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* Department of Medicine, University of Florida, Gainesville, FL 32610;
Institut Pasteur, Défense Innée et Inflammation, Paris, France; Institut National de la Santé et de la Recherche Médicale, E336, Paris, France; and
Institut Pasteur, Recherche et Expertise Histotechnologie et Pathologie, Paris, France
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Abstract |
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and KC in the airways. Bacterial and neutrophil counts in the lung were similar in control and TLR-deficient mice at 6 and 24 h after infection. MyD88–/– mice were, however, hypersusceptible, with 100% of mice dying within 48 h with a lower dose of P. aeruginosa. Of note there were normal levels of IL-6 and G-CSF in the airways of TLR mutant mice that were absent from the MyD88–/– mice. Thus, the susceptibility of mice to P. aeruginosa acute lung infection does not go through TLR2 or TLR4, implying that Pseudomonas LPS is not the most important virulence factor in acute pneumonia caused by this organism. Furthermore, G-CSF treatment of infected MyD88–/– mice results in improved clearance and survival. Thus, the resistance to infection in TLR2/TLR4–/– mice may be linked to G-CSF and possibly IL-6 production. |
Introduction |
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The role of LPS as a virulence factor in lung disease has been under considerable investigation for a number of organisms (8, 12, 13). Although the inhalation of P. aeruginosa LPS has been reported to result in severe lung inflammation (9), a critical role for LPS expressed by the whole organism has only been occasionally demonstrated to be responsible for susceptibility. Indeed, there are studies with C3H/HeJ mice, which have a loss-of-function mutation in the TLR4 gene, that do not support the idea that the LPS of this organism is the primary virulence factor (14, 15). It is believed that the proinflammatory action of LPS is mediated through TLR4 in cooperation with CD14 and MD-2 molecules making up the TLR4 receptor complex (16), although studies by Pier et al. in 1981 (17) indicated that C3H/HeJ mice do respond to Pseudomonas LPS. However, the LPS of P. aeruginosa has been reported to be recognized by both TLR4 and TLR2, depending on the origin of the strain of P. aeruginosa and the cell types used to examine the TLR4-LPS interaction (18). Thus, there may be other pathways by which cells respond to LPS. LPS from a strain adapted to the CF respiratory tract was recognized by human TLR4, whereas LPS from an environmental strain was not recognized (18). This differential recognition occurred with human cells, but not with mouse cells, i.e., mouse TLR4 recognizes LPS from the environmental strain (18). In contrast, LPS from a nonadapted or environmental strain of P. aeruginosa is recognized by human TLR2 (19). Such strains, coming from the environment, are likely to be found in acute lung disease. Thus, any analysis of the role of Pseudomonas LPS in animal models of disease needs to consider these variations in recognition of LPS by TLRs. To dissect the relevant virulence factors in acute lung disease due to P. aeruginosa, we have begun by examining the responses of mice that have deletions in the genes encoding either TLR4 or both TLR2 and TLR4. We find that neither mutation confers increased susceptibility to acute lung infections produced by the intratracheal injection of a reasonably well-characterized laboratory strain of P. aeruginosa. However, we note that LPS-independent susceptibility to the lung infection in this animal model goes through the MyD88 pathway, thus implicating another TLR or another receptor sharing a similar signaling pathway. We observed that this MyD88 pathway is essential for IL-6 and G-CSF production, and that G-CSF treatment was partially protective of P. aeruginosa-infected MyD88–/– mice.
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Materials and Methods |
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The P. aeruginosa strain PAK, a widely studied strain of P. aeruginosa originally obtained from S. Lory (Harvard University, Boston, MA) was grown overnight in Luria Bertoni (LB) broth, then transferred to fresh medium and grown for 4–5 h to midlog phase. The culture was centrifuged at 3000 x g for 15 min, and the cell pellet was washed twice with cold PBS. For LD50 determinations, the pellet was suspended in one-tenth the original volume. The bacterial count was ascertained by plating serial dilutions on LB agar plates. For other determinations, the bacterial pellet was diluted in its original volume, and the OD was adjusted to give the approximate desired inocula. The inocula were verified by serial 10-fold dilutions of the bacterial suspensions and plating on LB agar. This strain of P. aeruginosa is known to contain and express a full complement of virulence factors, including pili, flagella, and type III secreted exoenzymes S, T, and Y and has a smooth LPS belonging to serotype 6.
