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Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO 63110
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Abstract |
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 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
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, TNF-
, and NO responses, despite
evidence of macrophage activation and up-regulation of MHC class II
molecules. We demonstrate that although minor MyD88-independent
responses to live Listeria do occur, these are
insufficient for normal host defense. Lastly, we performed experiments
in vitro in which macrophages deficient in TLR2 or MyD88 were directly
infected with Listeria. Although TLR signaling was
required for macrophage NO and cytokine production in response to
Listeria, handling and direct killing of
Listeria by activated macrophages occurred by TLR2- and
MyD88-independent mechanisms. |
Introduction |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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In this study, we describe the innate immune response of mice deficient in TLR signaling during infection with the Gram-positive, facultative intracellular bacterium Listeria monocytogenes. Listeria is a widely used model of intracellular bacterial infection, known to require virtually all aspects of the innate and adaptive immune responses for effective control (11). We used mice deficient in either TLR2, the receptor which as a heterodimer with TLR6 is responsible for recognition of Gram-positive peptidoglycan, or MyD88, the adaptor molecule required for all but a subset of TLR-mediated signaling events (12, 13, 14, 15, 16, 17, 18, 19). MyD88 also serves as an adaptor molecule in signaling via the IL-1 and IL-18 receptors, such that MyD88-deficient cells also lack responses to these cytokines (20, 21, 22, 23).
Our results indicate a redundancy in the recognition of Listeria by TLRs, such that in the absence of TLR2 other molecules are sufficient for control of Listeria infection. However, MyD88 is absolutely required for early Listeria resistance and full activation of innate immune responses. We show that this requirement for MyD88 in Listeria resistance is in part due to its role in IL-1 and IL-18 signaling, but more importantly due to MyD88’s role in TLR signaling. We demonstrate that while partial innate immune responses are stimulated by Listeria in a MyD88-independent fashion, these responses are insufficient for in vivo resistance. Lastly, we show that direct Listeria killing by activated macrophages occurs through a TLR2- and MyD88-independent mechanism, such that macrophage handling of Listeria is not altered by the absence of TLR signals.
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Materials and Methods |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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C57BL/6 (Charles River Laboratories, Wilmington, MA), TLR2-/-, MyD88-/-, inducible NO synthase (iNOS)-/- (on a C57BL/6 background; The Jackson Laboratory, Bar Harbor, ME), B6129SF1/J (The Jackson Laboratory), and Caspase 1-/- mice were maintained and bred under SPF conditions in the Washington University mouse facility (St. Louis, MO) (12, 22, 24, 25). TLR2-/- and MyD88-/- mice, a kind gift of Dr. S. Akira (Osaka University, Osaka, Japan) via Dr. D. Golenbock (University of Massachusetts Medical School, Worcester, MA), were used after five generations of back-crossing to the C57BL/6 background, with C57BL/6 mice serving as controls. Caspase 1-/- mice (originally generated at BASF Bioresearch, Worcester, MA), a kind gift of Dr. D. Chaplin (University of Alabama, Birmingham, AL), were on a mixed C57BL/6 x 129Sv background, with B6129SF1/J mice serving as controls.
Bacteria
L. monocytogenes strains used in this study were the
following: the wild-type (WT) strain EGD, the listeriolysin O
(LLO) deletion mutant EJL1, and the WT parent strain of EJL1, 10403S
(26). The EGD strain was used for all in vivo experiments,
with an LD50 in C57BL/6 mice of 
1 x 106
bacteria. Listeria was stored as glycerol stocks at -80°C
and diluted into pyrogen-free saline for injection into mice. For ex
vivo use with bone marrow-derived macrophages (BMDMs), live
Listeria was used as in Ref. 26 . Heat-killed
L. monocytogenes (HKLM; strain EGD) was prepared by
incubation of mid-log bacteria at 70°C for 3 h followed by three
washes with sterile PBS.
In vivo experiments
Listeria was used at a dose of 5 x 105 Listeria/mouse i.p., except where indicated. Mice were sacrificed at day 3 postinfection for determination of serum cytokine and nitrate/nitrite levels, assessment of peritoneal exudate cells (PEC), and quantitation of organ Listeria burden. PEC were collected by peritoneal lavage and stained for flow cytometry with FITC-conjugated anti-I-Ab (BD PharMingen, San Diego, CA) and PE-conjugated anti-F4/80 (Caltag Laboratories, Burlingame, CA). For light microscopy, cells were cytospun onto slides and stained with the Hema 3 staining kit (Fisher Scientific, Pittsburgh, PA).
