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Microbiology and Tumorbiology Center, Karolinska Institute, Stockholm, Sweden
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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mRNA accumulation in lungs. In line with this,
IFN-R-/- (but not TNFRp55 -/-) mice
showed dramatically increased susceptibility to C.
pneumoniae, linked to reduced inducible nitric oxide synthase
(iNOS) mRNA accumulation, but not to diminished levels of specific Abs.
The increased susceptibility of iNOS-/- mice indicates a
protective role for iNOS activity during infection with C.
pneumoniae. The higher sensitivity of IFN-R-/-
mice to C. pneumoniae compared with that of SCID or
recombination-activating gene-1-/- mice suggested a
relevant protective role of IFN--dependent innate mechanisms of
protection. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Multiple arms of the immune system are activated in response to infection with microorganisms. Although the primary immune response to infection is designed to clear the primary infection from the body and to provide protection against reinfection with the same pathogen, generation of tissue injury may also ensue, as exemplified by the sensitization to a more severe disease in individuals vaccinated against Chlamydia trachomatis 6 . Protective or adverse effects depend not only on the specific Ag(s) but also on the immune effector mechanisms that are mobilized. Furthermore, diverse innate immune mechanisms not only constitute a first barrier against pathogens, but also dictate the quality of the clonally dependent mechanisms elicited. Thus, knowledge of these mechanisms is central in vaccine design. In this context, a mouse model of C. pneumoniae pneumonitis showing extensive similarities to human disease has been recently developed 7, 8 . However, the arms of the immune response that participate in the outcome of the primary infection with C. pneumoniae have not been investigated.
In the present study we have compared the consequence of infection with C. pneumoniae in mice genomically lacking T cell coreceptors, cytokine receptors, and cytotoxic effector molecules. We propose different involvement(s) for these molecules in the outcome of C. pneumoniae pneumonitis.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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Mutant mouse strains without CD4 9 , CD8 10 , IFN-R 11 ,
TNF receptor p55 (TNFRp55) 12 , perforin 13 ,
recombination-activating gene-1
(RAG-1)3, 14 , TAP-1 15 ,
ß2-microglobulin (ß2m) 16 , Aß
(H2b) MHC II 17 , and inducible nitric oxide synthase
(iNOS) 18 were generated by homologous recombination in embryonic
stem cells. Mice (H2b) underwent several backcrosses (five
to nine) with C57BL/6 mice, which were used as controls. Unless
otherwise indicated, mice possess the B6 background. Mice heterozygous
for both the CD4 and the CD8 mutation
(CD4+/CD8+/-) were mated, and the offspring
were selected for the absence of both loci 19 .
TAP-1-/-/ß2m-/- were
similarly obtained 20 . SCID and CD8-/- animals were
backcrossed with BALB/c mice. 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. B6-Aß (H2b) mice were purchased from Tachonic
(Germantown, NY).
Mycoplasma-free C. pneumoniae isolate Kajaani 21 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 the bacterial preparation was determined in HL cell culture. Mice were mildly sedated with metofane and inoculated intranasally with 106 IFU diluted in 40 µl of PBS.
Infectivity assay
Mice 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 (DMEM). 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 an 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 per lung.
Competitive PCR assay
The accumulation of iNOS, IFN-, IL-10, and ß-actin mRNA in
freshly extracted lungs from infected mice was measured by competitive
PCR assays as previously described 22 . Competitor fragments with a
different length but using the same primers as the target DNA were
constructed using composite primers 23 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: 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 IFN-, 5'-AAC GCT ACA CAC TGC ATC TTG G-3'; antisense
IFN-, 5' GAC TTC AAA GAG TCT GAG G-3'; sense IL-10, 5'-GAG AGC TCT
GTC TAG GTC-3'; antisense IL-10, 5'-CGG GAA GAC AAT AAC TG-3'; sense
ß-actin, 5'-GTG GGC CGC TCT AGG CAC CAA-3'; and antisense ß-actin,
5'-CTC TTT GAT GTC ACG CAC GAT TTC-3'.
