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Cutting Edge |
,
* Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892;
Section of Immunobiology, Yale University School of Medicine and
Howard Hughes Medical Institute, New Haven, CT 06520; and
Department of Microbiology and Immunology, Cornell University College of Veterinary Medicine, Ithaca, NY 14853
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResults and DiscussionReferences |
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Introduction |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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In the present study, we have further examined the possible involvement
of TLR in innate immunity to protozoa, focusing on the induction of
host resistance to the apicomplexan parasite Toxoplasma
gondii. During early infection, this parasite stimulates a potent
IL-12 response that leads to IFN-
-dependent control of its
replication (4). In turn, a series of in vitro and in vivo
studies have demonstrated that dendritic cells (DC), as well as
neutrophils and IFN--primed macrophages, produce IL-12 in response
to parasite stimulation (5, 6, 7). More recently, the
chemokine receptor CCR5 has been shown to play a major role in T.
gondii-induced IL-12 production by DC (8).
Correlating with this observation, CCR5-deficient animals exhibit
increased susceptibility to the parasite (8), succumbing
by 20 days postinfection (J. Aliberti and A. Sher, unpublished
data).
To determine the possible function of TLR in the induction of IL-12-dependent host resistance to T. gondii, we tested the requirement for the TLR-associated adapter protein MyD88 in control of parasite infection. MyD88 has been shown to be a critical signaling element for most TLR as well as IL-1R family-triggered responses (9), and APC from MyD88-deficient mice have been shown to mount defective IL-12 responses to a number of microbial stimuli (10, 11, 12). As reported here, MyD88-deficient mice infected with T. gondii displayed a complete loss in acute resistance to infection, a defect associated with impaired IL-12 production by DC, macrophages, and neutrophils. These findings implicate TLR triggering as a critical step in the initiation of innate immunity to T. gondii and in the case of DC argue that full induction of IL-12 by this pathogen involves both G protein-coupled and MyD88-dependent signaling pathways.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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MyD88-/-, TLR-2-/-, and TLR-4-/- mice (13, 14, 15) on a partially backcrossed 129/Ola x C57/Bl6 background were kindly provided by Drs. S. Akira (Osaka University, Osaka, Japan) and D. T. Golenbock (University of Massachusetts, Worcester, MA). These animals, along with CCR5-/- mice (16), were bred and maintained at an American Association of Laboratory Animal Care-accredited National Institute of Allergy and Infectious Diseases animal facility. Wild-type control mice (129/Ola x C57BL/6) were obtained from The Jackson Laboratory (Bar Harbor, ME). Mice of both sexes between 5 and 12 wk old were used for experiments.
Parasites, experimental infection, and treatments
Mice were infected with 20 cysts of the avirulent ME49 T. gondii strain by i.p. inoculation and cumulative mortality was determined (17). In vivo tachyzoite growth was assessed at 5 days after infection by microscopic examination of Diff-Quik (Dade Behring, Newark, DE)-stained cytocentrifuge smears of peritoneal exudate cells (PEC) (17). RH strain T. gondii tachyzoites were maintained in tissue culture as previously described (6) and used to prepare soluble tachyzoite Ag (STAg) (18). For in vivo stimulation of DC, mice were i.p. injected with 5 µg STAg or with PBS alone, and spleens were harvested 6 h later (19). In some experiments, mice received pertussin toxin (PTx, 400 ng i.v.) 30 min before STAg or PBS injection (20).
Cell isolation and in vitro stimulation
For measurement of ex vivo cytokine production, single-cell suspensions were prepared from spleens and PEC 5 days after infection. PEC were cultured at 4 x 105 cells/well in 200 µl and spleen cells at 4 x 106 cells/well in 1 ml medium in the presence or absence of STAg (5 µg/ml) and supernatants were collected 3 days later. In some wells, 20 µg/ml blocking mAb to CD4 (GK1.5) and CD8 (2.43) were added to assess the contribution of these T cell subsets as previously described (21).