To determine organ Listeria burden, spleen and liver were homogenized in PBS plus 0.05% Triton X-100. Serial dilutions of homogenate were plated on brain heart infusion agar, and bacterial CFU were assessed after overnight growth at 37°C. Small portions of spleen and liver were also fixed in 10% formalin and stained with H&E.
Cytokine and nitrate/nitrite determinations
Serum IL-12 p40 levels were measured using the OptEIA ELISA set
(BD PharMingen). Serum IFN- and TNF- levels were measured in
ELISA using standard methods, with reagents provided by Dr. R.
Schreiber (Washington University). Serum nitrate and nitrite levels
were determined by converting nitrate to nitrite with aspergillus
nitrate reductase (Sigma-Aldrich, St. Louis, MO), followed by nitrite
measurement using the Griess reagent.
BMDM experiments
Bone marrow was collected from femurs of mice and cultured as
described to generate BMDM (27). Briefly, cells were
cultured for 6 days in complete DMEM containing 10% heat-inactivated
FCS, 5% heat-inactivated horse serum, and 20% culture supernatant
from L929 cells. After day 6, cells were cultured in the above media
without L929 supernatant. To assess BMDM responses to HKLM, live
Listeria, and LPS (Escherichia coli serotype
O55:B5; Sigma-Aldrich), macrophages at day 8 of culture were stimulated
in antibiotic-free media containing 300 U/ml murine IFN- in
triplicate in 96-well plates at 5 x 104
cells/well. Two hours after addition of stimuli, penicillin and
streptomycin were added to all wells. Supernatants were collected after
48 h and assessed for nitrite, TNF-, and IL-12 p40 using the
methods described above.
To assess intracellular Listeria growth in BMDM, cells were
cultured for 48 h, beginning on day 8, in antibiotic-free media in
the presence or absence of 300 U/ml IFN-. Cells were then plated at
2.5 x 105 cells/well on 12-mm glass
coverslips in 24-well plates. Nonadherent cells were removed after a
2-h incubation at 37°C. Infection of cells, determination of
CFU/coverslip at various time points postinfection, and assessment of
intracellular Listeria localization at 4 h
postinfection (scoring individual organisms as either "phagosomal"
or "cytosolic"), were performed as described (26).
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Results |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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WT, TLR2-/-, and
MyD88-/- mice were infected with
Listeria and sacrificed at day 3 postinfection (Fig. 1
). TLR2-/- mice
showed normal immunity, with Listeria titers in both spleen
and liver equivalent to WT mice. Histologic assessment of
TLR2-/- mice was identical with WT mice (data
not shown). However, MyD88-/- mice showed a
profound deficiency in their innate immune response to
Listeria, with an 3-log greater spleen
Listeria burden, and 4-log greater liver Listeria
burden. Spleens from normal mice showed moderate lymphocyte depletion
and apoptosis (as determined by the presence of pyknotic nuclei on
light microscopy, consistent with Ref. 28) located
centrally within white pulp regions, affecting <25% of follicles
(Fig. 1C). MyD88-/- spleens showed
complete destruction of all white pulp follicles, with apoptosis
extending throughout the follicles to the marginal zone (Fig. 1D). Livers of WT mice showed scattered, small foci of
infection with macrophages often surrounding a core of dead hepatocytes
(Fig. 1E). MyD88-/- livers showed
much more numerous, large foci of infection consisting of extensive
neutrophil infiltrates (Fig. 1F). Lung, kidney, and pancreas
from three of four MyD88-/- mice showed no
signs of infection, with one mouse showing neutrophil infiltrates in
the lung and patches of Listeria growth in the exocrine
pancreas. MyD88-/- mice were found to die at
day 4 postinfection due to overwhelming bacteremia.
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, IL-1
, and IL-18 in response to inflammatory
challenge (25). Caspase 1-/- mice
showed minimally increased spleen Listeria titers, and an
2-log increase in liver titers (Fig. 2). We interpret these results to mean
that while both IL-1 and IL-18 do play a role in the innate immune
response to Listeria (29, 30, 31), MyD88 serves an
even greater role in resistance by also providing TLR signals in
response to Listeria.