Mouse strains
Males from several mouse strains were used for the challenge experiments. TLR2–/–, TLR4–/–, and MyD88–/– mice were obtained from S. Akira (Osaka University, Osaka, Japan) and were backcrossed eight times with C57BL/6 to ensure similar genetic backgrounds. Double-knockout TLR2/TLR4–/– mice were generated by breeding TLR2–/– mice and TLR4–/– mice. C57/BL6 mice from which these mice were derived were used as the control mice. These latter mice were supplied by Centre d’Elevage R. Janvier and were used at 
8 wk of age. Mice were fed normal mouse chow and water ad libitum and were reared and housed under standard conditions with air filtration. Mice were cared for in accordance with Pasteur Institute guidelines in compliance with European animal welfare regulations.
Animal infections
Several different types of challenge experiments were performed. In the first series of experiments, LD50 determinations were made on the control mice, TLR4–/– mice, and TLR2/TLR4–/– mice. LD50 determinations were not performed on MyD88–/– mice, because these mice were known to be very susceptible to P. aeruginosa strain PAK (20). Mice were anesthetized by i.m. injection of a mixture of ketamine-xylazine and were placed supine. A plastic catheter (diameter, 0.86 mm) was inserted into the trachea via the oropharynx. The proper insertion was verified by checking the formation of mist due to expiration on a mirror placed in front of the external end. A 50-µl bacterial suspension was laid down at the internal end of the catheter with a micropipette using a sterile disposable tip for gel loading that was introduced into the catheter. Mice were then immediately held upright to facilitate bacterial inhalation and until normal breathing resumed. This protocol allows highly reproducible infection of the whole lung and has been used in studies of invasive pulmonary Aspergillosis by us (21). It may also mimic the main mechanism, aspiration, by which P. aeruginosa is acquired in acute infections, as opposed to aerosolization of the organisms, where much of the inoculum may bypass the airways and reach the alveoli depending on the particle size used. For the LD50 determinations, groups of five mice were infected by direct intratracheal injection of the bacterial strain, whose numbers were adjusted to deliver >108 CFU into the lungs at the highest concentration. Initial LD50 determinations used five groups of mice receiving 10-fold dilutions; however, later determinations required only four groups to obtain both 100 and 0% mortality.
After ascertaining the LD50 of the mouse strains, the survival times of the different mouse strains were examined using between one and two LD50 doses for the normal control mice. Similar survival experiments were performed with the MyD88–/– mice using one-tenth of the wild-type (WT) LD50 to ascertain that susceptibility was mediated through a MyD88-dependent pathway and to verify that the clone of strain PAK used in these experiments was capable of causing rapid death in a susceptible mouse strain.
A last series of animal experiments was performed to ascertain the effects of the TLR and MyD88 mutations in defense against this strain of P. aeruginosa. Groups of eight mice were infected by the intratracheal route using approximately one-tenth of the LD50 for the control mice. Bronchoalveolar lavages (BAL) were performed on these mice 6 and 24 h after infection, after pentobarbital euthanasia. The lavage fluids were diluted or used undiluted and plated on LB agar plates to obtain viable bacterial counts in the lavage fluid. Total and differential cell counts were performed on the lavage fluid. Total cell counts were measured in the BAL fluids with a Coulter counter (Coulter Electronics), and cell differential counts were determined after cytospin centrifugation and staining with Diff-Quick products. Murine cytokine concentrations in BAL fluid were determined using DuoSet ELISA kits obtained from R&D Systems and the Multiplex assay was performed with a Bio-Plex cytokine assay kit (Bio-Rad). Finally, in a last set of experiments, MyD88–/– mice were treated s.c. with 3 µg of G-CSF/mouse (Neupogen; Amgen Europe) given 1 h before and at the time of infection, followed by the same treatment at 24 and 48 h after infection.
Histology
Mutant and WT mice infected with one-tenth of the LD50 for the control mice were killed with pentobarbital 24 h after infection. The lungs were fixed in formalin, sectioned and stained with H&E.