Neutrophils were isolated from bone marrow of noninfected mice as
described elsewhere (22) and plated at 2–2.5 x
106 cells/well. Cells were 95% neutrophils based
on microscopic examination of stained preparations. Peritoneal
macrophages were prepared from thioglycolate-elicited PEC
(17) by overnight plating at 4 x
105 cells/well in the presence or absence of 100
U/ml murine rIFN- (Genentech, South San Francisco, CA) as a priming
signal followed by removal of nonadherent cells. DC were isolated by
low-density separation of collagenase-treated spleen (5)
and plated at 1 x 106 cells/well.
For in vitro stimulation, macrophages and DC were exposed to STAg (20 µg/ml) and neutrophils to either STAg (100 µg/ml) or live RH tachyzoites (1 x 106/well). Supernatants were collected at 16 h for cytokine measurements.
IL-12 and IFN- measurements
IL-12p40 and IFN- levels were assayed by ELISA as previously
described (17). IL-12p70 was measured using a commercial
ELISA kit (R&D Systems, Minneapolis, MN).
Statistical analyses
The statistical significance of differences in data means was analyzed using an unpaired, two-tailed Student’s t test.
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Results and Discussion |
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TopAbstractIntroductionMaterials and MethodsResults and DiscussionReferences |
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To evaluate the role of MyD88 in host resistance to T.
gondii, MyD88 -/- and control mice were
infected with cysts of the avirulent ME49 parasite strain and survival
of the animals was monitored. In contrast to control mice that survived
for >60 days, MyD88-deficient animals succumbed to acute infection,
dying between 13 and 16 days after parasite inoculation (Fig. 1
). The latter mortality kinetics closely
resemble those observed for similarly infected IL-12p40-deficient mice
(Fig. 1). Since mortality during acute T. gondii infection
can result either from uncontrolled inflammation (23) or
increased parasite replication (17), we also assessed
parasite burden in the same animals by enumerating parasitized PEC 5
days postinoculation. A dramatic increase in parasite load was seen in
the MyD88-/- vs control mice which was
comparable to, if not exceeding, that observed in the
IL-12p40-deficient mice (Fig. 1, inset). Thus, MyD88 plays
an essential role in host resistance by influencing the control of
T. gondii replication.
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responses
Host resistance to T. gondii in the murine model is
mediated by IL-12-dependent IFN- production (24). To
determine whether impaired resistance of
MyD88-/- mice stems from a defect in this
pathway, we measured IL-12 and IFN- in plasma from 5-day infected
mice. The Myd88-/- mice displayed greatly
reduced levels of plasma IL-12p40 (Fig. 2A) and IL-12p70 (data not
shown). Plasma IFN- levels in MyD88-deficient mice also were much
lower relative to control animals (Fig. 2B). Nevertheless,
IFN- production in the MyD88-/- mice was
significantly greater than that observed in IL-12p40-deficient animals
(Fig. 2B). To confirm this defect at the cellular level, we
examined IFN- production by spleen cells from the same animals after
in vitro restimulation with STAg. MyD88-deficient animals showed
dramatically reduced IFN- production, again slightly elevated over
that displayed by IL-12p40-deficient mice (Fig. 2C).
Experiments adding blocking Abs to CD4 and/or CD8 to these cultures
indicated that the IFN- response of control mice is only partially
dependent on T cells (Fig. 2C), consistent with the
previously described role of NK cells as a major source of this
cytokine during acute infection (4, 7). In contrast, the
residual response seen in the MyD88-/- mice was
found to be totally CD4+ T lymphocyte dependent
(Fig. 2C).
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Previous studies have demonstrated that macrophages, DC, as well
as neutrophils produce IL-12 in response to stimulation with T.
gondii in vitro (7, 8, 25) and, in the case of DC and
neutrophils, in vivo (6, 8). To examine whether MyD88
controls IL-12 responsiveness in one or more of these cell types,
highly enriched bone marrow-derived neutrophils, splenic DC, and
thioglycolate-elicited peritoneal macrophages were stimulated in vitro
with STAg or live tachyzoites and IL-12p40 production was measured by
ELISA. The STAg-induced IL-12 response observed in IFN--primed
macrophages from control mice was completely absent in comparable cell
populations from MyD88-deficient mice (Fig. 3A). IL-12 responsiveness was
also greatly impaired in neutrophils from
MyD88-/- mice stimulated in vitro with either
live tachyzoites or with STAg (Fig. 3B). Finally, the IL-12
response of splenic DC was highly reduced in the absence of MyD88 (Fig. 3C) but not to the extent seen in
MyD88-/- macrophages and neutrophils. A similar
reduction in the DC cytokine response was observed when IL-12p70 was
measured rather than p40 (Fig. 3D).
