These mice are subsequently challenged with TT (without adjuvant), which results in not only cytokine production, including IL-2 and IFN-γ, by TT-specific memory CD4+ T cells, but also stimulates the pre-activated OT-II T cells. Notably, the use of mice not exposed to a TT prime-boost regimen (thus not containing TT-specific memory CD4+ T cells) prior to adoptive transfer of pre-activated OT-II T cells or the adoptive transfer of naïve OT-II T cells into

TT-prime-boosted mice fails to induce selleck kinase inhibitor bystander activation of pre-activated or naïve OT-II T cells, respectively, following TT challenge. Interestingly, TT booster-induced bystander activation of pre-activated OT-II T cells correlates with IL-2 and IFN-γ production in TT-specific memory CD4+ T cells. Moreover, pre-activated OT-II T cells express high levels of IL-2 receptors α and β (CD25 and CD122, respectively), as well as high levels of IL-7Rα (CD127), and proliferate strongly in the presence of IL-2 or IL-7 in vitro. Crizotinib solubility dmso These data suggest that TT challenge leads to marked IL-2 production by TT-specific memory CD4+ T cells, thus causing IL-2-mediated bystander proliferation of pre-activated OT-II CD4+ T cells. A question that arises is to what extent these results are applicable to the in vivo situation, especially in terms of the

cytokine signals implicated and the CD4+ T cells responding to them. Previous reports showed that bystander activation of CD4+ T cells was confined to the CD44high memory subset and that the kinetics of activation in the CD44high MP CD4+ cells was similar to that of the MP CD8+ T cells 1, 2, suggesting that the same cytokine, namely IL-15, might be implicated in both processes (Fig. 1). Indeed, CD44high MP CD4+ T cells express intermediate levels of CD122 7 and might thus respond not only to IL-15, but also to IL-2. Moreover, other data suggest that IL-2 might be implicated in bystander activation of CD8+ T cells

8, 12, which is consistent with the data of Di Genova et al. on CD4+ T cells 8, 12. As for the in Pregnenolone vitro pre-activated CD4+ T cells used by Di Genova et al. 8, 12, these cells are clearly different from memory CD4+ T cells, the latter of which are known to express low levels of CD25, intermediate levels of CD122, and high levels of CD127 13, 14. Moreover, memory CD4+ T cells are known to be responsive to IL-7 and IL-15 signals under steady-state conditions in vivo 14, 15, while in vitro pre-activated CD4+ T cells are, by contrast, very sensitive to IL-2 and IL-7, but not IL-15 12. This discrepancy in the IL-2- and IL-15-responses further illustrates that in vitro pre-activated CD4+ T cells crucially depend on high surface expression of CD25, as the other two IL-2 receptor subunits, CD122 and γc should have been sufficient to confer responsiveness to IL-15.

J Am Soc Nephrol. 2008; 19:2384–2395. 5. Kajiyama T, Suzuki Y, Kihara M, et al. Different pathological roles of toll-like receptor 9 on mucosal B cells and dendritic cells

in murine IgA nephropathy. Clin Dev Immunol. 2011; 2011:819646. 6. Maiguma PLX3397 molecular weight M, Suzuki Y, Suzuki H, et al. Dietary zinc is a key environmental modifier in the progression of IgA nephropathy. PLoS One. 2014; 28;9:e90558. 7. Moldoveanu Z, Wyatt RJ, Lee JY, et al. Patients with IgA nephropathy have increased serum galactose-deficient IgA1 levels. Kidney Int. 2007;71:1148–1154. 8. Suzuki H, Kiryluk K, Novak J, et al. The pathophysiology of IgA nephropathy. J Am Soc Nephrol. 2011; 22:1795–1803. 9. Nakata J, Suzuki Y, Suzuki H, et al. Changes in Nephritogenic Serum

Galactose-Deficient IgA1 in IgA Nephropathy following Tonsillectomy and Steroid Therapy. PLoS One. 2014; 21;9:e89707. WANG JI-GUANG Centre for Epidemiological Studies and Clinical Trials, The Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, China Excessive sodium in the human body, as a consequence of either increased dietary intake or decreased urinary excretion, is a well-established risk factor of hypertension. However, the blood pressure response to dietary sodium intake varies substantially between individuals. For instance, even within a population of a similar modern lifestyle, people may have quite different levels of blood pressure and different risks of hypertension. fantofarone If the blood pressure response to a certain amount of sodium intake is typically greater, this

phenomenon is called “salt-sensitive”. The opposite is called “salt-insensitive” Ixazomib or “salt-resistant”. Salt-sensitive hypertension is more likely to be seen in Asians than other populations and often shows a non-dipping pattern. The mechanism of salt-sensitive phenomenon is complex and influenced by many factors, such as renal function, functions of the neuronal and hormonal regulatory system, and the structure and function of the vascular system. Salt-sensitive can be inherited genetically or acquired in the lifetime. Among the complex mechanisms for salt-sensitive, renal sodium handling must play a major role in the determination of the inter-individual variability in the blood pressure response to dietary sodium intake, because the kidney determines whether sodium is reabsorbed back to the blood or excreted into the urine. Our recent data has indicated that proximal renal tubular reabsorption of sodium impacts the relationship between dietary sodium intake and blood pressure, especially during sleeping night-time hours. When the proximal tubular reabsorption is high, blood pressure is high at the current usual range of dietary sodium intake. However, when the proximal tubular reabsorption is low, blood pressure is positively associated with dietary sodium intake. Renal tubular dysfunction might be a cause of salt-sensitive volume expansion hypertension.

[80] Protein–DNA selleck products cross-linking studies have suggested that cRAG1/cRAG2 may form specific contacts with the heptamer of RSS.[81, 82] In addition, binding assays have shown that cRAG1, even in the absence of RAG2, could bind to RSS in a manner that was specific to both heptamer and nonamer.[38, 82] RAG1 and RAG2 can interact and exist as a complex.[83] Modification interference and direct footprinting studies indicated that RAG1 alone could make extensive contacts with the nonamer,

whereas RAG2 is needed for the heptamer occupancy.[81] Direct interaction between RAG2 and DNA in the RAG1/RAG2/RSS complex has also been reported.[77] Fluorescence anisotropy and gel mobility shift assays indicate that RAG1 exhibits sequence specific binding character. It has been suggested that this property is masked by its non-specific DNA interactions and addition of RAG2 effectively rescues RAG1 from this non-specific binding.[84] Using chromatin immunoprecipitation, it was shown that in vivo RAG binding was focused at the ‘recombination centres’ involving a small region encompassing J (and where present, J-proximal D) subexons

in the IgH, IgK, TCRB and TCRA loci.[85, 86] The study showed that RAG2 binds throughout the genome at sites with substantial levels of H3K4me3. RAG1 binding was shown to be restricted to highly active chromatin in the presence of arrays of RSSs.[85, 86] Expression of RAG in early B cells occurs in two waves, the former is responsible for V(D)J rearrangement of IgH genes in pro-B and pre-B-I cells and the latter for Selleckchem 5-Fluoracil VJ recombination of the IgL genes

in small pre-B-II cells.[87] There are also reports of a third wave of RAG expression, induced in activated mature B cells in vitro and in vivo.[88] Spleen B cells from mice activated with lipopolysaccharide Tangeritin or interleukin-4 showed expression of RAGs.[88] Mice immunized with the antigen trinitrophenyl-keyhole limpet haemocyanin also showed expression of RAG1 and RAG2 in the inguinal and popliteal cells of draining lymph nodes.[88] In addition, immature B cells carrying self-reactive receptors exhibited up-regulated RAG expression. Following B-cell antigen receptor cross-linking, an increased level of RAG mRNA was reported in cultures of developing B cells.[89, 90] The sustained RAG expression allowed secondary V(D)J recombination that involves the replacement of self-reactive antibody V region genes by the V(D)J recombination. During this process, B cells with a non-self-reactive receptor are allowed to exit from prolonged V(D)J recombination, whereas the self-reactive cells are retained for further editing, until they produce a non-self-reactive receptor.[91] ‘Receptor editing’ refers to the secondary rearrangement that occurs in immature B and T cells, which plays a role in mediating tolerance.

The determination of the chemical composition of the extracellular polymeric substances (EPS) of the biofilm matrix, as well as the elucidation of the sensitivity of biofilms to enzymatic degradation should facilitate

the development of new therapies against biofilm-related infections. Ponatinib The chemical analyses of EPS had shown qualitative and quantitative variations of their nature, depending on the strains and culture conditions. The poly-N-acetylglucosamine (PNAG) is considered the main component of staphylococcal biofilms. However, certain strains form biofilms without PNAG. In addition to PNAG and proteins, extracellular teichoic acid was identified as a new component of the staphylococcal biofilms. The sensitivity of staphylococcal biofilms to enzymatic treatments depended on their relative chemical composition, and a PNAG-degrading enzyme, in conjunction with proteases, could be an efficient solution to eliminate the staphylococcal biofilms. A detection of specific ‘antibiofilm’