Calculations
The LD50 was calculated by the Reed-Muench method (22) using a computer program available at 
http://ntri.tamuk.edu/cgi-bin/ld50/ld50
and verified by probit analysis to obtain exact confidence intervals. Survival of the different mouse strains was compared using Kaplan-Meier analysis log-rank test. Cytokine levels, polymorphonuclear neutrophil (PMN) counts, and bacterial counts were expressed as the mean ± SEM. Differences between groups were assessed for statistical significance using the Kruskal-Wallis ANOVA test, followed by the Mann-Whitney U test. A value of p < 0.05 was considered statistically significant.
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Results |
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LD50 determinations for the control C57BL/6 and TLR4–/– mice were performed twice using a total of 45 mice for each mouse strain in two experiments, because the doses given were slightly different. The LD50 determination for the TLR2/TLR4–/– mutant mice was performed only once. The results are shown in Table I. The LD50 of the TLR4–/– mice was 3–4 times that of the control mice, indicating that TLR4–/– mice were not hypersusceptible to P. aeruginosa given directly into the lungs despite reports of hypersusceptibility of such mice to Gram-negative bacteria. In fact, the mice appeared to be slightly more resistant, but these values were not statistically significant using probit analysis. The LD50 for the TLR2/TLR4–/– mice was 3 times that of the control mice, indicating that these mice were also not hypersusceptible to P. aeruginosa.
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To examine whether there were any differences in the time to death that may be reflective of how the different mutant mice handle the Pseudomonas infection, survival experiments were performed using between one and two LD50 doses of the microorganism for the control C57BL/6 mice. The survival curves are shown in Fig. 1. Analysis of these data using a Kaplan-Meier test indicated that there was no significant difference in time to death when the TLR knockout mice were compared with the control C57BL/6 mice and confirmed that there were no significant differences in the susceptibility of the TLR knockout mice vs the control mice, because the survival rates were similar using a fixed dose of bacteria.
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C57BL/6 control mice and TLR knockout mice were infected intratracheally with one-tenth of the LD50 of P. aeruginosa used for control mice. Animals were killed 6 and 24 h after infection. BAL fluids were cultured to obtain bacterial numbers in the airspaces and were examined for total cell count, differential cell counts, and cytokine/chemokine content.
Bacterial counts obtained from the BAL fluid of the different mouse strains are shown in Fig. 2. There were no significant differences in the numbers of P. aeruginosa obtained at the time intervals indicated. The total PMN counts performed on the same BAL fluids were similar in the TLR4 mutant and WT mice and were slightly reduced in the TLR double-mutant animals (Fig. 3). Cytokine determinations on the BAL fluids indicated an impaired production of TNF- and KC in response to the P. aeruginosa challenge in the TLR4–/– mice and the TLR2/TLR4–/– mice, but there was no impairment of the IL-6 response 6 h after infection in these mice (Fig. 4). BAL fluids were then further analyzed by a multiplex cytokine assay to determine whether other cytokines, not measured in the initial assays were similarly unaffected by the TLR mutations. A total of 18 cytokines/chemokines were measured (Table II). A number of these were present in small quantities and were not different in the three mouse lines. The production of several cytokines/chemokines was impaired in the mutant mice, as noted in the ELISA, e.g., TNF- and KC production, but additionally RANTES and MIP-1 production, were also impaired to a large extent. IL-1
production was also reduced, but due to the wide disparity of the values, the difference was only important for the double mutant compared with the WT mice. Notably, however, IL-6 and G-CSF production was not impaired 6 h after infection, confirming the observations on IL-6 made in the previous assays.
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MyD88 is an adaptor molecule for the signaling pathway of TLR2 and TLR4 as well as for most of the other TLR. The susceptibility of MyD88–/– mice reported by Power et al. (23) was confirmed in our hands. Thus, using 1/10 to 1/20 of the bacterial dose used for control mice, MyD88–/– mice died within 72 h (Fig. 5A). To gain insight into this increased susceptibility, BAL fluids were collected at 6 and 24 h. There was no appreciable PMN response 6 h after infection in MyD88–/– mice, but there was a response at 24 h, which was 5 times lower than that in WT mice (Fig. 5B). By contrast, the bacterial counts in MyD88–/– mice increased dramatically 24 h after infection (Fig. 5C). To determine whether this susceptibility of MyD88–/– mice was connected to a lack of IL-6 and G-CSF, we also examined whether these cytokines were present in these mice. As illustrated in Fig. 6, both IL-6 and G-CSF productions were impaired in MyD88–/– mice. As anticipated, synthesis of TNF- and KC was totally abolished under the same experimental conditions (Fig. 6).
