If, however, these Th cell responses are not regulated, immune disease ensues. In the glomerulus, this leads to inflammatory impairment, or glomerulonephritis (GN). In GN, disease outcomes have largely been explained around

the Th1–Th2 paradigm. Th1 immunopathology is characterized by an influx of delayed type hypersensitivity (DTH) effectors (macrophages, T cells and fibrin) and IgG subclass switching to IgG1 and IgG3 subclasses (in humans), while Th2 immunopathology is associated with the absence of DTH effectors and a predominance of the IgG4 antibody subclass. The explosive nature of crescentic GN is often associated with the Th1 cell subset exemplified in anti-glomerular basement selleckchem membrane (GBM) GN and pauci-immune crescentic GN while glomerular diseases such as membranous GN are associated with the Th2 cell subset. Some diseases such as IgA nephropathy and lupus nephritis are not exclusively Th1 or Th2 mediated but exhibit heterogeneic characteristics.2 A further distinct subset of Th cells, the Th17 subset, was identified in 2005, called Th17 cells because they produce IL-17A and IL-17F, members of the IL-17 cytokine family.3 Th17 cells

have been implicated in experimental models of organ-specific autoimmune inflammation, and their roles in GN will be the find more focus of this review. The discovery of Th17 cells in mice came from studies that documented the effects of IL-12 and IL-23 in experimental murine models of multiple sclerosis, rheumatoid arthritis and inflammatory bowel disease.4–6 In all three models of autoimmune disease, IL-23 played an important role whereby IL-23-deficient, but not IL-12-deficient mice, were completely protected from disease. IL-12 and IL-23 are heterodimeric cytokines of the same family and share

the same p40 subunit with different second subunits, p35 and p19, respectively.7 Prior to the identification of the p19 subunit and hence 4��8C IL-23, it was believed that IL-12 was the key cytokine in inflammatory diseases as neutralizing antibodies to p40 ameliorated disease in experimental autoimmune encephalomyelitis (EAE) (a mouse model of multiple sclerosis).8,9 IL-12 had been known to direct Th1–IFN-γ responses,10 and it was presumed that inflammatory diseases were caused by an unregulated Th1 response. It was however unexpectedly observed that mice deficient in IFN-γ11 or the receptor for IFN-γ were not protected from EAE.12 Shortly after these paradoxical observations, the IL-23p19 subunit was discovered7 and as mentioned, IL-23 is now regarded as the key cytokine in the pathogenesis of EAE, collagen induced arthritis (CIA) and mouse inflammatory bowel disease. Experimental evidence in EAE showed that IL-23 was responsible for driving the development and expansion of the distinct Th17 subset that produces IL-17A, IL-17F, tumour necrosis factor (TNF)-α and IL-6.

Apart from recognition

of triphosphate group of ATP, arginine fingers may be responsible for displacement of water out from the binding site. Such a role of arginine fingers was recently demonstrated for the Ras–RasGAP complex in the QM/MM calculations (Heesen et al., 2007). A more detailed analysis of JEV NS3 helicase/NTPase structure may lead to the conclusion that to function as a catalytic base, the pKa of Glu286 would need to be much higher than that of a typical glutamic acid residue in a protein, as Selleck Cobimetinib suggested for HCV helicase (Frick, 2007). It was thus proposed that the neighboring aspartic acid residue (Asp285 in JEV NS3 helicase/NTPase) may serve as a catalytic base instead. Docking of known JEV NS3 helicase/NTPase inhibitors 1–2 revealed engagement of crucial binding pocket residues in the interactions

with ligands. In particular, the role of Glu286 and Arg464 was clearly depicted. Moreover, docking of 1–2 allowed the identification of Arg202 as an additional important residue of the binding pocket, making this arginine a straightforward candidate for mutational studies. The analysis of ATP–enzyme complex allowed speculation about the role of conserved threonine Thr201. Most probably, it directs the ligand properly toward interactions with Lys200 and the conserved arginine residues. A similar role may be assigned to the branched side chains of apolar amino acids (especially Val227 and Ile411), which was demonstrated in the case of 2 and was suggested BGB324 clinical trial earlier for ionotropic glutamate receptors (Kaczor et al., 2008). Docking of 1–2 indicated Asn417 as an additional