Ten- or threefold 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 58°C for IL-10).
Southern blot of RT-PCR-amplified IL-4 transcripts
IL-4 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 IL-4 cDNA were: sense IL-4, 5'-ATG GGT CTC AAC CCC CAG CTA-3'; and antisense IL-4, 5'-GCT CTT TAG GCT TTC CAG GAA GTC-3'.
After amplification (45 cycles, annealing step at 60°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, Aylesbury, U.K.) was performed overnight at room
temperature as previously described 24 . After baking and
prehybridization in a buffer containing 2x SSPE, 5x Denhart’s
solution, and 0.5% SDS for 2 h at 62°C, membranes were
hybridized with 5 x 106 cpm/membrane of
[32P]5'-IL-4 probe (5'-GTA GGG CTT CCA AGG TGC TTC GCA
TAT TT-3') in prehybridization buffer overnight at 62°C. The labeling
of the probe with [-32P]ATP was catalyzed by T4
polynucleotide kinase. After hybridization, the membranes were washed
twice with 0.2x SSPE and 0.5% SDS for 15 min at 62°C. The signal
intensity of Southern blots was quantitated using a PhosphorImager
(Molecular Dynamics, Sunnyvale, CA).
Isolation, purity, and passive transfer of T cells
CD4+ and CD8+ T cell and
CD4+ T cell suspensions were prepared from spleens from
uninfected BALB/c or BALB/c CD8-/- mice. Briefly, spleen
cell suspensions were obtained and washed once with RPMI 1640 medium
containing 5% heat-inactivated FCS, 100 U/ml of penicillin, 100
µg/ml of streptomycin, and 5 x 10-5 M 2-ME
(RPMI-5% FCS). RBC were removed by hypotonic shock, and the remaining
cells were washed twice in cold RPMI-5% FCS. Cells were filtered
through a nylon wool column, and B cells were depleted by using
anti-B220-coated magnetic beads (Dynabeads, Dynal, Oslo, Norway).
The resulting population contained >95% 
ß+ T cells
and <2% B cells (anti-Ig+) as analyzed by flow
cytometry. Rhodamine-labeled mouse anti-ß mAbs (PharMingen,
San Diego, CA) or FITC-labeled anti-mouse Igs (Dakopatts, Glostrup,
Denmark) were used for this purpose. More than 95% of such purified
cells from BALB/c CD8-/- mice were stained with
anti-CD4 Abs (PharMingen). SCID mice were reconstituted with T
cells in 0,2 ml of PBS 24 h before intranasal inoculation of
C. pneumoniae. Mononuclear infiltrates were detected in
infected SCID reconstituted mice but not in unreconstituted controls.
Recombinant outer membrane protein-2 (OMP-2) production
The C. pneumoniae OMP-2 gene (GenBank accession no. X5311) was amplified by PCR using pKTH339 (a gift from M. Sarvas, National Public Health Institute, Helsinki, Finland) as a template. The signal sequence was deleted from the template, and the OMP-2 gene was cloned into a pTrx-ABP expression vector (J. Nilsson, unpublished observations). The DNA sequence was confirmed. The pTrx-ABP encodes a 26-kDa affinity fusion partner consisting of Escherichia coli thioredoxin (Trx) protein 25 and an albumin binding protein (ABP) derived from streptococcal protein G.
E. coli BL-21 (DE3, Novagen, Madison, WI) harboring pTrx-ABP-OMP sequences were grown overnight at 37°C in 100 ml Luria broth supplemented with 100 mg/l ampicillin. Thereafter, culture was diluted 1/100 in Luria broth and grown for 3–5 h. Expression of the recombinant fusion protein was induced by adding of isopropyl-ß-D-thiogalactosidase. Protein production continued for 4–5 h at room temperature until bacteria reached an OD600 nm of 1.8–3. Cells were then centrifuged, and pellets were frozen at -20°C; thawed; resuspended in 50 mM Tris-HCl, 0.2 mM NaCl, and 0.05% Tween (pH 7.5); and sonicated. The sonicated cells were then centrifuged, and the supernatant was collected and applied to a human serum albumin-Sepharose column (Pharmacia). The size and purity of Trx-ABP-OMP were verified by SDS-PAGE and were further confirmed by Western blot.