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Histological examination was performed on the lungs collected 24 h after infection with one-tenth of the LD50 for WT mice. As shown in Fig. 7, a diffuse and acute alveolitis was observed in WT mice (A1). Numerous PMN were present in the alveoli and around the vessels (A2). For TLR4–/– (B1 and B2) and TLR2/TLR4–/– (C1 and C2) mice, the picture was not very different; there was a diffuse recruitment of PMN within the alveoli without necrosis or hemorrhages. The inflammatory response, as best as can be judged, was thus similar in all mouse groups except MyD88–/– mice. Indeed, multiple focal alveolitis with inflammatory cells, especially aggregates of PMN and macrophages, were observed within these foci of alveolitis (D1), whereas few PMN were observed in the unaffected alveoli (D2).
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Due to the normal G-CSF production of TLR mutant mice and the lack of such a response in MyD88–/– mice, which succumbed rapidly to the pulmonary infection, MyD88–/– mice were infected with similar doses of P. aeruginosa (3 x 105/mouse) and were given 3 µg of G-CSF/mouse 1 h before and at the time of infection, followed by the same treatment 24 and 48 h after infection. Saline-treated mice served as controls. G-CSF-treated and saline-treated animals (eight per group) were observed for 4 days to measure their survival. The log-rank test for comparisons of Kaplan-Meier survival curves indicates a significant increase in survival of G-CSF-treated mice (p = 0.009). As shown in Fig. 8, 48 h after infection all control mice had died, whereas 60% of the treated mice were alive. Another group of animals was infected and treated in the same way, but BAL were performed 6 h (four animals per group) and 24 h (three animals per group) after infection to ascertain whether the administration of G-CSF was a protective factor against the pulmonary challenge. Consistent with the survival data, G-CSF-treated mice were able to mount an inflammatory PMN response and had 1000-fold fewer bacteria in the lungs (Fig. 8).
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Discussion |
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and TNF- expression as well as an inflammatory infiltrate (25) suggested that LPS was an important virulence factor in the pathogenesis of Gram-negative bacterial pneumonia. However, most experiments involving lung inflammation and LPS have been performed with isolated E. coli LPS (24, 26, 27, 28). Nevertheless, the LPS of P. aeruginosa has also been implicated as a pathogenetic factor in acute lung disease, because Pseudomonas LPS given to mice by inhalation, intranasally or intratracheally, results in lung inflammation (7, 8, 9, 10).
Although these experimental approaches demonstrate that Pseudomonas LPS is capable of eliciting an innate immune response, proof that an LPS-mediated innate immune response via TLR2 or TLR4, is essential for clearance of whole organisms from the lungs or that LPS-mediated inflammation via these TLRs is a critical response for virulence during an actual infection has not been conclusively demonstrated. This kind of information would be best obtained with the use of whole organisms carrying nonsignaling mutations in the lipid A portion of the Pseudomonas LPS molecule, but Pseudomonas lipid A mutants have been generally nonviable. Another approach to elucidating the role of Pseudomonas LPS in lung infections is the use of mice that are unresponsive to LPS. Such mice, mainly C3H/HeJ that have a loss-of-function mutation of the tlr4 gene, have been described to be hypersusceptible to a variety of systemic Gram-negative infections (29, 30, 31, 32, 33). Pseudomonas challenge studies with such mice have not been conclusive. George et al. (14) reported that intranasal challenge of C3H/HeJ with several P. aeruginosa strains did not demonstrate differences in the LD50 between these mice and LPS-sensitive mice. Similarly, Yu et al. (15) showed that for the P. aeruginosa strain PAO1 given i.p., there was no difference in susceptibility between C3H/HeJ mice and C57BL/6 mice. However, in a study to examine the role of TLR4 in the defense against P. aeruginosa, using the cytotoxic Pseudomonas strain PA103 to challenge C3H/HeJ mice via the intratracheal route (34), the authors concluded that TLR4 signaling was essential for survival. Another recent study (23) has also examined this question concerning the role of LPS in susceptibility using a mucoid P. aeruginosa strain and has concluded that susceptibility does indeed go through MyD88, and that both TLR2 and TLR4 are involved. However, no LD50 or survival data were provided. It is of note that in both studies, P. aeruginosa strains were defective in many virulence factors (35). Finally, a recent abstract report by Hajjar et al. (Toll 2004 Meeting, www.umassmed.edu/toll2004/abstracts.cfm) appears to support our findings that the control of P. aeruginosa replication is independent of TLR2 and TLR4. It should, however, be pointed out that our conclusions are based on the study of a single invasive strain of P. aeruginosa that produces exoenzyme S, and it is possible that other strains may behave differently with regard to the response mediated by TLR2 or TLR4. Undoubtedly, this study contrasts with those that have used purified LPS, where the inflammatory response is quite florid (9). The most likely explanation may be that the actual amounts of LPS released during an acute pulmonary infection may be much less than what is delivered by the inhalation of pure LPS, partly accounting for differences seen.
