Thus, IL-7 must be controlling naïve T-cell survival by mechanism

Thus, IL-7 must be controlling naïve T-cell survival by mechanisms other than simply regulating expression level of Bcl2 family members. Taken together, our data

strongly suggest that IL-7 controls homeostatic fitness of T cells in replete hosts by non-transcriptional mechanisms. IL-7 can activate PI3K 23, 37 and downstream Akt/PKB whose kinase activity can potentially modulate multiple pathways and that could constitute such non-transcriptional mechanisms. Consistent with this view, IL-7 has been reported to prevent apoptosis in IL-7 responsive cell lines by inhibiting Bad activity following Small molecule library Akt/PKB phosphorylation of Bad 31. However, using F5 T cells over-expressing Bad, we could find no evidence that Bad was regulating naïve T-cell fitness in vitro, or in vivo in a range of homeostatic environments or in the absence of IL-7 signalling altogether. This is also consistent with experiments showing that inhibition of PI3K does not block the

pro-survival properties Imatinib ic50 of IL-7 23 in vitro. However, in vitro, any potential pro-apoptotic consequence of PI3K blockade may be masked by the effects of upregulation of Bcl2 expression by IL-7. Furthermore, it is unclear whether or to what extent IL-7 activates PI3K in naïve T cells in vivo. Thus, it is not possible to exclude a potential pro-survival role for IL-7-dependent PI3K activation in vivo. The non-transcriptional mechanisms by which IL-7 promotes T-cell survival in vivo remain obscure. However, since we observed no differences in abundance of key Bcl2 family members in IL-7R− F5 T cells, it seems likely that regulation at the level of sub-cellular localization of pro- or

anti-apoptotic proteins and/or their interaction with one another may rather account for the perturbed mitochondrial homeostasis we observed in IL-7R− F5 T cells. Furthermore, another study suggests that posttranslational regulation of glucose transporters may be involved 36. In conclusion, we show for the first time that homeostatic fitness of T cells is dynamically regulated by IL-7, involving multiple mechanisms that differ between lymphoreplete and lymphopenic conditions. Molecular motor The view that T-cell fitness is not a digital state of either survival or death but rather dynamic state is consistent with concepts of competition for survival resources. Such a view is also consistent with the recent insights into the high mobility of lymphocytes within the 3-dimensional structure of the lymph node 38, 39, and that the source of IL-7, and likely other survival factors within these structures, is not homogeneously distributed, but rather focal and from specific cell types 11. In such a context, a dynamic fitness model of T-cell survival would permit integration and interpretation of multiple and likely sporadic survival cues.

This discrepancy raised concerns as to a possible difference betw

This discrepancy raised concerns as to a possible difference between human and mouse Th17 cells. Subsequent studies addressing the role of TGF-β in human Th17-cell differentiation confirmed an inhibitory effect of TGF-β at high doses, but emphasized the requirement of low doses of this cytokine for Th17-cell this website differentiation [32-34]. The strict dose dependency of the TGF-β requirement and the finding of constitutive

TGF-β signaling in freshly isolated human T cells [35] raise the question of whether TGF-β is a limiting factor for Th17-cell differentiation in vivo or whether it may be required in vitro depending on the culture conditions. Interestingly, more recent studies in the mouse demonstrated that Th17-cell differentiation LDK378 nmr could occur also in the absence of TGF-β signaling, and only Th17 cells generated in the absence of TGF-β were found to be pathogenic in an EAE model [36]. These findings suggest that there may be different pathways for the generation of Th17 cells (and possibly Th1 and Th2 cells) and that our definition of a T-cell lineage based on a single cytokine and transcription factor may not be sufficient

to explain the complex heterogeneity of effector T cells. Given the heterogeneity of IL-17-producing T cells and the variety of cytokines involved in their differentiation, it would be important to develop new approaches based on the physiological function of these cells in the immune response. Since Th17 cells are key players in host defense, attempts were made to prime directly in vitro human naïve T cells against whole microbes, in order to induce Protein kinase N1 Th17-cell differentiation in a more physiological system and identify the signals involved in driving this process. A method was developed that takes advantage of the complexity