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PEC from uninfected and Listeria-infected WT,
TLR2-/-, and MyD88-/-
mice were examined by light microscopy and flow cytometry. Macrophages
from all uninfected mice were of normal size and nonvacuolated, with
high surface expression of F4/80 and low expression of the MHC class II
molecule I-Ab (Fig. 3, A and B).
Macrophages from infected WT and TLR2-/- mice
showed an activated phenotype, with an 2-fold increase in size,
membrane ruffling, and vacuolization (Fig. 3C, data not
shown for TLR2-/- mice). By flow cytometry,
these cells were F4/80low and
I-Abhigh. Peritoneal macrophages from
infected MyD88-/- mice also showed an activated
phenotype by both light microscopy and flow cytometry (an equivalent
decrease in F4/80 and increase in I-Ab compared
with WT cells), but were also hypervacuolated in comparison to WT cells
(Fig. 3D). Several MyD88-/-
macrophages showed the presence of intracellular (often intravacuolar)
Listeria organisms, with extracellular Listeria
also present. Listeria was never evident in preparations of
PEC from WT or TLR2-/- mice.
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We assessed several parameters of inflammation at day 3
postinfection in Listeria-infected WT and
MyD88-/- mice challenged with a dose of 5
x 105 organisms (Fig. 4, left panels). Because
MyD88-/- mice challenged with this dose had
profoundly increased Listeria titers, we also performed a
separate experiment in which WT mice were challenged with three graded
doses of Listeria (5 x 105,
5 x 106, and 5 x
107), resulting in increasing Listeria
titers at day 3 postinfection (Fig. 4, right panels). This
provided us a way to measure whether the responses of
MyD88-/- mice were commensurate with their
large Listeria burden. MyD88-/- mice
challenged with a dose of 5 x 105
Listeria had roughly equivalent bacterial titers to WT mice
challenged with 5 x 107 organisms. It is
noteworthy that three of four WT mice died before day 3 at this dose.
MyD88-/- mice appear to survive with higher
bacterial burdens than WT mice before succumbing to infection,
suggesting that death of WT mice is in part a consequence of the
massive inflammatory response taking place.
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, C and
D). MyD88-/- showed a slightly
diminished neutrophil response (25% polymorphonuclear leukocyte
(PMN)) relative to their high Listeria titers vs WT
mice (30% PMN in mice challenged with the 5 x
106 dose, and 40% PMN with the 5 x
107 dose).
The next parameters assessed were the serum levels of IL-12, IFN-,
and TNF-; three cytokines known to be required for normal in vivo
Listeria resistance (11). WT mice showed a
small but detectable increase in serum IL-12 levels when challenged
with 5 x 105 Listeria (Fig. 4, E and F). However, with increasing bacterial
titers IL-12 levels decreased below basal levels (Fig. 4F).
Infected MyD88-/- mice also showed lower than
basal levels of IL-12 (Fig. 4E). In light of the inverse
relationship between IL-12 levels and bacterial titers in WT mice, we
are unable to definitively say whether IL-12 production was abnormal in
Listeria-infected MyD88-/-
mice.
Serum levels of both IFN- and TNF- were increased above basal
levels upon Listeria infection of
MyD88-/- mice (Fig. 4, G and
I), indicating the existence of Listeria-induced
MyD88-independent pathways of cytokine production in vivo. However,
levels of both cytokines in MyD88-/- mice were
below the levels found in WT mice with equivalent
Listeria titers (100-fold decrease in IFN- and 10-fold
decrease in TNF-; Fig. 4, H and J). IL-10
levels in serum from all mice shown in Fig. 4 were found to be
virtually undetectable (data not shown), indicating no role for this
anti-inflammatory cytokine in the susceptibility of
MyD88-/- mice.
Lastly, we assessed the serum levels of nitrate and nitrite as a marker
of in vivo iNOS-mediated NO production, an inflammatory response known
to be required for in vivo Listeria resistance
(32, 33, 34). Infected MyD88-/- mice
showed a minimally increased level of nitrate/nitrite in the serum
(Fig. 4K). This small response was 10-fold decreased
relative to WT mice harboring a similar Listeria burden
(Fig. 4L), and also likely contributed to the susceptibility
of MyD88-/- mice.
Macrophage responses to Listeria in vitro: TLR2- and MyD88-dependent and -independent responses
To further characterize the inflammatory responses of macrophages
to Listeria, we performed a series of in vitro experiments
using BMDM derived from WT, TLR2-/-,
MyD88-/-, and iNOS-/-
mice. NO, TNF-, and IL-12 production were determined after
stimulation with HKLM, live Listeria, and LPS, all in the
presence of simultaneous stimulation with IFN- (Fig. 5, A–E). TLR2 was found to be
absolutely required for stimulation by HKLM, but played only a very
minor role with live Listeria.
MyD88-/- cells showed no responses to HKLM, yet
showed small but detectable NO and TNF- responses to both live
Listeria and LPS (with 100-fold less sensitivity, and
with lower maximums). As expected, iNOS-/-
cells showed no NO production but normal TNF- and IL-12 responses to
all stimuli.
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Listeria killing by IFN- activated macrophages is
TLR2-, MyD88-, and iNOS-independent
To determine whether signals through TLR2 or MyD88 contribute to
Listeria killing by macrophages in vitro, experiments were
performed in which the intracellular growth of Listeria was
followed in BMDM in vitro (Fig. 6, A–C). In Fig. 6A, both resting and
IFN--activated BMDM from all strains of mice tested were shown to
handle Listeria equivalently, with resting cells allowing
significant intracellular bacterial growth and activated macrophages
showing powerful listericidal activity. This result demonstrates no
role for TLR2, MyD88, or NO in Listeria killing induced by
IFN-.
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acts to control
Listeria growth by blocking this escape
(37, 38, 39, 40), we also measured the efficiency of
Listeria escape to the cytosol in WT,
TLR2-/-, and MyD88-/-
cells (Fig. 6B). No differences were seen in BMDM in the
absence of TLR2 or MyD88, indicating no role for the signals deriving
from these molecules in direct Listeria handling by
macrophages. Lastly, we compared the intracellular growth of WT (strain
10403S) vs LLO-deficient Listeria (strain EJL1, unable to
escape to the cytosol due to deletion of LLO) in BMDM from WT and
MyD88-/- mice (Fig. 6C). Again, no
role for MyD88 was seen in the killing of WT Listeria by
activated macrophages, or in the killing of LLO-deficient
Listeria by both resting and activated macrophages. |
Discussion |
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TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
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MyD88-deficient mice were highly sensitive to Listeria infection, allowing uncontrolled bacterial growth in spleen and liver. We hypothesize that this overall susceptibility results from a combination of defects resulting from the lack of the MyD88 protein. IL-1 and IL-18, molecules whose signaling pathways require MyD88, have both been shown to be required for normal defense against Listeria, and indeed we found Caspase 1-deficient mice, which lack production of these cytokines, to have increased bacterial titers in the liver (20, 21, 22, 23, 29, 30, 31). However, the susceptibility of Caspase 1-deficient mice was significantly less than that seen for MyD88-deficient mice. This implies a critical role for MyD88 beyond the IL-1 and IL-18 pathways, in other words acting as an adaptor for TLR-mediated signaling.
MyD88-deficient mice showed compromised inflammatory responses to
Listeria infection, including diminished PMN responses and
diminished IL-12, IFN-, TNF-, and NO production. Each of these is
independently known to be required for normal Listeria
resistance; and therefore, the combination of these defects likely
resulted in overwhelming infection (11). It is important
to note that each of the above mentioned responses (with the exception
of IL-12) is not absent in Listeria-infected MyD88-deficient
mice, only reduced. This indicates that MyD88-independent responses are
taking place in vivo, although at an insufficient level for normal host
defense. Macrophage activation during in vivo infection, as determined
by microscopic evaluation and assessment of surface levels of F4/80 and
MHC class II molecules, was also seen to be an MyD88-independent
response. Up-regulation of MHC class II molecules is known to require
IFN-, suggesting that the low level of this cytokine induced in
MyD88-deficient mice is sufficient to mediate this response
(43).
In vitro experiments confirmed that live Listeria can induce low level cytokine and NO production by MyD88-deficient macrophages. To date, only TLR4 has been shown to mediate MyD88-independent signaling events. Therefore, we hypothesize that MyD88-independent responses to live Listeria may involve TLR4 by way of surface lipoteichoic acid (12, 18, 19). This point has not yet been tested. It should be noted that the Listeria proteins LLO, inlB, plcA, and plcB can stimulate cellular responses through presumably non-TLR-mediated events (44, 45, 46, 47). We have ruled out LLO as contributing to the stimulation of MyD88-deficient macrophages by use of live LLO-deficient Listeria (data not shown). The contribution of other non-TLR stimulatory molecules cannot be determined at this time.
Our studies surprisingly demonstrate no role for TLR2 or MyD88 in the
killing of phagosome-retained Listeria; that is to say
Listeria organisms which are unable to escape to the cytosol
either through macrophage activation by IFN- or due to the use of
LLO-deficient Listeria. This indicates that the
Listeria killing mechanisms present within the vacuolar
system do not require any TLR-mediated signals for their induction. We
are currently investigating the nature of these listericidal
mechanisms.
These results differ from that reported for murine macrophage killing
of intracellular Mycobacterium tuberculosis, in which TLR2
signals were required for microbicidal activity, via stimulation of NO
production (48). However, in this experimental system, a
purified exogenous mycobacterial TLR2 ligand (19-kDa lipoprotein) was
added to infected cells in addition to TLR2 ligand(s) presumably
provided by the infecting bacterium itself. It is noteworthy that in
the absence of this additional TLR2 stimulus, no difference
was noted between mycobacterial growth in WT vs TLR2-deficient cells.
This suggests that live mycobacterial infection itself was an
insufficient stimulus for TLR2-induced NO production. It is also
important to note that murine macrophage killing of Listeria
differs from the killing of M. tuberculosis in that the
former occurs in IFN--activated macrophages in an NO-independent
fashion (Fig. 6A and Ref. 26), while the latter
requires NO (48).
Our results highlight the fact that in vivo resistance to Listeria infection requires MyD88, while in vitro Listeria killing by activated macrophages occurs in a MyD88-independent manner. Similar results were reported in iNOS-deficient mice and macrophages (34). In vivo innate immunity to Listeria requires a coordinated interplay of cytokines, NO, and cellular responses that require MyD88 for their appropriate induction. Macrophage listericidal activity is only one component of this response, which when occurring in isolation is insufficient for in vivo resistance. It also remains a possibility that in vivo macrophage Listeria killing differs from in vitro macrophage Listeria killing, with the former being MyD88-dependent. Studies are underway to address this possibility.
In conclusion, our results demonstrate both the redundancy of TLR-mediated recognition of Listeria during in vivo infection, and the absolute requirement for the MyD88 adaptor molecule for in vivo resistance to this pathogen. Surprisingly, we have shown in this study that in vitro macrophage listericidal mechanisms occur in a MyD88-independent manner. These different requirements for MyD88 during in vivo infection vs during the simplified model of in vitro macrophage infection add to our understanding of the innate immune response to Listeria, and highlight the need for further investigation into the nature of macrophage listericidal mechanisms.
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Acknowledgments |
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Footnotes |
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2 Address correspondence and reprint requests to Dr. Emil R. Unanue, Department of Pathology and Immunology, Washington University School of Medicine, 660 South Euclid Avenue, Box 8118, St. Louis, MO 63110. E-mail address: unanue{at}pathbox.wustl.edu
3 Abbreviations used in this paper: TLR, Toll-like receptor; LLO, listeriolysin O; BMDM, bone marrow-derived macrophage; HKLM, heat-killed L. monocytogenes; PEC, peritoneal exudate cell; iNOS, inducible NO synthase; WT, wild type; PMN, polymorphonuclear leukocyte.
Received for publication June 6, 2002. Accepted for publication July 31, 2002.