Ab determinations
The contents of anti-OMP.2 Abs in the sera from infected
mice were measured by ELISA. The plates were coated overnight with 0.7
µg/ml of Trx-ABP-OMP fusion protein. After blocking, sera from
individual mice were then added at 1/100 or 1/400 dilutions. The plates
were subsequently developed with horseradish peroxidase-conjugated
rabbit anti-mouse IgG (-chain specific; Sigma, St. Louis, MO) or
anti-mouse IgM (µ-chain specific; Sigma). The assay was
standardized between plates by including the titration of pooled sera
from C. pneumoniae-infected IFN-R-/- mice.
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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). Similar levels of
bacteria were found in lungs from MHC II- and wild-type
mice, corroborating data from CD4- mice (Fig. 2). Furthermore, a higher number of IFU
was found in CD8-/- than in
CD4-/-/CD8-/- or SCID (which lack mature T
and B cells) mice on days 14 and 24 after infection (Fig. 1). However,
both T cell populations seem to play a protective role during late
infection (60 days after infection; Fig. 1A) or reinfection
(Fig. 1B) as indicated by the higher IFU in lungs of
CD4-/-/CD8-/- mice compared with the level
in single mutants. Thus, our data indicate that early after infection
(14 and 24 days) CD4+ T cells, in fact, promote bacterial
growth in the absence of CD8+ T cells. Also, BALB/c
CD8-/- mice showed a 10-fold higher bacterial load than
controls, indicating that CD8+ T cell-mediated protection
against C. pneumoniae infection is not restricted to the B6
strain (Fig. 3). To confirm data obtained
from CD8- mice, we infected
TAP-1/ß2m-deficient mice, lacking both MHC class
I-restricted CD8+ T cells and CD1-restricted T cells. These
mice also showed enhanced susceptibility compared with wild-type mice
(Fig. 4).
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). Although different Th cell
responses might occur after the transfer of different numbers of cells
26 , our data obtained after inoculation of a constant number of
different cell populations support the conclusions obtained with
genomically deficient mice.
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). We likewise detected higher levels of
IL-4 mRNA in lungs from CD8-/- mice than in B6 mice at 14
days after infection (Fig. 8). On the
contrary, levels of IFN- mRNA were lower in CD8-/-
mice compared with those in B6 mice at 7, but not 14, days after
infection, suggesting a delayed kinetics of production (Fig. 7). More
direct evidence that IFN- made a significant contribution to the
clearance of bacteria was obtained in IFN-R-/- mice
lacking IFN- signaling. IFN-R-/- mice showed
100-fold increased bacterial load compared with B6 counterparts
throughout the infection (Fig. 9). The
susceptibility of IFN-R-/- mice largely exceeded that
of B and T cell-deficient RAG-1-/- mice, suggesting an
important role for non-T cell-mediated IFN--producing cells in the
resistance against C. pneumonmiae (Fig. 9). Resistance to
infection was not associated with increased titers of specific Abs, as
higher titers of anti-OMP.2 IgG were detected in sera from
susceptible IFN-R-/- mice than in those from B6
controls (Fig. 10). Moreover,
TNFRp55-/- mice displayed similar susceptibility to
infection as controls but showed diminished levels of specific IgG,
further suggesting that Abs play no major role in control of C.
pneumoniae (Fig. 10). To analyze whether increased susceptibility
of IFN-R- mice was due to an altered differentiation of
Th cells, IL-4 and IL-10 transcripts were measured. Similar levels of
IL-10 mRNA were found in lungs from IFN-R- mice
(54 ± 26 mol of IL-10/mol of ß-actin mRNA x
10-3; n = 4) and wild-type controls
(33 ± 23 mol of IL-10/mol of ß-actin mRNA x
10-3 ± SEM; n = 4) 14 days after
infection with C. pneumoniae. Levels of IL-4 in both strains
were not different from those in noninfected controls, suggesting that
these mice do not mount a polarized Th2 response. The susceptibility of
IFN-R-/- mice was associated with diminished levels of
iNOS mRNA accumulation in lungs (Fig. 11). To determine whether the
iNOS-mediated high output of NO activity plays a role in resistance to
C. pneumoniae, iNOS-/- mice were infected.
iNOS-deficient mice showed higher sensitivity to infection with
C. pneumoniae than B6 controls, but were not as susceptible
as IFN-R-/- mice (Fig. 11).