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Since DC are thought to represent an important cell population in
the initiation of cell-mediated immunity to T. gondii
(5), we further investigated the effect of MyD88 in a
STAg-induced IL-12 response in these cells. We have previously shown
that splenic DC recovered from STAg-injected mice produce high levels
of IL-12 ex vivo (5). As shown in Fig. 4A, splenic DC from
STAg-injected MyD88-/- mice showed a highly
impaired IL-12p70 response compared with that displayed by DC from
comparably injected control mice and indicate that the defect in
MyD88-deficient DC function occurs in vivo and in vitro.
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A), indicating that the MyD88 defect in T.
gondii-induced IL-12 production does not involve either of
these TLR. MyD88 and CCR5 influence T. gondii-induced IL-12 production by DC through independent pathways
Previous studies have demonstrated that the IL-12 response
triggered by T. gondii in DC is highly dependent on the
chemokine receptor CCR5 (8). The discovery that the same
response also partially depends on MyD88 raised the question of whether
CCR5 and MyD88 are components of distinct or common pathways involved
in signaling for IL-12 production. A side-by-side comparison revealed
that MyD88-/- and
CCR5-/- mice display quantitatively comparable
defects in the IL-12p70 response to injected STAg (Fig. 4B).
To analyze the interdependence of the two defects, we treated mice with
PTx, an agent that uncouples the G protein signaling pathway utilized
by CCR5 and other chemokine receptors (26). As expected,
in vivo PTx treatment reduced the STAg-triggered IL-12 response of
control mice to a level comparable to that of
CCR5-/- animals (Fig. 4B),
suggesting that the residual response in both cases is due to a non-G
protein-dependent signaling mechanism. At the same time, PTx treatment
completely abolished the residual response of
MyD88-/- animals (Fig. 4B), arguing
that it is the product of a G protein signaling pathway. Together,
these two observations are consistent with a model in which potent
T. gondii-induced IL-12 production stems from two
independently triggered pathways that either overlap or augment one
another.
Our findings establish a major role for MyD88 in IL-12-dependent
resistance to T. gondii as well as in parasite-induced IL-12
production by the three principal cell types known to mount this
response. Since we were unable to simultaneously identify the
involvement of a specific or combination of specific TLR in the pathway
leading to parasite-triggered IL-12 synthesis, a role for TLR in innate
recognition of T. gondii in this system, although likely,
remains to be formally demonstrated. Such a role for TLR would be
consistent with previous studies demonstrating the function of TLR2 in
the induction of cytokines by the intracellular protozoa T.
cruzi (3), although our data argue against the
involvement of this TLR (as well as TLR4) in the response to T.
gondii. The alternate hypothesis that MyD88 may regulate IL-12
production through its participation in IL-18 and IL-1R signaling at
present cannot be ruled out but appears unlikely based on previous
evidence implicating a limited role for these cytokines in host
resistance to T. gondii (27, 28). Additionally,
although IL-1
recently has been reported to induce IL-12p70 in human
DC, this response requires costimulation of the cells with CD40
ligand or IFN- (29), a feature not shared by the
murine DC and neutrophil responses studied here.
Interestingly, while MyD88 signaling usually involves NF-
B-dependent
downstream events, IL-12 production by T. gondii has been
shown not to require the major NF-B transcription factors
NF-B1, NF-B2, relB,
or c-rel (30), suggesting the existence of a unique
pathway for MyD88 triggering of cytokine production by T.
gondii. Although apparently NF-B independent, T.
gondii-induced IL-12 synthesis is known to require the IFN
regulatory factor family member IFN consensus sequence-binding protein
(31), raising the possibility that MyD88 triggers IL-12
production through an alternative pathway involving this transcription
factor.