anchoring point, whereas docking of identified hits 8–22 also indicated Glu231 as a potentially important residue for interactions with inhibitors. Virtual screening procedure made it possible to identify 15 potential inhibitors of JEV NS3 helicase/NTPase. Only one of them, namely the one containing pentose moiety 14, may be treated as a far analog of nucleosides. This structural diversity may prove beneficial because it increases the likelihood that the new inhibitors will be selective toward human ATPases. This is a significant problem: Cell press it is worth emphasizing that ring-expanded nucleosides 1 and 2 also have high affinity to human Suv3 mitochondrial helicase (routinely used to test the selectivity of novel inhibitors of viral helicase/NTPase), which excludes them as drug candidates (Zhang et al., 2003). On the other hand, compounds 1 and 2 were also active toward all the tested viral helicase/NTPases: WNV and HCV. This seems promising, as the research on specific anti-JEV compounds may lead to the development of a drug with broad antiviral spectrum of activity.

001). Conclusions:  Pentoxifylline reduces circulating IL-6 and improves haemoglobin in non-inflammatory moderate to severe CKD. These changes are associated with changes in circulating transferrin saturation and ferritin, suggesting improved iron release. It is hypothesized that pentoxifylline improves iron disposition possibly through modulation of hepcidin. “
“Aims:  A recent report showed that fractalkine (CX3CL1), which functions as both a potent chemoattractant and adhesion molecule for monocytes and natural killer (NK) cells was significantly increased in cisplatin-induced acute renal failure (CisARF) in mice. Therefore, we

developed Pexidartinib the hypothesis that increased CX3CL1 expression in CisARF initiates NK cell infiltration in the kidney. The aim of the present study was to determine the role of NK cells in CisARF in mice. Methods:  Time course of pan-NK positive cells in CisARF was investigated by using immunohistochemistry (IHC) for CD49b.

Pan-NK positive cells were reduced by using anti-NK1.1 mAb. The model of pan-NK positive cells reduction was confirmed by flow cytometry of the spleen and IHC of the kidney. The expression of granzyme A and caspase-1 was examined, and the activity of caspase-1 was also determined. We performed a study on whether there was significant protection of selleck kinase inhibitor renal function after reduction of pan-NK positive cells. Results:  (i) Infiltration of pan-NK positive cells was prominent on day 3 after cisplatin administration. (ii) granzyme A expression was significantly increased in CisARF and CisARF+NK1.1 Ab compared to vehicle. (iii) Caspase-1 expression and activity was significantly increased in CisARF mice compared to vehicle and CisARF+NK1.1 Ab. (iv) Reduction of pan-NK positive cells was not protective in cisplatin-induced acute renal failure in mice. Conclusions:  Although infiltration of pan-NK cells

was significantly increased in CisARF, reduction of infiltration of pan-NK cells into the kidney was not protective against CisARF in mice. “
“Antiphospholipid syndrome (APS) may occur in isolation or in association with systemic lupus erythematosus (SLE), with the potential to cause renal failure via several distinct pathologies. Renal transplantation in the presence of APS carries a risk of early graft loss from arterial or venous thrombosis, or CYTH4 thrombotic microangiopathy (TMA). Whilst perioperative anticoagulation reduces the risk of large vessel thrombosis, it may result in significant haemorrhage, and its efficacy in preventing post-transplant TMA is uncertain. Here, we report a patient with end-stage kidney disease (ESKD) due to lupus nephritis and APS, in whom allograft TMA developed soon after transplantation despite partial anticoagulation. TMA resolved with plasma exchange-based therapy albeit with some irreversible graft damage and renal impairment. We discuss the differential diagnosis of post-transplant TMA, and current treatment options.

15 mL min−1 for each channel) at room temperature as previously described (Moller et al., 1996). Bacteria

were inoculated into 10 mL of LB10 broth and incubated overnight (16–18 h) at 37 °C with shaking. Flow-cell channels were inoculated with 5 mL of the overnight culture and incubated without flow for 1 h for PAO1 and 2 h for 18A at room temperature, owing to the decreased efficiency of attachment for 18A, as described by O’May et al. (2006). M9 medium containing 48 mM Na2HPO4, 22 mM KH2PO4, 9 mM NaCl, 19 mM NH4Cl, 2 mM MgSO4, 100 μM CaCl2 and 5.5 mM glucose was used to cultivate flow-cell biofilms. All chemicals were purchased from Univar, Australia, unless otherwise indicated. Every 2 days, 2 mL of biofilm effluent was collected from the outflow of the biofilm flow cell, serially diluted using M9 salts solution without glucose and spread-plated onto LB10 agar plates. CFUs RO4929097 cell line JQ1 and biofilm variants were enumerated according to the colony morphologies exhibited after 2 days of incubation at 37 °C. As a control, planktonic cultures of the parental strains were inoculated into 10 mL of M9 medium and cultured at 37 °C with shaking and subcultured daily after overnight growth for 14 days. Sampling was performed every