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J.-H. Park, Y.-G. Kim, C. McDonald, T.-D. Kanneganti, M. Hasegawa, M. Body-Malapel, N. Inohara, and G. Nunez RICK/RIP2 Mediates Innate Immune Responses Induced through Nod1 and Nod2 but Not TLRs J. Immunol., February 15, 2007; 178(4): 2380 - 2386. [Abstract] [Full Text] [PDF]
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J. Jablonska, K. E. Dittmar, T. Kleinke, J. Buer, and S. Weiss Essential Role of CCL2 in Clustering of Splenic ERTR-9+ Macrophages during Infection of BALB/c Mice by Listeria monocytogenes Infect. Immun., January 1, 2007; 75(1): 462 - 470. [Abstract] [Full Text] [PDF]
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D. D. Bolz, R. S. Sundsbak, Y. Ma, S. Akira, J. H. Weis, T. G. Schwan, and J. J. Weis Dual Role of MyD88 in Rapid Clearance of Relapsing Fever Borrelia spp. Infect. Immun., December 1, 2006; 74(12): 6750 - 6760. [Abstract] [Full Text] [PDF]
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 R. Appelberg Macrophage nutriprive antimicrobial mechanisms J. Leukoc. Biol., June 1, 2006; 79(6): 1117 - 1128. [Abstract] [Full Text] [PDF]
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A. M. van der Sar, O. W. Stockhammer, C. van der Laan, H. P. Spaink, W. Bitter, and A. H. Meijer MyD88 Innate Immune Function in a Zebrafish Embryo Infection Model Infect. Immun., April 1, 2006; 74(4): 2436 - 2441. [Abstract] [Full Text] [PDF]
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N. Ozoren, J. Masumoto, L. Franchi, T.-D. Kanneganti, M. Body-Malapel, I. Erturk, R. Jagirdar, L. Zhu, N. Inohara, J. Bertin, et al. Distinct Roles of TLR2 and the Adaptor ASC in IL-1beta/IL-18 Secretion in Response to Listeria monocytogenes J. Immunol., April 1, 2006; 176(7): 4337 - 4342. [Abstract] [Full Text] [PDF]
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E. d. Cerro-Vadillo, F. Madrazo-Toca, E. Carrasco-Marin, L. Fernandez-Prieto, C. Beck, F. Leyva-Cobian, P. Saftig, and C. Alvarez-Dominguez Cutting Edge: A Novel Nonoxidative Phagosomal Mechanism Exerted by Cathepsin-D Controls Listeria monocytogenes Intracellular Growth J. Immunol., February 1, 2006; 176(3): 1321 - 1325. [Abstract] [Full Text] [PDF]
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 J. H. Fritz and S. E. Girardin How Toll-like receptors and Nod-like receptors contribute to innate immunity in mammals Innate Immunity, December 1, 2005; 11(6): 390 - 394. [Abstract] [PDF]
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L. Romics Jr, A. Dolganiuc, A. Velayudham, K. Kodys, P. Mandrekar, D. Golenbock, E. Kurt-Jones, and G. Szabo Toll-like receptor 2 mediates inflammatory cytokine induction but not sensitization for liver injury by Propioni- bacterium acnes J. Leukoc. Biol., December 1, 2005; 78(6): 1255 - 1264. [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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Y. Sang, B. Ramanathan, C. R. Ross, and F. Blecha Gene Silencing and Overexpression of Porcine Peptidoglycan Recognition Protein Long Isoforms: Involvement in {beta}-Defensin-1 Expression Infect. Immun., November 1, 2005; 73(11): 7133 - 7141. [Abstract] [Full Text] [PDF]
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 A. M. Hajjar, H. Harowicz, H. D. Liggitt, P. J. Fink, C. B. Wilson, and S. J. Skerrett An Essential Role for Non-Bone Marrow-Derived Cells in Control of Pseudomonas aeruginosa Pneumonia Am. J. Respir. Cell Mol. Biol., November 1, 2005; 33(5): 470 - 475. [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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Y. Naiki, K. S. Michelsen, N. W. J. Schroder, R. Alsabeh, A. Slepenkin, W. Zhang, S. Chen, B. Wei, Y. Bulut, M. H. Wong, et al. MyD88 Is Pivotal for the Early Inflammatory Response and Subsequent Bacterial Clearance and Survival in a Mouse Model of Chlamydia pneumoniae Pneumonia J. Biol. Chem., August 12, 2005; 280(32): 29242 - 29249. [Abstract] [Full Text] [PDF]
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R. E. Berg, E. Crossley, S. Murray, and J. Forman Relative Contributions of NK and CD8 T Cells to IFN-{gamma} Mediated Innate Immune Protection against Listeria monocytogenes J. Immunol., August 1, 2005; 175(3): 1751 - 1757. [Abstract] [Full Text] [PDF]
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A. L. Kau, S. M. Martin, W. Lyon, E. Hayes, M. G. Caparon, and S. J. Hultgren Enterococcus faecalis Tropism for the Kidneys in the Urinary Tract of C57BL/6J Mice Infect. Immun., April 1, 2005; 73(4): 2461 - 2468. [Abstract] [Full Text] [PDF]