T. gondii is a particularly potent stimulator of IL-12 production by DC, a response previously shown to be highly dependent on G protein-coupled signaling mediated by the chemokine receptor CCR5 (8). The data presented here establish a dual role for CCR5 and MyD88 in T. gondii-induced IL-12 synthesis by DC and suggest that these elements signal through distinct pathways. The mechanism by which CCR5 and MyD88 interact to provide high level induction of IL-12 in the response of DC to T. gondii is currently under investigation.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Charles A. Scanga, Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Building 50, Room 6148, 50 South Drive, Bethesda, MD 20892. E-mail address: cscanga{at}niaid.nih.gov
3 Abbreviations used in this paper: TLR, Toll-like receptor; STAg, soluble tachyzoite Ag; DC, dendritic cell; PEC, peritoneal exudate cells, PTx, pertussin toxin.
Received for publication March 15, 2002. Accepted for publication April 25, 2002.
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 K. S. Masek, J. Fiore, M. Leitges, S.-F. Yan, B. D. Freedman, and C. A. Hunter Host cell Ca2+ and protein kinase C regulate innate recognition of Toxoplasma gondii J. Cell Sci., November 1, 2006; 119(21): 4565 - 4573. [Abstract] [Full Text] [PDF]
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H. Negishi, Y. Fujita, H. Yanai, S. Sakaguchi, X. Ouyang, M. Shinohara, H. Takayanagi, Y. Ohba, T. Taniguchi, and K. Honda Evidence for licensing of IFN-{gamma}-induced IFN regulatory factor 1 transcription factor by MyD88 in Toll-like receptor-dependent gene induction program PNAS, October 10, 2006; 103(41): 15136 - 15141. [Abstract] [Full Text] [PDF]
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L. Kim, B. A. Butcher, C. W. Lee, S. Uematsu, S. Akira, and E. Y. Denkers Toxoplasma gondii Genotype Determines MyD88-Dependent Signaling in Infected Macrophages J. Immunol., August 15, 2006; 177(4): 2584 - 2591. [Abstract] [Full Text] [PDF]
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C.-H. Liu, Y.-t. Fan, A. Dias, L. Esper, R. A. Corn, A. Bafica, F. S. Machado, and J. Aliberti Cutting Edge: Dendritic Cells Are Essential for In Vivo IL-12 Production and Development of Resistance against Toxoplasma gondii Infection in Mice J. Immunol., July 1, 2006; 177(1): 31 - 35. [Abstract] [Full Text] [PDF]
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L. A. Minns, L. C. Menard, D. M. Foureau, S. Darche, C. Ronet, D. W. Mielcarz, D. Buzoni-Gatel, and L. H. Kasper TLR9 Is Required for the Gut-Associated Lymphoid Tissue Response following Oral Infection of Toxoplasma gondii. J. Immunol., June 15, 2006; 176(12): 7589 - 7597. [Abstract] [Full Text] [PDF]
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L. Kim and E. Y. Denkers Toxoplasma gondii triggers Gi-dependent PI 3-kinase signaling required for inhibition of host cell apoptosis J. Cell Sci., May 15, 2006; 119(10): 2119 - 2126. [Abstract] [Full Text] [PDF]
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A. K. Behera, E. Hildebrand, R. T. Bronson, G. Perides, S. Uematsu, S. Akira, and L. T. Hu MyD88 Deficiency Results in Tissue-Specific Changes in Cytokine Induction and Inflammation in Interleukin-18-Independent Mice Infected with Borrelia burgdorferi Infect. Immun., March 1, 2006; 74(3): 1462 - 1470. [Abstract] [Full Text] [PDF]
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 Y.-T.A. Teng Protective and Destructive Immunity in the Periodontium: Part 1--Innate and Humoral Immunity and the Periodontium Journal of Dental Research, March 1, 2006; 85(3): 198 - 208. [Abstract] [Full Text] [PDF]
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S. Zimmermann, P. J. Murray, K. Heeg, and A. H. Dalpke Induction of Suppressor of Cytokine Signaling-1 by Toxoplasma gondii Contributes to Immune Evasion in Macrophages by Blocking IFN-{gamma} Signaling J. Immunol., February 1, 2006; 176(3): 1840 - 1847. [Abstract] [Full Text] [PDF]
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K. A. Rogers, A. B. Rogers, B. A. Leav, A. Sanchez, E. Vannier, S. Uematsu, S. Akira, D. Golenbock, and H. D. Ward MyD88-Dependent Pathways Mediate Resistance to Cryptosporidium parvum Infection in Mice Infect. Immun., January 1, 2006; 74(1): 549 - 556. [Abstract] [Full Text] [PDF]
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 J H Chang, P J McCluskey, and D Wakefield Toll-like receptors in ocular immunity and the immunopathogenesis of inflammatory eye disease Br J Ophthalmol, January 1, 2006; 90(1): 103 - 108. [Abstract] [Full Text] [PDF]
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R. E. Molestina and A. P. Sinai Host and parasite-derived IKK activities direct distinct temporal phases of NF-{kappa}B activation and target gene expression following Toxoplasma gondii infection J. Cell Sci., December 15, 2005; 118(24): 5785 - 5796. [Abstract] [Full Text] [PDF]
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S. B. Su, P. B. Silver, R. S. Grajewski, R. K. Agarwal, J. Tang, C.-C. Chan, and R. R. Caspi Essential Role of the MyD88 Pathway, but Nonessential Roles of TLRs 2, 4, and 9, in the Adjuvant Effect Promoting Th1-Mediated Autoimmunity J. Immunol., November 15, 2005; 175(10): 6303 - 6310. [Abstract] [Full Text] [PDF]
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 K. Fuse, G. Chan, Y. Liu, P. Gudgeon, M. Husain, M. Chen, W.-C. Yeh, S. Akira, and P. P. Liu Myeloid Differentiation Factor-88 Plays a Crucial Role in the Pathogenesis of Coxsackievirus B3-Induced Myocarditis and Influences Type I Interferon Production Circulation, October 11, 2005; 112(15): 2276 - 2285. [Abstract] [Full Text] [PDF]
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L.-Y. Huang, K. J. Ishii, S. Akira, J. Aliberti, and B. Golding Th1-Like Cytokine Induction by Heat-Killed Brucella abortus Is Dependent on Triggering of TLR9 J. Immunol., September 15, 2005; 175(6): 3964 - 3970. [Abstract] [Full Text] [PDF]
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M. B. Drennan, B. Stijlemans, J. Van Den Abbeele, V. J. Quesniaux, M. Barkhuizen, F. Brombacher, P. De Baetselier, B. Ryffel, and S. Magez The Induction of a Type 1 Immune Response following a Trypanosoma brucei Infection Is MyD88 Dependent J. Immunol., August 15, 2005; 175(4): 2501 - 2509. [Abstract] [Full Text] [PDF]
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 F. Yarovinsky, D. Zhang, J. F. Andersen, G. L. Bannenberg, C. N. Serhan, M. S. Hayden, S. Hieny, F. S. Sutterwala, R. A. Flavell, S. Ghosh, et al. TLR11 Activation of Dendritic Cells by a Protozoan Profilin-Like Protein Science, June 10, 2005; 308(5728): 1626 - 1629. [Abstract] [Full Text] [PDF]
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P. M. Robben, M. LaRegina, W. A. Kuziel, and L. D. Sibley Recruitment of Gr-1+ monocytes is essential for control of acute toxoplasmosis J. Exp. Med., June 6, 2005; 201(11): 1761 - 1769. [Abstract] [Full Text] [PDF]
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L. Kim, L. D. Rio, B. A. Butcher, T. H. Mogensen, S. R. Paludan, R. A. Flavell, and E. Y. Denkers p38 MAPK Autophosphorylation Drives Macrophage IL-12 Production during Intracellular Infection J. Immunol., April 1, 2005; 174(7): 4178 - 4184. [Abstract] [Full Text] [PDF]
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 G. I Lancaster, Q. Khan, P. Drysdale, F. Wallace, A. E Jeukendrup, M. T Drayson, and M. Gleeson The physiological regulation of toll-like receptor expression and function in humans J. Physiol., March 15, 2005; 563(3): 945 - 955. [Abstract] [Full Text] [PDF]