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Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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CD8+ T cells are particularly prominent in mucosal tissues,
where they may provide a first line of defense against potential
pathogens, fulfilling an immunological gatekeeper function. The
conventional view of CD8+ T cells has primarily been as
killers of infected cells by direct cytolysis or actors via secretion
of cytokines such as IFN- and TNF-. The primary cytolytic
mechanism of lymphocytes involves the release of perforin-containing
granules upon contact with target cells 13, 27 . We showed that such a
mechanism is not necessary for CD8-mediated protection against C.
pneumoniae infection, since perforin-/- mice show a
normal course of infection. In line with this, infection with another
intracellular microorganism, Mycobacterium tuberculosis, is
also normal in perforin- or granzyme-deficient mice 28 . Thus, it
seems more likely that the ability of CD8+ T cells to
release certain cytokines can down-modulate disease activity during
C. pneumoniae infection, as also suggested for infection
with C. trachomatis 29 . Different functional subsets of
CD4+ T cells have been described based on the cytokines
produced by these T cells, Th1 CD4+ T cells that secrete
IL-2 and IFN-, and Th2 T cells that secrete IL-4, IL-5, and IL-10.
We found that the early higher susceptibility of CD8-deficient mice
correlates with an immune deviation from the normal Th1 response to
a Th2 cytokine pattern, characterized by high IL-10 and IL-4 and a
delayed accumulation of IFN- mRNA in lungs from infected mice
ex vivo. The increased resistance to early infection with C.
pneumoniae of CD4-/-/CD8-/-
compared with CD8-/- mice coupled with lower levels of
IL-10 mRNA suggest that CD8+ T cells normally tilt a
CD4-mediated immune response from a Th2- to a protective Th1- or
Th0-like phenotype. In line with this, CD8+ T cells from
rats and mice suppress IgE production and thereby regulate allergic
immune responses, by modifying the CD4+ T cell cytokine
pattern 30, 31, 32 . Moreover, CD8+ T cells have been shown to
prevent Th2 responses in murine Schistosoma infection 33 ,
and depletion of CD8+ T cells in young nonobese diabetic
mice prevents the onset of insulitis 34 .
Bacterial load in lungs from SCID or RAG-1-/- mice show
no difference compared with wild-type counterparts early (7 and 14
days) after infection. Both SCID and RAG-1-/- mice show
higher levels of IFN- mRNA than wild-type infected controls,
indicating a role for compensatory innate mechanisms in mice lacking T
and B cells and suggesting the participation of acquired immune
mechanisms early after infection (data not shown). Thus, we propose
that CD4+ in the absence of CD8+ T cells would
inhibit immune mechanisms of chlamydial control early after infection.
Concordingly, Th2-derived cytokines such as IL-4, IL-10, and TGF-ß
have been shown to inhibit IFN--dependent microbicidal mechanisms of
macrophages 35 . In line with this, a major involvement of
IFN--dependent innate mechanisms in the control of infection with
C. pneumoniae is suggested by the higher susceptibility of
IFN-R-/- mice compared with SCID or
RAG-1-/- infected mice. Identification of non-T cell,
IFN--producing cells in these mice remains to be elucidated.