2 days, and these cultures were serially diluted using M9 salt solution and spread-plated onto LB10 agar plates to detect and quantify phenotypic variants. For phenotypic characterisation, variants from PAO1 and 18A biofilms were collected PRKACG on days 6 and 10, respectively, which were determined by confocal laser scanning microscopy to correlate with hollow colony formation and cell death, hallmarks of dispersal. The mutation frequency of strains 18A and PAO1 was quantified as described by Oliver et al. (2002). Briefly, independent triplicate cultures were grown in LB10 broth (overnight, with agitation) and serially diluted, and 100-μl aliquots were plated onto LB10 agar or LB10 agar containing rifampicin (300 μg mL−1). Plates

were incubated at 37 °C for 48 h. Mutation frequencies were estimated as the mean number of rifampicin-resistant CFU divided by the total CFU (LB10 agar plates without rifampicin). Biofilms of both PAO1 and 18A strains were cultivated as continuous cultures in silicon tubing (Silastic® Laboratory Tubings) as described by Barraud et al. (2009). Briefly, 5 mL of the overnight culture was inoculated into each tube (inner diameter 2.64 mm) using a syringe, under conditions of no flow, and the injection site was subsequently sealed with silicone glue (Plastic Putty; Selleys Pty Ltd, Australia). The inoculated tubes were incubated under static conditions for 1 or 2 h for strain PAO1 and strain 18A, respectively, to allow bacteria to attach to the walls of the tubing, after which time medium flow was resumed at a rate of 0.15 mL min−1.

15 HC10 (anti HLA-B and C) and HCA2 (anti HLA-A) were kind gifts from J. Neefjes (Amsterdam, the Netherlands). Anti V5 tag (Pk) was a kind gift from R. Randall (St Andrews,

UK). BB7.2 (anti HLA-A2) was a kind gift from T. Elliott (Southampton, UK). Horseradish peroxidase -coupled anti-mouse IgG was obtained from Sigma (Poole, UK). CH-11 (anti-FasR/CD95) was obtained from Beckman Coulter, High Wycombe, UK. Approximately 30 × 106 cells were incubated overnight in serum-free RPMI-1640. Cells were removed by centrifugation at 1000 g. Supernatants were alkylated with 10 mmN-ethylmaleimide (Sigma), and then spun at 10 000 g for 30 min to remove debris, and RGFP966 molecular weight 100 000 g for 2 hr to isolate exosomes. Pellets were resuspended

directly in non-reducing sample buffer. Approximately 1 × 106 cells were treated with 1 mm diamide (Sigma) in RPMI-1640, Enzalutamide mouse 10% fetal bovine serum for 20 min at 37°. A similar number of cells were incubated with the indicated concentration of hydrogen peroxide up to 1 mm (Sigma), 5 μm thimerosal (Sigma) and 0·5 μg/ml anti-CD95 antibody for 16 hr in RPMI-1640, 10% fetal bovine serum. Cells were then isolated by centrifugation and lysed in 50 μl lysis buffer (1% nonidet P-40, 150 mm NaCl, 10 mm Tris–HCl pH 7·6, 1 mm PMSF, 10 mmN-ethylmaleimide). Lysates were centrifuged at 20 000 g for 5 min and the supernatant was heated with an equal volume of non-reducing sample buffer. For immunoprecipitation, 10 × 106 diamide-treated cells were lysed in 0·5 ml lysis buffer and immunoprecipitated with 100 μl BB7.2 antibody supernatant and 20 μl Protein G–Sepharose beads (Sigma). Washed beads were resuspended in 40 μl non-reducing sample buffer. For staining of apoptotic cells with propidium

iodide (Sigma), cells were washed twice in PBS, fixed in 70% ethanol at 4° for at least 30 min, washed twice in PBS and then resuspended in PBS containing 8 μg/ml propidium iodide. Apoptosis was also measured by staining with Annexin V-FITC. Briefly, 1 × 105 cells were resuspended in 100 μl binding buffer (10 mm HEPES, pH 7·4, 140 mm NaCl, 2·5 mm CaCl2), and 5 μl FITC-Annexin selleck products V (Invitrogen, Paisley, UK) for 10 min at room temperature. Cells were then analysed on a FACScan (BD Biosciences, Oxford, UK) using Cellquest software. Incubation of 1 × 105 of the indicated cells in 100 μl medium with 10 μl of Dojindo cell counting kit-8 (CCK-8/WST-8) reagent (NBS Biologicals, Cambs, UK) for 3 hr at 37° was followed by reading of the resulting colour shift at 495 nm on a Dynex MRX plate reader. The same number of cells were incubated with 50 μm monochlorobimane (Sigma) for 20 min at 37°, the supernatant was then removed carefully, and cells were lysed in PBS containing 0·1% SDS.

“
“Dengue is a mosquito-borne viral disease selleck chemicals llc of humans,

and animal models that recapitulate human immune responses or dengue pathogenesis are needed to understand the pathogenesis of the disease. We recently described an animal model for dengue virus (DENV) infection using humanized NOD-scid IL2rγnull mice (NSG) engrafted with cord blood haematopoietic stem cells. We sought to further improve this model by co-transplantation of human fetal thymus and liver tissues into NSG (BLT-NSG) mice. Enhanced DENV-specific antibody titres were found in the sera of BLT-NSG mice compared with human cord blood haematopoietic stem cell-engrafted NSG mice. Furthermore, B cells generated during the acute phase and in memory from splenocytes of immunized BLT-NSG mice secreted DENV-specific IgM antibodies with neutralizing activity. Human T cells in engrafted BLT-NSG mice secreted

interferon-γ in response to overlapping DENV peptide pools and HLA-A2 restricted peptides. The BLT-NSG mice will allow assessment of human immune responses to DENV vaccines and the effects of previous immunity on subsequent DENV infections. Dengue virus (DENV) is a mosquito-borne member of Angiogenesis inhibitor the Flavivirus genus and includes four serotypes (DENV-1, DENV-2, DENV-3 and DENV-4). The virus infects approximately 50 million individuals each year, leading to over 500 000 hospitalizations. Infection results in a range of symptoms from mild fever to acute febrile illness (dengue fever). In a small percentage of cases, however, individuals develop a severe capillary leakage syndrome, dengue haemorrhagic fever and dengue shock syndrome, which can be life-threatening.1,2 Studies in humans suggest that dengue haemorrhagic fever and dengue shock syndrome are more likely to occur in individuals experiencing Exoribonuclease their second DENV infections and in infants born to DENV-immune mothers. Experimental manipulation of in vivo immune responses to DENV is a critical step in exploration of the role of previous immunity in subsequent DENV infection

and testing of candidate vaccines and therapeutics. Progress in understanding the pathogenesis of dengue haemorrhagic fever has come largely from controlled well-designed clinical studies of patients with mild and severe forms of dengue disease in endemic areas.3–10 Most patients who present to hospital live in endemic areas and are experiencing a secondary infection; however, the serotype of the previous DENV infection is difficult to determine. Furthermore, controlled virus challenge studies are not feasible in humans, and it is difficult to assess the contribution of antibodies or T cells to DENV pathogenesis. Immunodeficient mice bearing components of a human immune system (humanized mice) present a novel approach for studying human immune responses to DENV.

These findings therefore demonstrate that IVIg operates through distinct pathways in naïve mice versus mice in which disease had already been initiated. Nevertheless, the therapeutic function of IVIg still required the inhibitory Fc receptor FcγRIIB [5], suggesting some conserved molecular checkpoints between the preventive and therapeutic modes of actions of IVIg. A possible interpretation for the facultative role of SIGN-R1 in the therapeutic

context could be that a distinct “SIGN-R1-like” receptor is upregulated during the course of the disease. Based on the role of SIGN-R1 in naïve mice, it is tempting to speculate that this role would also be played by a C-type lectin receptor after disease onset. A particularly interesting JAK inhibitor candidate is the dendritic cell immunoreceptor (DCIR), which

was recently identified as a crucial receptor for IVIg in a model of allergic airway disease [29], and is one of the few C-type lectin receptors containing a classical immunoreceptor tyrosine-based inhibitory signaling motif (ITIM) in its intracytoplasmic tail [30]. Noteworthy, the glycan binding specificity of C-type lectins is strongly determined by an amino acid triplet in their carbohydrate recognition domain [31]. These triplets are EPS and EPN for DC-SIGN and DCIR, respectively, suggesting that these receptors might share ligand-binding properties, as indicated by their shared capacity to bind IVIg. The immunosuppressive potential of Rho DCIR is further illustrated by the fact that mice Ivacaftor price deficient in the corresponding gene spontaneously developed autoimmune symptoms typically found in Sjogren’s syndrome, rheumatoid arthritis, or ankylosing spondylitis [32]. Moreover, polymorphisms in the Dcir gene have been associated with rheumatoid arthritis [33]. Further studies will be required to assess the role of DCIR in the

beneficial effect of IVIg in the antibody-driven disease models listed above. Another critical question will be to identify the cell type(s) responsible for the therapeutic effect of IVIg. In this context, the study of Schwab et al. [5] is important because it emphasizes the importance of focusing on a therapeutic rather than a preventive context to dissect the mode of action of IVIg. In this new blueprint, sialic acid on IVIg and FcγRIIB remain essential components of the anti-inflammatory effect, yet the mode of action of IVIg retains some mystery concerning the receptor(s) and cell type(s) targeted. The previous identification of SIGN-R1 and DCIR as key players may facilitate solving these novel enigmas. The laboratory of S.F. is supported by grants from the Deutsche Forschungsgemeinschaft (SFB-650, TRR-36, TRR-130, FI-1238/02), Hertie Stiftung, and an advanced grant from the Merieux Institute.

Female mice, aged-matched at 8–16 wk, were used in the described experiments. Treatment of animals was in compliance with federal and institutional guidelines, and approved by the TPIMS institute animal care and use committee. T-cell lines reactive to TCR peptides B1, B4 or B5, or MBP Ac1-9 were generated from naive B10.PL mice by stimulating splenocytes with peptide

(40 μg/mL) in RPMI 1640 media containing 10% FBS 6. CD4+ T-cell selleck chemical clones were isolated from peptide-reactive T-cell lines by the technique of two sequential limiting dilution clonings at 0.2 cells per well (as previously described, 6). T-cell line and clone cultures were maintained by the addition of rIL-2 (10 U/mL) every 3 days, and stimulated with TCR peptide and irradiated autologous spleen cells (2–5×106 spleen cells/well) in alternate weekly cycles. L-cell-transfectants expressing-I-Au MHC molecules were used as described earlier 25. TCR peptides were synthesized by S. Horvath (California Institute of Technology, Pasadena,

CA) using Tamoxifen nmr a solid phase technique on a peptide synthesizer (430A; Applied Biosystems) and purified on a reverse phase column by HPLC, as described earlier 46. TCR Vβ8.2 chain peptides are as follows (single-letter amino acid code): B1, aa 1–30(L): EAAVTQSPRNKVAVTGGKVTLSCNQTNNHNL; B4, aa 61–90: PDGYKASRPSQENFSLILELATPSQTSVYF and B5, aa 76–101: LILELATPSQTSVYFCASGDAGGGYE. MBP peptide: MBPAc1-9 (AcASQKRPSQR) was purchased from Macromolecular Resources, Colorado State University. For induction of EAE, mice were immunized s.c. with MBPAc1-9 emulsified very in CFA and i.p. with 0.15 μg of pertussis toxin (PTx; List Biological Laboratories) in PBS. After 48 h mice were injected with 0.15 μg PTx in PBS. Mice were observed daily for the clinical appearance of EAE. Disease severity was scored on a 5-point scale 6: 1, Flaccid tail; 2, hind limb weakness; 3, hind limb paralysis; 4, whole body paralysis; 5, death. Murine DC were derived from tibias and femurs by flushing out the BM with RPMI 1640 medium. Red blood cells were lysed, and BM was cultured in 24-well plates at 1×106 cells/mL in complete medium containing

10 ng/mL IL-4 and 25 ng/mL GM-CSF for 5–7 days 24. The medium was refreshed on day 3 and day 5. For some experiments DC were fixed by suspending the cells at 2×106/mL in PBS containing 0.05% glutaraldehyde for 30 s at 37°C. About 0.2 M of Lysine was added to stop the reaction. Recombinant IL-4 and GM-CSF were both purchased from Peprotech. Subsets of APC were isolated from the spleen and DLN of naïve mice, and mice during active EAE, by positive selection using Microbeads conjugated to antibodies against cell surface markers. For isolation of B cells, anti-CD45R (B220); DC, anti-CD11c (N418); Macrophages, anti-CD11b (Mac-1); Th cells, anti-CD4 (L3T4) conjugated beads were used to manufacturers’ instructions (Miltenyi Biotec). IFN-γ levels in the supernatants from T-cell assays were measured by a sandwich ELISA 19.

Recent data suggest that the decrease in EDH may be the result of disturbances in MEGJs [78, 79]. Alterations in endothelium-dependent relaxation have also been investigated in the rat RUPP model of preeclampsia. Deficits in endothelium-dependent relaxation have been noted in uterine [5, 114] and mesenteric arteries; reports range from a significant reduction in relaxation [110, 113] to no change relative to normal-pregnant animals [6]. In the aorta, a substantial decrease in relaxation has been noted in some studies [110], while others report a more subtle change [31, 91]. Interestingly, Morton and colleagues recently found that impaired relaxation in aortas from RUPP dams was accompanied

by increased levels of LOX-1 and eNOS [91]. Ex vivo experiments NU7441 using vessels and/or plasma from preeclamptic pregnancies have also provided insight into the mechanisms of vascular dysfunction. Incubation of resistance vessels from normal-pregnant women with plasma from women with preeclampsia causes a decrease in endothelium-dependent relaxation in response to bradykinin [56]. Microparticles isolated from plasma of women with preeclampsia, rather than the plasma itself, have been identified BAY 57-1293 molecular weight as the instigator of dysfunction [142]. A recent study found that plasma-mediated dysfunction is augmented in isolated arteries by

exposure to oxLDL [42]. Furthermore, inhibition of LOX-1 can prevent this deficit, protecting endothelial function [42]. Interestingly, plasma collected from pregnant women who would later develop preeclampsia has the capacity to reduce endothelium-dependent

relaxation in vessels from women with uncomplicated pregnancies, highlighting the importance of Low-density-lipoprotein receptor kinase circulating factors well before clinical manifestation and diagnosis [95]. Consistent with human studies, in the rat RUPP model, vessels from normal-pregnant animals show impaired endothelium-dependent vasodilatation following incubation with RUPP plasma [148]. Experiments in both humans and rats have found that plasma-mediated endothelial dysfunction is prevented by incubating vessels in the presence of a PARP inhibitor, suggesting a role for vascular dysfunction mediated by oxidative stress-stimulated PARP activation [32, 147]. Preeclampsia is a complex, multifactorial disorder and while its etiology remains elusive, the maternal syndrome, characterized by widespread vascular dysfunction, stems from circulating factors released as a consequence of placental ischemia/hypoxia. Disparity in the production of pro- and antiangiogenic factors, excessive inflammation, and the induction of oxidative stress within the endothelium are major contributors to endothelial dysfunction. Interestingly, research shows that women that have had preeclampsia continue to show signs of endothelial dysfunction postpartum, leaving them at increased risk for CVD later in life ([2, 20], reviewed in [47]).

parapertussis infection. Because previous investigations in our lab have demonstrated a role for PT in the enhancement of infection with B. pertussis (Carbonetti et al., 2003), we considered that PT may also facilitate infection by B. parapertussis. Coadministration of PT in mice has been shown to enhance infection of PT-deficient strains of B. pertussis (Carbonetti et al., 2003) and also enhances influenza virus infection (Ayala et al., 2011). We found that coadministration

ERK inhibitor of PT with B. parapertussis, which does not produce PT itself, resulted in a significant increase in the bacterial load. The effect of coadministered PT was small in the mixed infection, probably because B. pertussis in the inoculum provides a source of PT. This enhancing effect in a mixed infection was lost when a PT-deficient

B. pertussis strain was used. We conclude that PT produced by B. pertussis has an enhancing effect on B. parapertussis infection. PT has immunosuppressive effects on both innate and adaptive immunity to B. pertussis infection (Carbonetti et al., 2004; Kirimanjeswara et al., 2005; Andreasen & Carbonetti, 2008), and a suppressive effect on innate immunity is a likely mechanism by which PT enhances B. parapertussis infection. We also found that AM depletion Selleck Atezolizumab altered the dynamics of the mixed infection, providing B. pertussis with a significant advantage over B. parapertussis. We found previously that AM depletion enhances B. pertussis infection, but is also associated with Arachidonate 15-lipoxygenase an influx of neutrophils (Carbonetti et al., 2007), and so it is possible that this influx has a negative effect on B. parapertussis infection. However, neutrophil depletion did not enhance B. parapertussis infection or alter its advantage in the

mixed infection, calling into question any role for neutrophils in this competition. It is unclear why B. parapertussis did not significantly outcompete B. pertussis in PL-treated control mice, and we cannot rule out the possibility that liposomes had some negative effect on B. parapertussis infection. We can, however, conclude that AM depletion does not enhance B. parapertussis infection and that AM do not play a major role in protection against infection with this organism, unlike B. pertussis. