
participate in protection. On the other hand, such protective
adaptive immune responses may diminish IFN- and IL-12p40 gene
expression early after infection, as suggested by the enhanced IFN-
and IL-12p40 mRNA levels in RAG-1-/- compared
with WT infected mice. For instance, IL-12 has been shown to induce
IL-10 production by Th2 cells, which in turn inhibits IL-12 production
by phagocytic cells (37). Other cytokines such as IL-4,
IL-13, or TGF-ß also have been shown to inhibit IL-12 and IFN-
(7). Alternatively, an increased density of inflammatory
cells in lungs could also account for the enhanced IL-12 and IFN-
levels in RAG1-/- mice.
IFN- was necessary for accumulation of iNOS, gp91 NADPH ox, and IDO
mRNA during C. pneumoniae infection of
RAG-1-/- mice. The levels of these transcripts
were accordingly positively associated with increased levels
of IFN- and IL-12p40 mRNA in RAG-1-/-
compared with those in WT animals. The iNOS mRNA level was increased in
lungs from infected WT mice compared with the level in lungs from
noninfected controls, but no increase of gp91 NADPH ox and IDO
mRNA could be detected in the same tissues. Thus, IDO and NADPH ox are
probably not involved in resistance to infection with C.
pneumoniae in normal immunocompetent mice.
Increased susceptibility to C. pneumoniae of both
IFN-R-/- and
RAG-1-/-/IFN-R-/-
mice compared with IFN-R+/+ controls was
accompanied by a major shift in the inflammatory infiltrate
toward an abundance of neutrophils over macrophages (data not
shown). In accordance, mice given IL-12 show diminished levels of
polymorphonuclear cells during infection with C. psitacci
(34). Likewise, IFN- has been shown to promote the
formation of inflammatory exudates rich in monocytes to the relative
exclusion of granulocytes, through chemokine induction (38, 39). Whether the qualitative changes in the pathology in the
present system are due to different levels of bacterial
chemoattractants or to altered levels of IFN--regulated adhesion
molecules or chemokines (40) is a question that requires
investigation.
NK cells have been suggested to play a role during genital but
not pulmonary experimental infection with C. trachomatis
(41, 42). We demonstrate by using
RAG-1-/-/perforin-/-
mice that NK cytotoxicity does not play a relevant role in control of
C. pneumoniae. Also, NK cell depletion in
RAG-1-/- mice given anti-asialo GM-1 did
not alter the bacterial load. However, pretreatment of infected mice
with anti-asialo GM-1 diminished the level of IFN- mRNA in the
lungs, which is in line with the fact that IFN- is also released by
NK cells, as shown during infection with C. trachomatis.
Pulmonary macrophages can secrete IFN-, as shown during infection
with Mycobacterium bovis (43), and they are
likely candidates to secrete IFN- in the
RAG-1-/- anti-asialo GM-1-treated mice.
Alternatively, a small number of IFN--secreting NK cells surviving
anti-asialo GM-1 treatment could account for the nonaltered
susceptibility of the Ab-treated mice.
In conclusion, we show that IFN--mediated protection is important
for the control of infection with C. pneumoniae. IL-12
participates in resistance to C. pneumoniae, probably by
enhancing IFN- mRNA. In turn, IL-12p40 mRNA is induced by IFN-.
IFN- produced by innate cells can control the bacterial load and
increases accumulation of transcripts of enzymes controlling
high-output NO release, superoxide production, and catalyzis of
tryptophan. Adaptive immune reponses may directly or indirectly
diminish the levels of IFN- and IL-12 mRNA early after infection and
thereby may alter the quality of the protective immune responses. NK
cell cytotoxicity is not necessary for the control of C.
pneumoniae, but NK cells and probably other innate immune cells
release IFN- during infection with C. pneumoniae.
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Acknowledgments |
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R-/- mice were provided by Dr.
M. Aguet (Institute of Molecular Biology, University of Zurich,
Zurich, Switzerland). We also thank Benedict Chambers for his comments
to our manuscript. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Martín E. Rottenberg, Microbiology and Tumorbiology Center, Karolinska Institutet, S-171 77 Stockholm, Sweden.
3 Abbreviations used in this paper: WT, wild type; IDO, indoleamine 2,3-dioxygenase; iNOS, inducible nitric oxide synthase; ox, oxidase; RAG-1, recombination-activating gene-1; IFU, inclusion-forming unit; OMP, outer major protein; i.n., intranasal(ly).
Received for publication November 8, 1999. Accepted for publication February 17, 2000.