Interestingly, CD4+ T cells seem to play a dual role, promoting bacterial growth and disease early after infection, but participating in the control of bacterial growth at later time points as well as in protection against reinfection. Moreover, the role of CD4+ T cells might have been underestimated (from involved to necessary in late control of infection), since CD4-/- mice possess MHC class II restricted T cells incapable of mounting a Th2 response 9, 36, 37 that might be protective. Also, CD8+ T cells seem to suffer qualitative changes; they inhibit a deleterious role of CD4+ T cells early (14–24 days) after infection but seem to participate participate in direct protection later (60 days) after infection or during reinfection.
Our data demonstrate a major contribution of IFN- in the control of
infection with C. pneumoniae, as also shown during
infections with other species of Chlamydia 38, 39 .
Accordingly, mice treated intranassaly with eukaryotic expression
plasmids encoding IFN- or IL-12, but not the backbone plasmid alone,
showed increased resistance against infection with C.
pneumoniae (data not shown). Interestingly, the presence of
IFN- did not result in a major manner change in the cytokine
pattern, since lung tissues from IFN-R-/- and control
animals showed similar IL-4 and IL-10 mRNA levels. However, reduced
levels of iNOS transcripts were noticed in lungs of infected
IFN-R-/- mice. Moreover, iNOS-/- mice
showed increased susceptibility to C. pneumoniae. Nitric
oxide produced after cell activation by cytokines is important for
killing or inhibiting the growth of various microorganisms 40 .
However, a protective role of iNOS during infection with other
chlamydial species is controversial, being found by some 41 but
disregarded by others 42 . The presence of both iNOS-dependent and
-independent IFN--mediated effector mechanisms is suggested by the
fact that although iNOS-/- mice are more susceptible than
B6 controls, IFN-R-/- mice show diminished resistance
to C. pneumoniae compared with iNOS-/-
mutants. The identification of iNOS-independent chlamydiotoxic
mechanisms remains to be elucidated. To our mind, induction of
indoleamine-2,3-dioxygenase, a tryptophan-decyclizing enzyme, may
account for the IFN--mediated protection, as it is responsible for
inhibition of chlamydial growth in IFN--treated human cells
43 .
TNF activity is regulated by two homodimeric receptors with molecular masses of 55 and 75 kDa. TNFRp75 has been implicated in thymocyte proliferation and apoptosis, whereas TNFRp55 appears responsible for most of the biological functions of TNF 44 . TNFRp55 participates in creating resistance to parasites, fungi, and intracellular bacteria, as shown by the increased susceptibility of TNFRp55-/- mice to infections with Leishmania, Listeria, Candida, Trypanosoma, and Mycobacterium 12, 45, 46, 47 . It was therefore surprising that infection of mice with C. pneumoniae was largely unaffected by TNFRp55 deficiency. TNFRp55-/- mice show a lack of primary follicles and aberrant germinal center formation and are thereby defective in Ig- switch and affinity maturation 48, 49 . We confirmed such Ig switch deficiency, also suggesting a subordinate role for specific Abs in the resistance to C. pneumoniae.
To our knowledge, this manuscript constitutes the first immunogenetic analysis of the roles of acquired and innate components of the immune response in an experimental infection with C. pneumoniae. Extensive differences are apparent when comparing our data with those obtained in experimental infections with C. trachomatis. In infections with the later microorganism, a predominant role for CD4+ class II-restricted cells in protection has been shown, whereas a protective role for CD8+ T cells is controversial 29, 50, 51 . Such differences are not surprising, as the two organisms display only 5 and 10% homology at the DNA and protein levels, respectively, as also reflected in the different pathobiologies of these infections 52 .
In conclusion, our data illustrate the relevance of CD4+ T
cells in advocating bacterial growth and pathology early after
infection. Such deleterious activity is transient, as CD4+
T cells play a protective role later during infection. CD8+
T cells inhibit this CD4+ T cell early activity.
CD8+ T cell protection is perforin independent and
associated with an altered cytokine balance as indicated by increased
IL-4 and IL-10 and delayed accumulation of IFN- mRNA in
CD8-/- mice. Accordingly, IFN-R and thereby IFN-
(but not TNF-Rp55) molecules play a relevant role in protection
against C. pneumoniae. IFN-R-requiring resistance was
associated with iNOS induction, but not with the induction of specific
Abs. iNOS activity played a protective role during infection with
C. pneumoniae, although it accounts only partially for
IFN--mediated protection.