Besides LPS, the TTSTs are now being implicated as major virulence factors in acute lung disease due to P. aeruginosa (3). Thus, an exoenzyme U mutant does not cause lung injury or death in mice (34). The actions of these toxins may involve TLR4, because exoenzyme S, an important TTST, has been reported to activate both TLR2 and TLR4 in vitro (36). The studies we describe, however, do not support an important role for exoenzyme S activation of TLR2 or TLR4 in determining resistance to this organism or susceptibility, because the strain of P. aeruginosa used is known to produce large quantities of exoenzyme S (37). Porins of P. aeruginosa were also shown to be as effective as LPS in inducing leukocyte activation (38). Although this has not been demonstrated, Pseudomonas porins may be active through TLR2 as reported for neisserial and Haemophilus influenzae porins (39, 40). The findings of our study suggest that the failure to recognize LPS, exoenzyme S, and porins, three known potent agonists of TLR2 and/or TLR4, does not result in hypersusceptibility.
The conclusions achieved in these studies are consistent with several other observations of the role of Pseudomonas LPS in triggering an innate immune response. Hybiske et al. (41) recently reported that the application of strain PAK to the apical surface of polarized CF epithelial cells evoked a very low cytokine response, and fewer genes were up-regulated than when the organism was placed basally. This observation suggests that LPS on bacterial surfaces is not efficiently recognized by the apical surface of epithelial cells, which may be explained by either TLR expression at this location or even the poor agonist activity of Pseudomonas LPS. Along the same lines of evidence, it has been reported that polarized airway epithelial cells, both normal and CF, do not express TLR4 on the apical surfaces, but in an intracellular compartment (42) or on the basolateral aspects (43). The latter report also showed that challenging the apical surfaces with Pseudomonas LPS did not result in activation of NF-
B, even after 24 h, but that TLR2 is activated in response to a whole organism challenge to these cell lines.
Based on the data obtained with MyD88–/– mice, the present study suggests that susceptibility to or defense against acute Pseudomonas lung infection goes through a MyD88-dependent pathway, but does not involve the two TLRs examined. A similar observation has been made with Legionella pneumophilia, another Gram-negative organism, where TLR4-deficient mice were also shown to respond normally to a lung challenge (44). These results are in contrast with studies of other acute Gram-negative bacterial pneumonia models, such as H. influenzae (32), P. hemolytica (45), and Klebsiella pneumoniae (33), where innate immunity mediated through TLR4 has been demonstrated to be necessary for survival. The factors that determine this differential susceptibility among these Gram-negative bacteria, however, are unknown. It is possible that the agonistic activity of Pseudomonas LPS is lower than that of other pathogen-associated molecular patterns (PAMPs) expressed by P. aeruginosa. Conversely, in H. influenzae, P. hemolytica, and K. pneumoniae, the agonistic activity of LPS may be higher than that of other PAMPs. Other PAMPs expressed by P. aeruginosa that may account for the MyD88-dependent response of the lung to infection are flagellin and CpG DNA through the activation of TLR5 and TLR9, respectively. However, LPS may still be a possible agonist; Schroeder et al. (46) reported that NF-B may be activated by a pathway that involves CF transmembrane conductance regulator-mediated uptake of LPS. Such a pathway would allow these mutant mice to respond to LPS as an agonist, as reported by Pier et al. (17) for C3H/HeJ mice.