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 M. Chen, C. Barnfield, T. I. Naslund, M. N. Fleeton, and P. Liljestrom MyD88 Expression Is Required for Efficient Cross-Presentation of Viral Antigens from Infected Cells J. Virol., March 1, 2005; 79(5): 2964 - 2972. [Abstract] [Full Text] [PDF]
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M. R. Power, Y. Peng, E. Maydanski, J. S. Marshall, and T.-J. Lin The Development of Early Host Response to Pseudomonas aeruginosa Lung Infection Is Critically Dependent on Myeloid Differentiation Factor 88 in Mice J. Biol. Chem., November 19, 2004; 279(47): 49315 - 49322. [Abstract] [Full Text] [PDF]
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N. J. Mason, J. Fiore, T. Kobayashi, K. S. Masek, Y. Choi, and C. A. Hunter TRAF6-Dependent Mitogen-Activated Protein Kinase Activation Differentially Regulates the Production of Interleukin-12 by Macrophages in Response to Toxoplasma gondii Infect. Immun., October 1, 2004; 72(10): 5662 - 5667. [Abstract] [Full Text] [PDF]
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V. S. Conlin, S. B. Curtis, Y. Zhao, E. D. W. Moore, V. C. Smith, R. M. Meloche, B. B. Finlay, and A. M. J. Buchan Helicobacter pylori Infection Targets Adherens Junction Regulatory Proteins and Results in Increased Rates of Migration in Human Gastric Epithelial Cells Infect. Immun., September 1, 2004; 72(9): 5181 - 5192. [Abstract] [Full Text] [PDF]
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A. S. McKee, F. Dzierszinski, M. Boes, D. S. Roos, and E. J. Pearce Functional Inactivation of Immature Dendritic Cells by the Intracellular Parasite Toxoplasma gondii J. Immunol., August 15, 2004; 173(4): 2632 - 2640. [Abstract] [Full Text] [PDF]
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D. D. Bolz, R. S. Sundsbak, Y. Ma, S. Akira, C. J. Kirschning, J. F. Zachary, J. H. Weis, and J. J. Weis MyD88 Plays a Unique Role in Host Defense but Not Arthritis Development in Lyme Disease J. Immunol., August 1, 2004; 173(3): 2003 - 2010. [Abstract] [Full Text] [PDF]
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N. Liu, R. R. Montgomery, S. W. Barthold, and L. K. Bockenstedt Myeloid Differentiation Antigen 88 Deficiency Impairs Pathogen Clearance but Does Not Alter Inflammation in Borrelia burgdorferi-Infected Mice Infect. Immun., June 1, 2004; 72(6): 3195 - 3203. [Abstract] [Full Text] [PDF]
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L. Del Rio, B. A. Butcher, S. Bennouna, S. Hieny, A. Sher, and E. Y. Denkers Toxoplasma gondii Triggers Myeloid Differentiation Factor 88-Dependent IL-12 and Chemokine Ligand 2 (Monocyte Chemoattractant Protein 1) Responses Using Distinct Parasite Molecules and Host Receptors J. Immunol., June 1, 2004; 172(11): 6954 - 6960. [Abstract] [Full Text] [PDF]
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G. Mancuso, A. Midiri, C. Beninati, C. Biondo, R. Galbo, S. Akira, P. Henneke, D. Golenbock, and G. Teti Dual Role of TLR2 and Myeloid Differentiation Factor 88 in a Mouse Model of Invasive Group B Streptococcal Disease J. Immunol., May 15, 2004; 172(10): 6324 - 6329. [Abstract] [Full Text] [PDF]
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A. Mazzoni and D. M. Segal Controlling the Toll road to dendritic cell polarization J. Leukoc. Biol., May 1, 2004; 75(5): 721 - 730. [Abstract] [Full Text] [PDF]
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M. G. Netea, C. van der Graaf, J. W. M. Van der Meer, and B. J. Kullberg Toll-like receptors and the host defense against microbial pathogens: bringing specificity to the innate-immune system J. Leukoc. Biol., May 1, 2004; 75(5): 749 - 755. [Abstract] [Full Text] [PDF]