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Acknowledgments |
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R-/- mice were provided
by Dr. M. Aguet (Institute of Molecular Billogy, University
of Zurich, Zurich, Switzerland). We thank P. H. Mäkelä
(National Public Health Institute, Helsinki, Finland) for her comments
on the manuscript. |
Footnotes |
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2 Address correspondence and reprint requests to Dr. Martín Rottenberg, Microbiology and Tumor Biology Center, Karolinska Institute, S-171 77 Stockholm, Sweden. E-mail address:
3 Abbreviations used in this paper; RAG-1, recombination-activating gene-1; iNOS, inducible nitric oxide synthase; IFU, inclusion-forming units; OMP2, outer membrane protein-2; Trx, thioredoxin; ABP, albumin binding protein; ß2m, ß2-microglobulin.
Received for publication May 11, 1998. Accepted for publication October 30, 1998.
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C. S. Little, A. Bowe, R. Lin, J. Litsky, R. M. Fogel, B. J. Balin, and K. L. Fresa-Dillon Age Alterations in Extent and Severity of Experimental Intranasal Infection with Chlamydophila pneumoniae in BALB/c Mice Infect. Immun., March 1, 2005; 73(3): 1723 - 1734. [Abstract] [Full Text] [PDF]
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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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A. L. Gervassi, K. H. Grabstein, P. Probst, B. Hess, M. R. Alderson, and S. P. Fling Human CD8+ T Cells Recognize the 60-kDa Cysteine-Rich Outer Membrane Protein from Chlamydia trachomatis J. Immunol., December 1, 2004; 173(11): 6905 - 6913. [Abstract] [Full Text] [PDF]
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 E. S. Gold, R. M. Simmons, T. W. Petersen, L. A. Campbell, C.-C. Kuo, and A. Aderem Amphiphysin IIm Is Required for Survival of Chlamydia pneumoniae in Macrophages J. Exp. Med., September 7, 2004; 200(5): 581 - 586. [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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S. F. Fischer, T. Harlander, J. Vier, and G. Hacker Protection against CD95-Induced Apoptosis by Chlamydial Infection at a Mitochondrial Step Infect. Immun., February 1, 2004; 72(2): 1107 - 1115. [Abstract] [Full Text] [PDF]
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B. B Chesebro, E. Blessing, C.-C. Kuo, M. E Rosenfeld, M. Puolakkainen, and L. A. Campbell Nitric oxide synthase plays a role in Chlamydia pneumoniae-induced atherosclerosis Cardiovasc Res, October 15, 2003; 60(1): 170 - 174. [Abstract] [Full Text] [PDF]
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J. Xu, R. Lucas, M. Schuchmann, S. Kuhnle, T. Meergans, A. P. Barreiros, A. W. Lohse, G. Otto, and A. Wendel GM-CSF Restores Innate, But Not Adaptive, Immune Responses in Glucocorticoid-Immunosuppressed Human Blood In Vitro J. Immunol., July 15, 2003; 171(2): 938 - 947. [Abstract] [Full Text] [PDF]
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 U. Airaksinen, T. Penttila, E. Wahlstrom, J. M. Vuola, M. Puolakkainen, and M. Sarvas Production of Chlamydia pneumoniae Proteins in Bacillus subtilis and Their Use in Characterizing Immune Responses in the Experimental Infection Model Clin. Vaccine Immunol., May 1, 2003; 10(3): 367 - 375. [Abstract] [Full Text] [PDF]
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L. R. San Mateo, M. M. Chua, S. R. Weiss, and H. Shen Perforin-Mediated CTL Cytolysis Counteracts Direct Cell-Cell Spread of Listeria monocytogenes J. Immunol., November 1, 2002; 169(9): 5202 - 5208. [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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A. Saren, S. Pascolo, S. Stevanovic, T. Dumrese, M. Puolakkainen, M. Sarvas, H.-G. Rammensee, and J. M. Vuola Identification of Chlamydia pneumoniae-Derived Mouse CD8 Epitopes Infect. Immun., July 1, 2002; 70(7): 3336 - 3343. [Abstract] [Full Text] [PDF]