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 M. D. de Kruif, E. C.M. van Gorp, T. T. Keller, J. M. Ossewaarde, and H. ten Cate Chlamydia pneumoniae infections in mouse models: relevance for atherosclerosis research Cardiovasc Res, February 1, 2005; 65(2): 317 - 327. [Abstract] [Full Text] [PDF]
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 G.L. Biscione, J. Corne, A.J. Chauhan, and S.L. Johnston Increased frequency of detection of Chlamydophila pneumoniae in asthma Eur. Respir. J., November 1, 2004; 24(5): 745 - 749. [Abstract] [Full Text] [PDF]
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M. G. Netea, B. J. Kullberg, L. E. H. Jacobs, T. J. G. Verver-Jansen, J. van der Ven-Jongekrijg, J. M. D. Galama, A. F. H. Stalenhoef, C. A. Dinarello, and J. W. M. Van der Meer Chlamydia pneumoniae Stimulates IFN-{gamma} Synthesis through MyD88-Dependent, TLR2- and TLR4-Independent Induction of IL-18 Release J. Immunol., July 15, 2004; 173(2): 1477 - 1482. [Abstract] [Full Text] [PDF]
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 K. A. Swanson, Y. Zheng, K. M. Heidler, T. Mizobuchi, and D. S. Wilkes CDllc+ Cells Modulate Pulmonary Immune Responses by Production of Indoleamine 2,3-Dioxygenase Am. J. Respir. Cell Mol. Biol., March 1, 2004; 30(3): 311 - 318. [Abstract] [Full Text] [PDF]
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A. G. Rothfuchs, M. R. Kreuger, H. Wigzell, and M. E. Rottenberg Macrophages, CD4+ or CD8+ Cells Are Each Sufficient for Protection against Chlamydia pneumoniae Infection through their Ability to Secrete IFN-{gamma} J. Immunol., February 15, 2004; 172(4): 2407 - 2415. [Abstract] [Full Text] [PDF]
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D. J. Mitchell, H. Q. Huynh, P. J. M. Ceponis, N. L. Jones, and P. M. Sherman Helicobacter pylori Disrupts STAT1-Mediated Gamma Interferon-Induced Signal Transduction in Epithelial Cells Infect. Immun., January 1, 2004; 72(1): 537 - 545. [Abstract] [Full Text] [PDF]
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A. L. Mellor, B. Baban, P. Chandler, B. Marshall, K. Jhaver, A. Hansen, P. A. Koni, M. Iwashima, and D. H. Munn Cutting Edge: Induced Indoleamine 2,3 Dioxygenase Expression in Dendritic Cell Subsets Suppresses T Cell Clonal Expansion J. Immunol., August 15, 2003; 171(4): 1652 - 1655. [Abstract] [Full Text] [PDF]
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E. Eriksson, L. Dons, A. G. Rothfuchs, P. Heldin, H. Wigzell, and M. E. Rottenberg CD44-Regulated Intracellular Proliferation of Listeria monocytogenes Infect. Immun., July 1, 2003; 71(7): 4102 - 4111. [Abstract] [Full Text] [PDF]
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T. E. Toliver-Kinsky, C. Y. Lin, D. N. Herndon, and E. R. Sherwood Stimulation of Hematopoiesis by the Fms-Like Tyrosine Kinase 3 Ligand Restores Bacterial Induction of Th1 Cytokines in Thermally Injured Mice Infect. Immun., June 1, 2003; 71(6): 3058 - 3067. [Abstract] [Full Text] [PDF]
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 C. Fieschi, S. Dupuis, E. Catherinot, J. Feinberg, J. Bustamante, A. Breiman, F. Altare, R. Baretto, F. Le Deist, S. Kayal, et al. Low Penetrance, Broad Resistance, and Favorable Outcome of Interleukin 12 Receptor {beta}1 Deficiency: Medical and Immunological Implications J. Exp. Med., February 17, 2003; 197(4): 527 - 535. [Abstract] [Full Text] [PDF]
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J. Yang, W. C. Hooper, D. J. Phillips, M. L. Tondella, and D. F. Talkington Induction of Proinflammatory Cytokines in Human Lung Epithelial Cells during Chlamydia pneumoniae Infection Infect. Immun., February 1, 2003; 71(2): 614 - 620. [Abstract] [Full Text] [PDF]
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B. Wizel, B. C. Starcher, B. Samten, Z. Chroneos, P. F. Barnes, J. Dzuris, Y. Higashimoto, E. Appella, and A. Sette Multiple Chlamydiapneumoniae Antigens Prime CD8+ Tc1 Responses That Inhibit Intracellular Growth of This Vacuolar Pathogen J. Immunol., September 1, 2002; 169(5): 2524 - 2535. [Abstract] [Full Text] [PDF]
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X. Huang, S. A. McClellan, R. P. Barrett, and L. D. Hazlett IL-18 Contributes to Host Resistance Against Infection with Pseudomonas aeruginosa Through Induction of IFN-{gamma} Production J. Immunol., June 1, 2002; 168(11): 5756 - 5763. [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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N. M. Silva, C. V. Rodrigues, M. M. Santoro, L. F. L. Reis, J. I. Alvarez-Leite, and R. T. Gazzinelli Expression of Indoleamine 2,3-Dioxygenase, Tryptophan Degradation, and Kynurenine Formation during In Vivo Infection with Toxoplasma gondii: Induction by Endogenous Gamma Interferon and Requirement of Interferon Regulatory Factor 1 Infect. Immun., February 1, 2002; 70(2): 859 - 868. [Abstract] [Full Text] [PDF]
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A. Gigliotti Rothfuchs, D. Gigliotti, K. Palmblad, U. Andersson, H. Wigzell, and M. E. Rottenberg IFN-{alpha}{beta}-Dependent, IFN-{gamma} Secretion by Bone Marrow-Derived Macrophages Controls an Intracellular Bacterial Infection J. Immunol., December 1, 2001; 167(11): 6453 - 6461. [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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Y. Jin, L. Dons, K. Kristensson, and M. E. Rottenberg Neural Route of Cerebral Listeria monocytogenes Murine Infection: Role of Immune Response Mechanisms in Controling Bacterial Neuroinvasion Infect. Immun., February 1, 2001; 69(2): 1093 - 1100. [Abstract] [Full Text] [PDF]
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