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C. A. Scanga, A. Bafica, C. G. Feng, A. W. Cheever, S. Hieny, and A. Sher MyD88-Deficient Mice Display a Profound Loss in Resistance to Mycobacterium tuberculosis Associated with Partially Impaired Th1 Cytokine and Nitric Oxide Synthase 2 Expression Infect. Immun., April 1, 2004; 72(4): 2400 - 2404. [Abstract] [Full Text] [PDF]
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P. M. Robben, D. G. Mordue, S. M. Truscott, K. Takeda, S. Akira, and L. D. Sibley Production of IL-12 by Macrophages Infected with Toxoplasma gondii Depends on the Parasite Genotype J. Immunol., March 15, 2004; 172(6): 3686 - 3694. [Abstract] [Full Text] [PDF]
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L. C. Gavrilescu, B. A. Butcher, L. Del Rio, G. A. Taylor, and E. Y. Denkers STAT1 Is Essential for Antimicrobial Effector Function but Dispensable for Gamma Interferon Production during Toxoplasma gondii Infection Infect. Immun., March 1, 2004; 72(3): 1257 - 1264. [Abstract] [Full Text] [PDF]
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M. Kursar, H.-W. Mittrucker, M. Koch, A. Kohler, M. Herma, and S. H. E. Kaufmann Protective T cell response against intracellular pathogens in the absence of Toll-like receptor signaling via myeloid differentiation factor 88 Int. Immunol., March 1, 2004; 16(3): 415 - 421. [Abstract] [Full Text] [PDF]
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M. A. Campos, M. Closel, E. P. Valente, J. E. Cardoso, S. Akira, J. I. Alvarez-Leite, C. Ropert, and R. T. Gazzinelli Impaired Production of Proinflammatory Cytokines and Host Resistance to Acute Infection with Trypanosoma cruzi in Mice Lacking Functional Myeloid Differentiation Factor 88 J. Immunol., February 1, 2004; 172(3): 1711 - 1718. [Abstract] [Full Text] [PDF]
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A. Debus, J. Glasner, M. Rollinghoff, and A. Gessner High Levels of Susceptibility and T Helper 2 Response in MyD88-Deficient Mice Infected with Leishmania major Are Interleukin-4 Dependent Infect. Immun., December 1, 2003; 71(12): 7215 - 7218. [Abstract] [Full Text] [PDF]
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S. Bennouna, S. K. Bliss, T. J. Curiel, and E. Y. Denkers Cross-Talk in the Innate Immune System: Neutrophils Instruct Recruitment and Activation of Dendritic Cells during Microbial Infection J. Immunol., December 1, 2003; 171(11): 6052 - 6058. [Abstract] [Full Text] [PDF]
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C. G. Feng, C. A. Scanga, C. M. Collazo-Custodio, A. W. Cheever, S. Hieny, P. Caspar, and A. Sher Mice Lacking Myeloid Differentiation Factor 88 Display Profound Defects in Host Resistance and Immune Responses to Mycobacterium avium Infection Not Exhibited by Toll-Like Receptor 2 (TLR2)- and TLR4-Deficient Animals J. Immunol., November 1, 2003; 171(9): 4758 - 4764. [Abstract] [Full Text] [PDF]
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S. Shi, C. Nathan, D. Schnappinger, J. Drenkow, M. Fuortes, E. Block, A. Ding, T. R. Gingeras, G. Schoolnik, S. Akira, et al. MyD88 Primes Macrophages for Full-Scale Activation by Interferon-{gamma} yet Mediates Few Responses to Mycobacterium tuberculosis J. Exp. Med., October 6, 2003; 198(7): 987 - 997. [Abstract] [Full Text] [PDF]
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H.-S. Mun, F. Aosai, K. Norose, M. Chen, L.-X. Piao, O. Takeuchi, S. Akira, H. Ishikura, and A. Yano TLR2 as an essential molecule for protective immunity against Toxoplasma gondii infection Int. Immunol., September 1, 2003; 15(9): 1081 - 1087. [Abstract] [Full Text] [PDF]