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 J. Huang, F. J. DeGraves, S. D. Lenz, D. Gao, P. Feng, D. Li, T. Schlapp, and B. Kaltenboeck The quantity of nitric oxide released by macrophages regulates Chlamydia-induced disease PNAS, March 19, 2002; 99(6): 3914 - 3919. [Abstract] [Full Text] [PDF]
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 L.C. von Hertzen Role of persistent infection in the control and severity of asthma: focus on Chlamydia pneumoniae Eur. Respir. J., March 1, 2002; 19(3): 546 - 556. [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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S. Prebeck, C. Kirschning, S. Durr, C. da Costa, B. Donath, K. Brand, V. Redecke, H. Wagner, and T. Miethke Predominant Role of Toll-Like Receptor 2 Versus 4 in Chlamydia pneumoniae-Induced Activation of Dendritic Cells J. Immunol., September 15, 2001; 167(6): 3316 - 3323. [Abstract] [Full Text] [PDF]
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 G. Caligiuri, M. Rottenberg, A. Nicoletti, H. Wigzell, and G. K. Hansson Chlamydia pneumoniae Infection Does Not Induce or Modify Atherosclerosis in Mice Circulation, June 12, 2001; 103(23): 2834 - 2838. [Abstract] [Full Text] [PDF]
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 R. Coutinho-Silva, J.-L. Perfettini, P. M. Persechini, A. Dautry-Varsat, and D. M. Ojcius Modulation of P2Z/P2X7 receptor activity in macrophages infected with Chlamydia psittaci Am J Physiol Cell Physiol, January 1, 2001; 280(1): C81 - C89. [Abstract] [Full Text] [PDF]
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S. Halme, J. Latvala, R. Karttunen, I. Palatsi, P. Saikku, and H.-M. Surcel Cell-Mediated Immune Response during Primary Chlamydia pneumoniae Infection Infect. Immun., December 1, 2000; 68(12): 7156 - 7158. [Abstract] [Full Text] [PDF]
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 B. Agerberth, J. Charo, J. Werr, B. Olsson, F. Idali, L. Lindbom, R. Kiessling, H. Jornvall, H. Wigzell, and G. H. Gudmundsson The human antimicrobial and chemotactic peptides LL-37 and alpha -defensins are expressed by specific lymphocyte and monocyte populations Blood, November 1, 2000; 96(9): 3086 - 3093. [Abstract] [Full Text] [PDF]
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P. Liuba, P. Karnani, E. Pesonen, I. Paakkari, A. Forslid, L. Johansson, K. Persson, T. Wadstrom, and R. Laurini Endothelial Dysfunction After Repeated Chlamydia pneumoniae Infection in Apolipoprotein E-Knockout Mice Circulation, August 29, 2000; 102(9): 1039 - 1044. [Abstract] [Full Text] [PDF]
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M. E. Rottenberg, A. Gigliotti Rothfuchs, D. Gigliotti, M. Ceausu, C. Une, V. Levitsky, and H. Wigzell Regulation and Role of IFN-{gamma} in the Innate Resistance to Infection with Chlamydia pneumoniae J. Immunol., May 1, 2000; 164(9): 4812 - 4818. [Abstract] [Full Text] [PDF]
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J. M. Vuola, V. Puurula, M. Anttila, P. H. Makela, and N. Rautonen Acquired Immunity to Chlamydia pneumoniae Is Dependent on Gamma Interferon in Two Mouse Strains That Initially Differ in This Respect after Primary Challenge Infect. Immun., February 1, 2000; 68(2): 960 - 964. [Abstract] [Full Text] [PDF]
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 S. SINGH, S J. WORT, and T. W EVANS Inducible nitric oxide and pulmonary infection Thorax, November 1, 1999; 54(11): 959 - 960. [Full Text]
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