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 H. Bjorkbacka, K. A. Fitzgerald, F. Huet, X. Li, J. A. Gregory, M. A. Lee, C. M. Ordija, N. E. Dowley, D. T. Golenbock, and M. W. Freeman The induction of macrophage gene expression by LPS predominantly utilizes Myd88-independent signaling cascades Physiol Genomics, February 7, 2005; 19(3): 319 - 330. [Abstract] [Full Text] [PDF]
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R. M. O'Connell, S. A. Vaidya, A. K. Perry, S. K. Saha, P. W. Dempsey, and G. Cheng Immune Activation of Type I IFNs by Listeria monocytogenes Occurs Independently of TLR4, TLR2, and Receptor Interacting Protein 2 but Involves TANK-Binding Kinase 1 J. Immunol., February 1, 2005; 174(3): 1602 - 1607. [Abstract] [Full Text] [PDF]
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S. L. Pull, J. M. Doherty, J. C. Mills, J. I. Gordon, and T. S. Stappenbeck Activated macrophages are an adaptive element of the colonic epithelial progenitor niche necessary for regenerative responses to injury PNAS, January 4, 2005; 102(1): 99 - 104. [Abstract] [Full Text] [PDF]
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S. Stockinger, B. Reutterer, B. Schaljo, C. Schellack, S. Brunner, T. Materna, M. Yamamoto, S. Akira, T. Taniguchi, P. J. Murray, et al. IFN Regulatory Factor 3-Dependent Induction of Type I IFNs by Intracellular Bacteria Is Mediated by a TLR- and Nod2-Independent Mechanism J. Immunol., December 15, 2004; 173(12): 7416 - 7425. [Abstract] [Full Text] [PDF]
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R. Janssen, A. van Wengen, M. A. Hoeve, M. ten Dam, M. van der Burg, J. van Dongen, E. van de Vosse, M. van Tol, R. Bredius, T. H. Ottenhoff, et al. The Same I{kappa}B{alpha} Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes J. Exp. Med., September 7, 2004; 200(5): 559 - 568. [Abstract] [Full Text] [PDF]
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R. M. O'Connell, S. K. Saha, S. A. Vaidya, K. W. Bruhn, G. A. Miranda, B. Zarnegar, A. K. Perry, B. O. Nguyen, T. F. Lane, T. Taniguchi, et al. Type I Interferon Production Enhances Susceptibility to Listeria monocytogenes Infection J. Exp. Med., August 16, 2004; 200(4): 437 - 445. [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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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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D. Torres, M. Barrier, F. Bihl, V. J. F. Quesniaux, I. Maillet, S. Akira, B. Ryffel, and F. Erard Toll-Like Receptor 2 Is Required for Optimal Control of Listeria monocytogenes Infection Infect. Immun., April 1, 2004; 72(4): 2131 - 2139. [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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S. J. Skerrett, H. D. Liggitt, A. M. Hajjar, and C. B. Wilson Cutting Edge: Myeloid Differentiation Factor 88 Is Essential for Pulmonary Host Defense against Pseudomonas aeruginosa but Not Staphylococcus aureus J. Immunol., March 15, 2004; 172(6): 3377 - 3381. [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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N. M. Tsuji, H. Tsutsui, E. Seki, K. Kuida, H. Okamura, K. Nakanishi, and R. A. Flavell Roles of caspase-1 in Listeria infection in mice Int. Immunol., February 1, 2004; 16(2): 335 - 343. [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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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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J. L. Coleman and J. L. Benach The Urokinase Receptor Can Be Induced by Borrelia burgdorferi through Receptors of the Innate Immune System Infect. Immun., October 1, 2003; 71(10): 5556 - 5564. [Abstract] [Full Text] [PDF]
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L. Lefrancois, A. Marzo, and K. Williams Sustained Response Initiation Is Required for T Cell Clonal Expansion But Not for Effector or Memory Development In Vivo J. Immunol., September 15, 2003; 171(6): 2832 - 2839. [Abstract] [Full Text] [PDF]
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S. S. Way, T. R. Kollmann, A. M. Hajjar, and C. B. Wilson Cutting Edge: Protective Cell-Mediated Immunity to Listeria monocytogenes in the Absence of Myeloid Differentiation Factor 88 J. Immunol., July 15, 2003; 171(2): 533 - 537. [Abstract] [Full Text] [PDF]
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