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F. Debierre-Grockiego, N. Azzouz, J. Schmidt, J.-F. Dubremetz, H. Geyer, R. Geyer, R. Weingart, R. R. Schmidt, and R. T. Schwarz Roles of Glycosylphosphatidylinositols of Toxoplasma gondii: INDUCTION OF TUMOR NECROSIS FACTOR-{alpha} PRODUCTION IN MACROPHAGES J. Biol. Chem., August 29, 2003; 278(35): 32987 - 32993. [Abstract] [Full Text] [PDF]
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A. Bafica, C. A. Scanga, M. L. Schito, S. Hieny, and A. Sher Cutting Edge: In Vivo Induction of Integrated HIV-1 Expression by Mycobacteria Is Critically Dependent on Toll-Like Receptor 2 J. Immunol., August 1, 2003; 171(3): 1123 - 1127. [Abstract] [Full Text] [PDF]
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L.-Y. Huang, J. Aliberti, C. A. Leifer, D. M. Segal, A. Sher, D. T. Golenbock, and B. Golding Heat-Killed Brucella abortus Induces TNF and IL-12p40 by Distinct MyD88-Dependent Pathways: TNF, Unlike IL-12p40 Secretion, Is Toll-Like Receptor 2 Dependent J. Immunol., August 1, 2003; 171(3): 1441 - 1446. [Abstract] [Full Text] [PDF]
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T. Bartfai, M. M. Behrens, S. Gaidarova, J. Pemberton, A. Shivanyuk, and J. Rebek Jr A low molecular weight mimic of the Toll/IL-1 receptor/resistance domain inhibits IL-1 receptor-mediated responses PNAS, June 24, 2003; 100(13): 7971 - 7976. [Abstract] [Full Text] [PDF]
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E. Muraille, C. De Trez, M. Brait, P. De Baetselier, O. Leo, and Y. Carlier Genetically Resistant Mice Lacking MyD88-Adapter Protein Display a High Susceptibility to Leishmania major Infection Associated with a Polarized Th2 Response J. Immunol., April 15, 2003; 170(8): 4237 - 4241. [Abstract] [Full Text] [PDF]
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A. D. Edwards, S. P. Manickasingham, R. Sporri, S. S. Diebold, O. Schulz, A. Sher, T. Kaisho, S. Akira, and C. Reis e Sousa Microbial Recognition Via Toll-Like Receptor-Dependent and -Independent Pathways Determines the Cytokine Response of Murine Dendritic Cell Subsets to CD40 Triggering J. Immunol., October 1, 2002; 169(7): 3652 - 3660. [Abstract] [Full Text] [PDF]
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B. T. Edelson and E. R. Unanue MyD88-Dependent but Toll-Like Receptor 2-Independent Innate Immunity to Listeria: No Role for Either in Macrophage Listericidal Activity J. Immunol., October 1, 2002; 169(7): 3869 - 3875. [Abstract] [Full Text] [PDF]
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H. Weighardt, S. Kaiser-Moore, R. M. Vabulas, C. J. Kirschning, H. Wagner, and B. Holzmann Cutting Edge: Myeloid Differentiation Factor 88 Deficiency Improves Resistance Against Sepsis Caused by Polymicrobial Infection J. Immunol., September 15, 2002; 169(6): 2823 - 2827. [Abstract] [Full Text] [PDF]
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), MyD88-/-
mice (
), and IL-12p40-/- mice (
) were infected i.p.
with 20 cysts of the ME49 strain of T. gondii and
survival was monitored. Data are representative of two experiments
performed, each with five to eight mice per group.
Inset, Percentage (mean ± SD,
n = 5 mice/group) of tachyzoite-infected PEC from
the above animal groups at day 5 after infection.
) for 72 h. Blocking anti-CD4 (dark gray
bar), anti-CD8 (medium gray bar) or both Abs (light gray bar) were
added in parallel cultures at 20 µg/ml. IFN-
) mice were stimulated in vitro
with STAg (A–D) or live tachyzoites (B)
and IL-12p40 (A–C) or IL-12p70 (D)
measured in the supernatant by ELISA after overnight incubation. In the
case of the peritoneal macrophages, some of the cultures were primed
with IFN-