antibodies in the blood serum of patients could serve as a convenient noninvasive and inexpensive diagnostic tool for the detection of foreign body-associated staphylococcal infections. Used as a coating antigen in the enzyme-linked immunosorbent assay test, PNAG did not sufficiently discriminate healthy individuals from the infected patients. LDE225 While Staphylococcus aureus is known as a pathogen with a number of virulence factors (e.g. exotoxins and enzymes), Staphylococcus epidermidis is mainly a normal inhabitant of the healthy human skin and mucosal microbial communities. As a commensal bacterium, it has a low pathogenic potential. In recent decades, however, S. epidermidis and other coagulase-negative staphylococci

(CoNS) have emerged as a common cause of numerous nosocomial infections, mostly occurring in immunocompromised hosts or patients with implanted medical devices, such as intravascular and peritoneal dialysis catheters, prosthetic heart valves, or orthopaedic implants (Ziebuhr et al., 2006). These infections can be described as ‘chronic polymer-associated infections’ (Götz, 2002). A characteristic feature of this kind of infection is the ability of the causative microorganisms to colonize surfaces of biomaterials in multilayered biofilm-structured Exoribonuclease communities of cells enclosed in a self-produced polymeric matrix, an amorphous slimy material, which is loosely bound to staphylococcal cells. This ability to form biofilms is believed to make the microorganisms more resistant to administered antibiotics and to the defence mechanisms of host immunity (von Eiff et al., 1999). Evidence suggests that biofilm formation also plays a role in S. aureus wound infections (Akiyama et al., 1996) and osteomyeltis (Buxton et al., 1987). To date, no efficient treatment or early diagnostics of implant-associated infections has been proposed.

Our results demonstrated the bacteria were resistant to the extreme conditions faced in the gut, in line with previous reports [17]. The current studies assessed the ability of common probiotics to induce cytokine production from PBMCs, cord blood cells and spleen-derived macrophages. The substantial concentrations of IL-2, IL-12, IL-17 and IFN-γ produced by PBMCs in this study indicate the cells’ potential to prevent/fight infection. LGG has been reported to aid in the prevention of atopic dermatitis in infants and as well as alleviate food allergy [31,32]; if these effects are largely IL-12-driven, St1275, B94 and E. coli in our study may probably be as effective in their immunomodulatory effects. Miettinen

et al. [15] reported that LGG induced the production of proinflammatory cytokines such as IL-6, IL-12 and IFN-γ but limited IL-10 from human PBMC. Conversely, in our study LAVRI-A1, LGG and bifidobacteria induced KPT-330 in vivo significantly higher concentrations of IL-10 from PBMCs compared to the proinflammatory cytokines, which makes these probiotic strains good candidates for management of autoimmune disorders. In the current study we report that selected probiotics induced significant amounts of proinflammatory cytokines, including IL-2, which

is a critical cytokine for clonal expansion of recently antigen-activated T cells and in Treg homeostasis [33]. Macrophage-produced IL-12 stimulates IFN-γ production in T cells and natural killer cells, which accelerates the development of naive Farnesyltransferase CD4+ T cells into Th1-type cells [34]. Therefore, IL-12 is a key immunoregulator favouring Th1-type responses. However, IFN-γ in turn induces IL-12 production, which ABT-263 molecular weight can cause a positive feedback loop of IFN-γ and IL-12 production and can be detrimental,

leading to uncontrolled cytokine production and possible shock [35]. IL-17 has been found recently to be elevated in the intestinal tissue and serum of patients with inflammatory bowel disease (IBD) and other autoimmune disorders [36]. In contrast, anti-inflammatory cytokines IL-4, IL-10 and TGF-β were also found to be produced in significant concentrations by our healthy PBMCs with the co-culture of selected bacteria. These cytokines function to inhibit IL-12 and the production of other proinflammatory cytokines from antigen-presenting cells, including macrophages, as well by inducing expression of other co-stimulatory surface molecules and soluble cytokines [37]. Our findings show that all the selected bacteria, especially LAVRI-A1, LGG and bifidobacteria, induced significant secretion of IL-10 and TGF-β, which was in line with earlier reports on L. acidophilus and bifidobacteria [14,38,39]. In addition to its activity as a Th2 lymphocyte cytokine, IL-10 is also a potent deactivator of monocyte/macrophage proinflammatory cytokine synthesis [40]. TGF-β1 down-regulates monocyte and macrophage activity in a manner similar to IL-10, albeit less potently [41].

Thus, IgG-mediated protective immunity Panobinostat in vitro appears to act predominately against the larval stages of the parasite, which are also the major stimulus for acquired immunity and the target of acquired responses [36]. The next challenge will be to determine the mechanisms by which IgG antibodies target H. p. bakeri larvae. Numerous possibilities exist, perhaps acting in parallel or even synergistically, including neutralization of larval products required for tissue migration/feeding and for evasion of the

immune response or antibody-dependent cellular activation and the consequent destruction or trapping of larvae by immune cells. Of note, macrophages are also required for protective immunity against H. p. bakeri [73], and both antibodies and macrophages are abundant in the Th2-type granuloma surrounding the larvae [55, 73]. These findings raise the possibility that antibodies may activate macrophages to kill or trap parasitic larvae. Whether this occurs still needs to be determined, but it is known that larvae can survive in the granuloma for a long time, as they can be re-activated to continue their growth and maturation into fecund adults by treatment with immunosuppressive corticosteroids as

long as 3 weeks after challenge infection [74]. The entrapment of larvae in granuloma and their eventual destruction could involve binding of IgG to the high- or low-affinity receptors, FcγRI and FcγRIII, known to be expressed by macrophages [75]. Alternatively, antibodies may act in an indirect manner ICG-001 chemical structure by promoting the recruitment of immune cells into

the granuloma or by activating complement. In this find more regard, a recent publication indicated that antibodies play an important role in mediating the production of basophils within the bone marrow following H. p. bakeri infection [72]. However, specific depletion of basophils had a minor impact on larval killing, indicating that this is not the major pathway of antibody-mediated protective immunity [72]. As discussed, H. p. bakeri forms a chronic infection in most mouse strains following primary infection. In the poor responder strain, C57BL/6, B-cell deficiency had little impact on the development of adult worms 14 days following infection [55]. However, fecundity was strikingly increased and remained high for several weeks following primary infection of B cell–deficient mice [55]. Primary infection with H. p. bakeri infection elicits a striking, but largely polyclonal, IgG and IgE response, and the observed impact on worm fecundity could be ascribed to low-affinity IgG antibodies, [55]. These low-affinity IgG antibodies were present even in naïve animals presumably in response to environmental antigens or intestinal bacteria and were amplified by infection [55]. This contrasts with the ability of antibodies to provide protective immunity against challenge infections, where high-affinity parasite-specific antibodies are necessary. Thus, early production of polyclonal antibodies following primary infection with H.

We also tried to identify the origin of metanephric mesenchyme by lineage trace experiments utilizing T-GFPCreER mice. Next, we examined the combinations of factors which are required for

metanephric nephron progenitor specification from embryonic nascent mesoderm. Finally, by applying this protocol, we tried to establish the way to induce metanephric nephron progenitors and reconstitute three-dimensional kidney structures from PSCs. Results: We identified that the MM is originated from posteriorly located T+ precursors at embryonic day (E) 8.5, and that developmentally distinct from Osr1+ UB progenitors. T+ cells sorted from mouse embryos differentiate into the metanephric mesenchyme in vitro by posteriorization with a high concentration of PD-332991 Wnt agonist, followed by its graded attenuation and stage-specific growth factor addition. When mouse and human pluripotent stem cells were treated similarly, metanephric nephron progenitors were obtained that could reconstitute the three-dimensional structures of the kidney, including glomeruli with podocytes and renal tubules with proximal and distal regions and clear lumina. Furthermore, the glomeruli were

efficiently vascularized upon transplantation. ALK activation Conclusion: We have succeeded in inducing the metanephric nephron progenitors from both mouse embryonic stem (ES) cells and human induced pluripotent stem (iPS) cells, in vitro. The resultant progenitors readily formed the three-dimensional structures of the kidney, comprising renal tubules and notably glomeruli with podocytes, which has not previously been achieved. Thus, by re-evaluating the developmental origins of metanephric progenitors, we have provided key insights into kidney specification in vivo and taken important steps toward kidney organogenesis

in vitro. LIU CHUN-BEI1,2, KANAMARU YUTAKA1, WATANABE TOMONARI1, TADA NOBUHIRO3, Amrubicin SUZUKI YUSUKE1, TOMINO YASUHIKO1 1Division of Nephrology, Department of Internal Medicine, Juntendo University Faculty of Medicine, Tokyo; 2Research Institute of Nephrology, Jinling Hospital, Medical School of Nanjing University, Nanjing, China; 3Juntendo University Research Institutefor Diseases of Old Ages Introduction: Macrophages are crucial for the formation and progression of atherosclerosis. OxLDL, which could be accumulated by macrophage to form foam cell, has been described to promote atherosclerosis by the activation of mitogen-activated protein kinase(MAPK) induced phosphorylation evens. Whether FcαRI target therapy by monoantibody of FcαRI, which effectively inhibit MAPK pathway, could influence the progression of atherosclerosis is unclear. Methods: We constructed ApoE-deficient mice expressing human FcαRI/g and did a 2 times/month’s spleen macrophage transfer from these mice to APOE−/− mouse. Atherosclerosis was promoted by high fat diet for 3 months and FcαRI target therapy was given simultaniously for same duration.

We TSA HDAC purchase are grateful to Dr Morris Reichlin, Dr John Harley, the University of Oklahoma Health Science Center Molecular Biology Proteomics Facility and the Oklahoma Clinical Immunology Serum Repository and staff for access to samples and for all of their additional assistance. We are also grateful to Shelly Biby, Derek Handke and Roy Rindler for their technical

assistance. We also thank Julie Robertson, PhD for scientific editing. This work was supported in part by grants from the National Institutes of Health, Oklahoma Autoimmune Centers of Excellence and Rheumatic Disease Research Core Center (AI47575, AR45451, AR48045, RR15577, AR48940, RR020143, AR49084, AR053483 and AI082714) and from the Lou C. Kerr Chair in Biomedical Research at the Oklahoma Medical Research Foundation. The authors have no financial disclosures related to this manuscript. “
“Chronic inflammation is associated with promotion of malignancy and tumor progression. Many tumors enhance the accumulation of myeloid-derived suppressor cells (MDSC), which contribute to tumor progression and growth by suppressing anti-tumor immune responses. Tumor-derived IL-1β secreted into the tumor microenvironment has been shown to induce the accumulation of MDSC possessing an enhanced capacity to suppress T cells. In this study, we found that the enhanced

suppressive potential of IL-1β-induced MDSC was due to the activity of a novel subset of Selleckchem Sorafenib MDSC lacking Ly6C expression. This subset was present at low frequency in tumor-bearing mice in the absence of IL-1β-induced inflammation; however, under inflammatory conditions, Ly6Cneg MDSC were predominant. Ly6Cneg MDSC impaired NK cell development and functions in vitro and in vivo. These results SSR128129E identify a novel IL-1β-induced subset of MDSC with unique functional properties. Ly6Cneg MDSC mediating NK cell suppression may thus represent useful targets for therapeutic interventions. Epidemiological studies emphasize the role of chronic inflammation in the promotion of various types of cancers (reviewed in 1). The hallmarks of cancer-related inflammation include the presence at the tumor site of

cytokines such as IL-1β, TNF-α, IL-6 and IL-23 1–3. IL-1β is a pleiotropic cytokine and induces the production by stromal and tumor-infiltrating cells of a cascade of molecules, including IL-6, prostaglandins and adhesion molecules that induce, sustain and expand the inflammatory response (reviewed in 3, 4). In the tumor microenvironment, IL-1β promotes angiogenesis 5, 6, tumor invasiveness (reviewed in 7), carcinogenesis 8, 9 and affects immune function by many ways including indirectly through the accumulation of myeloid-derived suppressor cells (MDSC) 9–12. MDSC represent a heterogeneous population of myeloid cells defined in the mouse as Gr-1+CD11b+ cells encompassing granulocytes, macrophages, dendritic-like cells and early myeloid progenitors (reviewed in 13, 14).

[3] In the absence of a population-based study, the exact prevalence of mucormycosis in India remains difficult to elucidate.[3] However, on the basis of data available from certain groups of patients, the disease prevalence appears to be nearly 0.16% amongst diabetics and 1.2% amongst renal transplant Alisertib recipients, with most of these cases manifesting as the ROC form.[16, 17] Also, gastrointestinal mucormycosis reportedly occurs in nearly 20% of all operated cases of neonatal enterocolitis in one center.[18] In fact, the frequency of gastrointestinal mucormycosis was found to be so high in that

centre that clinicians suspect the disease in any neonate having intestinal perforation. We recently reviewed Indian literature for the past five decades (1960–2012), and developed a computational model to determine the burden of mucormycosis. The results reveal an

overall mucormycosis prevalence of 0.14 cases per 1000 population in India, with the prevalence range between 208 177 and 137 807 cases (Mean: 171 504; SD: 12 365.6; 95% CI: 195 777–147 688) and a mean of 65 500 (38.2%) attributable deaths per year.[19] Based on the clinical presentations, ROC is the most common form of mucormycosis in India, possibly due to its association Selleckchem Ulixertinib with uncontrolled diabetes and diabetic ketoacidosis.[1, 3, 20] According to the multiple case series reported from our tertiary care centre in North India, the prevalence of different clinical types amongst mucormycosis cases is: ROC (48–55%), cutaneous (13–15%), pulmonary almost (7–17%), disseminated (5–12%), gastrointestinal (5–13%) and isolated renal (5–14%).[4-6] Likewise, in a meta-analysis of all the zygomycosis cases reported from India, Diwakar et al. describe an overall prevalence of ROC (58%), cutaneous (14%), pulmonary (6%), disseminated (7%), gastrointestinal (7%) and isolated renal (7%).[21] This is consistent with the global trend, wherein pulmonary and sinus infections (with/without central

nervous system involvement), followed by cutaneous type have been found to be the most prevalent.[22-25] Cases of necrotising fasciitis due to zygomycetes, occurring via contaminated intramuscular injections, are also a common finding.[7, 26] This happens due to compromise in healthcare practices and the use of contaminated needles. In addition, majority of the patients (60%) with cutaneous infections due to Apophysomyces elegans are from India.[1, 7, 27] The patients are usually immunocompetent individuals, who acquire the infection following penetrating trauma or burns.[1, 7, 27] However, no correlation between the environmental prevalence of this fungus and clinical cases has been described yet.

The infected mice displayed a significant up-regulation in the expression of chemokines (Cxcl1, Cxcl2 and Ccl2), numerous pro-inflammatory cytokines (Ifng, Il1b, Il6, and Il17f), as well as Il22 and a number of anti-microbial peptides (Defa1, Defa28, Defb1, Slpi and Reg3g) at the site(s) of infection. This was accompanied by a significant influx of neutrophils, BAY 57-1293 dendritic cells, cells of the monocyte/macrophage lineage and all major subsets of lymphocytes to these site(s). However, CD4 T cells of the untreated and C. difficile-infected mice expressed similar levels of CD69 and CD25. Neither tissue had up-regulated levels of Tbx21, Gata3 or Rorc. The caeca and colons of the

infected mice showed a significant increase in eukaryotic initiation factor 2α (eIF2α) phosphorylation, but neither the splicing of Xbp1 nor the up-regulation of endoplasmic reticulum chaperones, casting doubt on the full-fledged induction of the unfolded protein response by C. difficile. They also displayed significantly higher phosphorylation of AKT and signal transducer and activator of transcription 3 (STAT3), an indication of pro-survival signalling. These data

underscore the local, innate, pro-inflammatory nature of the response to C. difficile and highlight eIF2α phosphorylation and the interleukin-22–pSTAT3–RegIIIγ axis as two of the pathways that could be used to contain and counteract the damage inflicted on the intestinal Pictilisib in vitro epithelium. Clostridium difficile is a Gram-positive, spore-forming, anaerobic bacterium.[1] It is the most prevalent cause of infectious Non-specific serine/threonine protein kinase diarrhoea in antibiotic-treated patients in hospitals.[2, 3] Infection with C. difficile can lead to a broad range of clinical outcomes, including asymptomatic colonization, mild diarrhoea and severe pseudomembranous colitis. Clostridium difficile encodes a number of toxins. Of these, two exotoxins, TcdA and TcdB, are the bacterium’s main virulence factors. Both toxins are glucosyltransferases that irreversibly inactivate small GTPases of the Rho family.[4, 5] This in turn leads to the depolymerization of the epithelial actin cytoskeleton, impaired function of tight junctions and severe epithelial cell damage.[6-8] The use of

ileal loop models has provided useful insights into the function of these toxins.[9] Studies using mouse models of C. difficile infection have proven the higher susceptibility of MyD88−/−[10] and Toll-like receptor 4−/−[11] mice and the protective effect of Toll-like receptor 5 stimulation against acute C. difficile colitis.[12] The higher susceptibility of MyD88−/− mice is at least in part due to impaired CXCL1 expression and the consequent reduction in neutrophil influx to the site of infection.[13] Interestingly, NOD1−/− mice also have reduced neutrophil recruitment to the site of infection, but show similar levels of epithelial damage as wild-type mice.[14] However, much remains to be determined about the host inflammatory and mucosal response to C.