The only clues concerning what may mediate resistance to this infection in TLR mutant mice are IL-6 and G-CSF production, because these responses were elicited in TLR mutant mice and were absent in MyD88 mutant mice. Both IL-6 and G-CSF have been implicated in defense against P. aeruginosa. G-CSF stimulates the proliferation of PMN, enhances their phagocytic and microbicidal activities, and has recently been shown to increase the survival of mice during the course of P. aeruginosa pneumonia (47). The current study shows that the defect in MyD88 mutant mice can be partially corrected by the administration of G-CSF, suggesting one major defect in MyD88–/– mice is failure of recruitment of PMN to the lungs, and that this response may have been protective in TLR mutant mice. IL-6 has also been implicated in P. aeruginosa corneal infections (48). IL-6 knockout mice are more susceptible to such infections, and exogenous IL-6 limits bacterial proliferation in these mice (48). It is also possible to link a well-recognized agonist, Pseudomonas flagellin (49), to IL-6, because this protein induces IL-6 expression and secretion by corneal cells (50) as well as after a lung challenge (51). However, flagellin should have evoked TNF-, KC, and other responses via TLR5, even in TLR4–/– mice (51) and TLR2/TLR4–/– mice, unless it uses a novel pathway to IL-6 synthesis in airway cells. Whatever the agonist is, it may use IL-6, G-CSF, and/or other unmeasured mediators to initiate the cellular response and goes through the MyD88 pathway.
In summary, the studies we report suggest that the recognition of LPS by TLR2 or the TLR4 complex is not central for susceptibility to or defense against acute P. aeruginosa lung infections. This suggests that the major PAMP may be another molecule that goes through a MyD88-dependent pathway. The studies also suggest that there are novel aspects of the signaling pathways triggered by this microorganism that leads to IL-6, G-CSF, and possibly other cytokine expressions that do not seem to parallel the expression of other major inflammatory cytokines and that may be protective. These studies, however, do not implicate this unknown pathway as the sole pathway, because there may be redundant innate immune responses to P. aeruginosa, such that removal of the TLR2 and TLR4 arms may still leave a protective response in place, and it is conceivable that if this unknown pathway is blocked, another pathway, such as the TLR4 pathway, may respond to protect the host. However, our findings do suggest that the lipid A part of the LPS molecule is not the principal susceptibility-determining PAMP. Identification of this pathway, the agonist, and the cell type that triggers the protective innate immune response in these mutant mice should provide more fundamental information on understanding acute lung infections caused by P. aeruginosa.
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Disclosures |
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Footnotes |
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1 This work was supported by National Institutes of Health Grants AI45014 and AI47852 (to R.R.). 
2 Address correspondence and reprint requests to Dr. Michel Chignard, Institut Pasteur, Défense Innée et Inflammation, Institut National de la Santé et de la Recherche Médicale E336, 25 rue du Dr. Roux, Paris 75015, France. E-mail address: chignard{at}pasteur.fr
3 Abbreviations used in this paper: CF, cystic fibrosis; BAL, bronchoalveolar lavage; LB, Luria Bertoni; PAMP, pathogen-associated molecular pattern; PMN, polymorphonuclear neutrophil; TTST, type III secreted toxin; WT, wild type.
Received for publication December 9, 2004. Accepted for publication July 8, 2005.
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B proteins in inflammatory responses to Escherichia coli LPS in mouse lungs. Am. J. Respir. Cell Mol. Biol. 27:575.-582. /cachectin and murine interleukin 1 protects mice from lethal bacterial infection. J. Exp. Med. 169:2021.-2027. and interleukin-6 by human leukocytes. Infect. Immun. 65:1683.-1687. [Abstract]
B translocation. Proc. Natl. Acad. Sci. USA 99:6907.-6912. This article has been cited by other articles:
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S. Jeyaseelan, S. K. Young, M. Yamamoto, P. G. Arndt, S. Akira, J. K. Kolls, and G. S. Worthen Toll/IL-1R Domain-Containing Adaptor Protein (TIRAP) Is a Critical Mediator of Antibacterial Defense in the Lung against Klebsiella pneumoniae but Not Pseudomonas aeruginosa J. Immunol., July 1, 2006; 177(1): 538 - 547. [Abstract] [Full Text] [PDF]
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