of the microbes that provide, at the same time, a large number of antigens that can be recognized by specific naïve T cells and a variety of stimuli for innate receptors that lead to the upregulation of costimulatory molecules and the production of polarizing cytokines by antigen presenting cells [37]. Monocytes exposed to C. albicans or S. aureus efficiently primed human naïve CD4+ naïve T cells in vitro, which subsequently proliferated and differentiated into Th17 cells producing high levels of IL-17, IL-22, and expressing CCR6 and RORγt [37]. However, the cells primed by C. albicans had a hybrid Th17/Th1 phenotype, that is, they produced IL-17 and IFN-γ and expressed RORγt and T-bet, while cells primed by S. aureus produced IL-17, no IFN-γ, but did produce IL-10 but only in a narrow time window by strongly activated proliferating Th17 cells [37]. Strikingly, in vivo primed C. albicans or S. aureus specific memory Th17 cells isolated from immune donors had the same cytokine profile as the in vitro C. albicans or S. aureus primed Th17 cells, producing IL-17 plus either IFN-γ or IL-10, respectively.

meningitidis (Schubert-Unkmeir et al , 2010) Meningitis caused b

meningitidis (Schubert-Unkmeir et al., 2010). Meningitis caused by S. pneumoniae in the neonatal rats is associated with the higher expression of MMP-3, MMP-8, and MMP-9, whereas in rabbits, only MMP-2 and MMP-9 are found to be responsible for the impairment of BBB and blood–CSF barriers (Azeh et al., 1998). Mycobacterium tuberculosis uses MMPs more effectively for the tissue and neural damage. Infected monocytes induce MMP-9 secretion from astrocytes, afforded by IL-1β and TNF-α (Harris et al., 2007). The importance

of MMP-9 in BBB disruption was proved elsewhere by diminishing the process of BBB disruption in MMP-9 knockout mice (Asahi et al., 2001). Borrelia burgdorferi causes the release of MMP-1 and MMP-9 from human cells, while plasmin-coated B. burgdorferi stimulates pro-MMP-9. This triggers a cascade that leads to the degradation of basement AUY-922 membranes (Gebbia et al., 2001). Selleck Midostaurin Borrelia burgdorferi–Anaplasma phagocytophilum coinfection of BMECs leads to increased reductions in transendothelial electrical resistance and elevated production of MMPs (MMP-1, MMP-3, MMP-7, MMP-8, and MMP-9) (Grab et al., 2007). Together with other factors, such as cytokines and chemokines, this expression leads to the increase in vascular permeability and inflammatory

responses. In fact, coinfection results in the higher many production of MMPs than B. burgdorferi alone (Grab et al., 2007). Acanthamoeba serine proteases

have been demonstrated to disrupt human BMEC monolayers (Alsam et al., 2005). Moreover, to the serine proteases, Acanthamoeba is able to use metalloproteinase activity (Sissons et al., 2006). In general, expression of MMP-9 during the bacterial meningitis is 10- to 1000-fold higher than in the cases of viral meningitis (Kolb et al., 1998). Interactions between protein molecules from host and pathogens are crucial to trigger translocation processes. Indeed, it takes two to tango: both host receptors and pathogen ligands. Underlying molecular basis of BBB translocation by various pathogens has been revealed in the last decade, however, yet an array of protein–protein interactions between many of the neuroinvasive pathogens and BBB remained fully unexplored. Identification and molecular characterization of these pathogens and host factors mediating BBB penetration can open novel perspectives in the development of more specific drugs and vaccine strategies. The research activities and authors of this review are supported by the research grants VEGA-1/0621/09, 1/0608/09, 2/0121/11, and APVV-0036-10. E.B. and P.M. contributed equally to this work. “
“To elucidate a potential role for H. pylori BabA and SabA adhesins in the pathogenesis of gastric mucosal lesions, the MBS of BabA and SabA was examined using an in-house ABA-ELISA.

Thus, infections caused by S epidermidis biofilms are particular

Thus, infections caused by S. epidermidis biofilms are particularly hard to eradicate. Biofilm formation by S. epidermidis is a multistep process and involves (1) attachment of the bacterial cells to a polymer surface or to the host-derived matrix that has previously coated the polymeric device and (2) accumulation to form multilayered cell clusters with cell-to-cell

adherence mediated by the production of a slimy extracellular matrix (Vadyvaloo & Otto, 2005). Several genes have been identified to play important roles in the biofilm formation of S. epidermidis (Mack et al., 2007). The atlE gene encodes autolysin AtlE, which mediates the initial attachment of S. epidermidis to a polymer surface (Heilmann et al., 1997), and the ica gene locus (icaADBC) encodes the biosynthesis

of polysaccharide intercellular adhesion (PIA), which is essential in the accumulation process (Heilmann et al., 1996). A few regulatory Ridaforolimus solubility dmso genes of biofilm formation were also identified (Mack et al., 2007). For example, the icaR gene affects the ability of biofilm formation by repressing the icaADBC operon (Conlon et al., 2002). The sarA gene encodes an activator of the icaADBC operon and positively regulates the biofilm formation of S. epidermidis (Tormo et al., 2005). The rsbU gene, a positive regulator of the alternative sigma factor, σB, positively regulates the biofilm formation of S. epidermidis by repressing icaR (Knobloch

et al., Nutlin-3a supplier 2004). Besides, LuxS (Xu et al., 2006) and Agr (Kong et al., 2006), a quorum-sensing system, also mediate biofilm formation in S. epidermidis. Recent work indicates that the regulation of biofilm formation in S. epidermidis is a complex networking and may involve mechanisms other than the ica system. The sarZ gene encodes a regulator that activates the transcription of the icaADBC operon in an icaR-independent manner and positively regulates the biofilm formation of S. epidermidis (Wang et al., 2008) Additionally, it is not uncommon to find clinical isolates that accumulate biofilm in an ica-independent mode (Ruzicka et al., 2004; Hennig et al., 2007; Qin et al., 2007), which indicates that there may be other mechanisms mediating biofilm formation. Protein degradation is essential for cell viability and homeostasis, and this process is commonly Sulfite dehydrogenase mediated by ATP-dependent proteases. One notable case is ClpXP proteases, which function in degrading SsrA-tagged misfolded proteins (Gottesman et al., 1998), controlling the RpoS concentration in Escherichia coli (Gottesman et al., 1998) and regulating bacterial adaptation to stress (Porankiewicz et al., 1999). ClpXP proteases also play a crucial role in the biofilm formation of Pseudomonas fluorescens (O’Toole & Kolter, 1998), Streptococcus mutans (Lemos & Burne, 2002), Staphylococcus aureus (Frees et al., 2004) and S. epidermidis (Wang et al., 2007).

Anticholinergics were used in tolterodine 1, 2 mg and propiverine

Anticholinergics were used in tolterodine 1, 2 mg and propiverine 10, 20 mg. Combination therapy significantly improved IPSS storage subscores, urgency, and QoL, compared with alpha-blocker monotherapy. There was no difference among combination therapy groups according to the kind and dosage of the drug.40 Efficacy and safety of low-dose propiverine in male LUTS patients with storage symptoms was studied in a prospective, randomized, single-blinded and multicenter clinical trial.41 Two hundred and nine men with LUTS/BPH with storage symptoms (IPSS score ≥12; storage symptoms ≥4) were randomly assigned to either the control group (alfuzosin

10 mg, once daily) or the combined group (alfuzosin 10 mg, once daily, and propiverine 10 mg, once daily) for 2 months. IPSS, Qmax, and PVR were used to grade symptoms, side-effects, and impact on QoL. In the combined group, IPSS total score and IPSS storage symptom score were significantly selleck products improved compared with the control group. The IPSS voiding symptom score, QoL, Qmax, and PVR did not differ

significantly. There were no serious side-effects in either group. In our study of propiverine 20 mg combination therapy,20 the incidence of dry mouth was 18.3%, but only 1.5% in this study. However, this study has several weak points. It is a Acalabrutinib datasheet prospective and multicenter, but open-label, single-blinded. And the follow-up period was only 8 weeks, which is shorter than in usual studies. The Qmax was not considered as an inclusion criterion and the mean prostate size was small. In addition the primary endpoint was only whether storage Carnitine palmitoyltransferase II symptoms of the IPSS improved. Recently Nishizawa et al.42 reported a randomized, controlled trial to evaluate the efficacy and safety of combination therapy of tamsulosin with propiverine in men with both BPH and OAB (TAABO study).

Men 50 years or older who had an IPSS of 8 or higher, an urgency item score of 1 or higher, and QOL score of 2 or higher were enrolled. After 8 weeks of tamsulosin 0.2 mg/day, patients who met the inclusion criteria (eight micturitions per 24 h and one urgency episode per 24 h, evaluated by bladder diary) were eligible for 12 weeks of continued Treatment II. Five hundred and fifteen patients were enrolled. Thereafter, 214 patients were assigned randomly to receive either tamsulosin alone (n = 67), tamsulosin plus propiverine 10 mg (n = 72), or tamsulosin plus propiverine 20 mg (n = 75) in Treatment II. The primary efficacy endpoint was a change in micturitions per 24 h documented in the bladder diary. The change from baseline in urgency episodes per 24 h, IPSS, IPSS/QOL subscore, urinary flow rate and PVR were assessed as secondary efficacy measures. A total of 141 men (47 tamsulosin, 49 tamsulosin plus propiverine 10 mg, and 45 tamsulosin plus propiverine 20 mg patients) were assessed by week 12.

These results suggest that the mannan within CMWS might be compos

These results suggest that the mannan within CMWS might be composed only of α-type mannose residues. For further structural characterization, we next analyzed the sample using NMR spectroscopy. Figure 4 shows the 1D-1H NMR spectra of CMWS. The spectrum of CMWS contained many

signals in the anomeric region of the mannose residues (δH 4.8–5.5 p.p.m.). Thus, we could not completely assign the signals using this technique. Therefore, we further examined samples using 1H, 13C-HSQC spectra to detect the number of signals from the mannose residues. Figure 5 shows the overlaid HSQC spectra of CMWS (black) and CAWS (blue). The overlaid HSQC spectra show 10 signals in the anomeric regions of their mannose residues (δH 4.8–5.5 p.p.m., δC 98–104 p.p.m.) that were arbitrarily labeled numbers 1–10 as described in Table 3. However, we could not completely assign all signals at this time. Therefore, we examined the anomeric conformation of their carbohydrate residues because numerous studies have reported that the anomeric conformation of mannose residues is crucial R788 order for their pathogenicity and antigenicity (27, 28).

From the observed 1JH1,C1 obtained from 1H, 13C-HSQC spectra without decoupling during acquisition, all mannose residues were assigned to α-mannose (Table 3). We next examined samples using 2D TOCSY spectra to determine the linkage types of each residue according to the method of Shibata et al. (29). The findings are described in Table 3. Notably, no qualitative differences compared to CAWS were identified. In the present study, we clearly revealed that the CMWS, which is composed of a mannoprotein-β-glucan complex, dramatically induces coronary arteritis similar to that of KD, as well as acute anaphylactoid shock, in mice. These pathogenic effects are similar to those induced Cell press by CAWS. Moreover, the structure of mannan, which is considered a factor

in induction of the above-described pathogenicities, within CMWS was quite similar to that within CAWS. Based on these findings, we concluded that Candida mannan, especially α-mannan, might contribute to Candida pathogenicity with respect to coronary arteritis and acute shock. The CMWS used in this study was mainly composed of carbohydrates (mannose and glucose) and protein, with no endotoxin contamination (Table 1). Moreover, CMWS dramatically induced coronary arteritis (Figs 1 and 2) and acute anaphylactoid shock in mice (Table 2) in the same way as CAWS does (10–17). CMWS contains 50% carbohydrates and 10% proteins. Therefore, we attempted to further purify CMWS by dialysis. After dialysis, the carbohydrate content reached 80%, after which we again assessed its biological activity in terms of induction of vasculitis and acute anaphylactoid shock in mice. We found that this purified CMWS also exhibited both pathogenic effects on mice (data not shown).

Interestingly, taurine

Interestingly, taurine selleck chemicals depletion has been found to decrease muscle force output [46], corroborating the link between amino acid level and proper tissue function both in vivo and ex vivo. Accordingly, taurine levels fluctuate in mdx muscles in relation to the disease phase, with compensatory increases being suggested after acute degenerative phases and glucocorticoid treatment [28–30]. Future studies will further evaluate the role of taurine as a pathology modifier as well as a biomarker. However, the significant increase in amino acid content presently

observed on combined treatment shows that taurine can be effectively up-taken by fast-twitch muscle, in line with previous observations [45], and that this mechanism may account for the amelioration of excitation-contraction coupling. However, the possible muscle-type and organ-specific actions also have to be taken into account in the overall action of taurine. The drug combination did not lead to any advantage in terms of plasma levels of CK vs. the two drugs alone, while the beneficial effect of taurine on LDH was

attenuated. The lack of effect of PDN on muscular enzyme activity in dystrophic subjects has been described, but no data are available about taurine. However, taurine supplementation has been found to reduce plasma levels of LDH and CK in an isoprenaline-induced cardiomyopathy click here model [47]. Thus, our result suggests that taurine controls metabolic distress in exercised dystrophic animals, being less effective on

a marker of sarcolemmal weakness such as CK. The correlation between muscle damage and level of muscular enzymes in the blood stream is puzzling. In fact, many drugs acting as anti-inflammatory and/or antioxidant, or strategies able to enhance others dystrophin, may exert a membrane protective effect leading to a significant reduction of CK, in parallel with histological evidence of decreased dystro-pathology signs [15,33,35]. However, in the absence of a specific membrane effect of the drug, an increased muscular activity due to an improved muscle function may also maintain elevated levels of CK. Thus, the evaluation of the histology profile was of importance to better verify the outcome of the present treatments. Interestingly, the combined drug treatment did not show any clear advantage on histology profile, with effects rather similar, if not smaller, than those observed by PDN alone. Thus, the results suggest that the amelioration of in vivo and ex vivo functional parameters are indeed related to the increased levels of the aminoacid and its action on calcium homeostasis, while the protection against dystrophic degeneration is mainly due to the action of PDN.

Thus, the data from ablation models cannot be interpreted without

Thus, the data from ablation models cannot be interpreted without also taking into account the actual rather than predicted ablation patterns, the kinetics of deletion and regeneration, the effect on the remaining DC compartment and the role the depleted cell populations may play in immune homeostasis in the steady state. Models in which MHC alleles required for specific antigen presentation are expressed only by a defined DC

subset would overcome most, if not all, of the problems associated with DC immunization, ABT-888 price antibody targeting and ablation strategies. By retaining the entire complement of DC subsets with their normal transcriptional and biochemical programme, these models have the potential

to define DC biology in a physiological context. So far, this aim has been achieved only for radioresistant DC subsets, namely LCs. A number of published models have studied responses to LCs in MHC-disparate bone marrow (BM) chimeras in which LCs remain of host origin, whereas the majority of DDCs and cDCs are replaced [6, 8, 80-82]. The functional capacity of LCs can then be assessed using well-characterized TCR transgenic T cells whose specificity is restricted by an MHC allele encoded within the radioresistant host genome. MHC I-restricted models have made use of the fact that the Kbm1 mutant allele does not allow presentation of the ovalbumin (OVA) epitope to CD8+ OT-I TCR-transgenic T cells. In these models, OT-I stimulation capacity is restricted to LCs and radioresistant stromal cells of the H-2k host reconstituted with H-2Kbm1 BM [82]. Peptide 17 The preservation of deletion of OT-I cells in response to skin-derived antigen has been interpreted as indicating that LCs can induce CD8+ T cell deletion in vivo, but the possibility that the effect was mediated via MHC I-expressing LN stromal Fossariinae cells cannot be excluded [82]. In contrast, MHC II-dependent skin responses are effectively restricted only to LCs in MHC II-disparate chimeras,

as LN stromal cells do not express MHC II [8]. Two groups have published results from such models. Allen et al. used wild-type hosts reconstituted with MHC II-knock-out (H2-Ab1–/–) BM and concluded that LCs were unable to support CD4+ T cell proliferation [80]. However, reconstitution with MHC II-knock-out BM would generate an immune system in which tonic MHC II-dependent TCR signalling was deficient due to a lack of MHC II expression by the vast majority of DCs [83-86]. Such tonic TCR signalling is known to be critical for the maintenance of TCR sensitivity and responsiveness to activation, motility and memory generation within the CD4+ T cell compartment [87-90]. Thus the lack of CD4+ T cell response may have been due to the failure of most DCs to express MHC II, rather than an inability of LCs to support T cell proliferation under physiological conditions.

The data showed consistency with a recent report suggesting the e

The data showed consistency with a recent report suggesting the expression of Il10 mRNA in CD19+ B cells of draining LN of susceptible mice at the first day post-inoculation, and it was shown that B cells play as a source of IL-10 which influences the susceptibility of BALB/c

mice to L. major infection [30]. At the late stage of the infection, augmented expression of this cytokine was documented at W3 and then tended to gradually decrease at W5 and W8 post-infection. DE5 strain showed the highest level of expression at W3 post-infection. It seems that IL-10 along with IL-4 cytokine is responsible for the susceptibility of the BALB/c mice to L. major infection, as suggested before [31]. Hence, our results showed that the contribution of DNA Damage inhibitor DA39 strain in eliciting Il10 mRNA expression is lower than most strains at 16 h and during the late stage of infection. Taken together, the results of this study show that different strains of L. major display different virulence and induce different patterns of cytokine expression in BALB/c mice. While DA39 strain induced the lowest parasite load, high-level expression of Th1-related cytokines mRNA RGFP966 and higher Ifng/Il4 mRNA ratio in LN of BALB/c mice, the SH25 strain elicited the highest number

of viable parasite in LN of the infected mice and a lower level of Ifng/Il4 mRNA ratio than DA39 strain at 40 h and 8 weeks post-infection. Interestingly, DA39 strain has failed to induce higher expressions of both Il4 and Il10 mRNA, especially at the late stage of the infection. It is noteworthy that in our previous study, similar results in the parasite burden and the generation of IFN-γ induced by DA39 strain were reported at 4 weeks post-infection, however at that study, we reported

higher levels of IFN- produced by DE5 strain than DA39 at W8 post-infection [14]. The reason for this discrepancy may be attributed to the methods used for the cytokine evaluation. It might be considered that the expression of the cytokines mRNA by real-time PCR seems to be a more precise method than assessment of the cytokine in lymphocyte culture. Moreover, the Thymidylate synthase present study was repeated for three times, and the third experiment results were reported as representative. Therefore, DA39 strain might be considered as an ideal strain for the vaccine studies. In conclusion, our results showed variable parasite loads and different expressions of cytokine mRNA in LN of mice infected with the four strains of L. major. Amongst the four strains isolated from the four endemic areas of Iran and analysed by SSCP, DA39 strain induced lower load of parasites in LN of the inoculated BALB/c mice. Moreover, this strain elicited higher expressions of Ifng and Il12 mRNA and lower expressions of Il4 and Il10 mRNA in draining LN of the infected BALB/c mice at early and late stages post-infection.

elegans genome has led to the conclusion that host defence is med

elegans genome has led to the conclusion that host defence is mediated by transcription factors that differ from the NF-kB/Relish family. The picture emerging from a series of recent studies is that of complex communication between organs to co-ordinate the host response to infection at a systemic level. What are the organs involved in the perception of and defence against infection? What signalling pathways are involved in each organ? What

are the systemic signals involved in host defence? Pathogen-mediated C. elegans killing correlates typically with accumulation of microorganisms in the intestinal lumen [4]. When C. elegans feeds on non-pathogenic E. coli there are few intact bacteria in the intestine, although this Alectinib manufacturer number increases with age – and, presumably, immunesenescence. In contrast, when

feeding on pathogenic microbes, large quantities of intact pathogen cells accumulate in the intestinal lumen, which can become grossly distended [4]. A vast majority of pathogen response genes identified by transcriptional profiling of infected animals are expressed in the intestinal epithelium, suggesting that it is a major immune organ [8–10](J. E. Irazoqui, E. R. Troemel and F. M. Ausubel, unpublished). This mirrors recent data showing that mammalian intestinal epithelial cells sense the presence of bacteria and mount a defensive host response [11,12]. What signalling pathways act in the C. elegans intestine for the perception of and response to bacterial Clomifene pathogens? The first piece of the puzzle was identified in a forward genetic screen for mutants that exhibited shortened longevity on Pseudomonas aeruginosa (but not on non-pathogenic E. coli). This approach identified the NSY-1/SEK-1/PMK-1 p38 mitogen-activated protein kinase (MAPK) cascade as a key component of the C. elegans immune response [13,14]. NSY-1 (MAPKKK), SEK-1 (MAPKK) and PMK-1 (p38 MAPK) are the C. elegans orthologues

of human ASK-1, MKK3/MKK6 and p38, respectively, that are involved in the mammalian cellular immune response [15]. As their counterparts in mammals, NSY-1, SEK-1 and PMK-1 function linearly in a phosphotransfer cascade (Fig. 1a) [13,14]. In insects and mammals the corresponding MAPK pathway acts downstream of TLRs, but the C. elegans TLR homologue TOL-1 does not appear to play a major role in the C. elegans immune response to most pathogens [6], although it is involved in conferring some resistance to Salmonella enterica[16]. Instead, the C. elegans p38 MAPK cascade functions downstream of TIR-1 [17], the only other C. elegans protein that contains a TIR (Toll, interleukin receptor) domain that is a hallmark of TLR-mediated signalling. TIR-1 is homologous to the human SARM protein that functions as a negative regulator of TIR domain-containing adaptor-inducing interferon β (TRIF)-dependent TLR signalling downstream of TLR-3 and TLR-4 [18]. In subsequent studies, the PMK-1 cascade was found to regulate intestinal gene induction in response to infection [19].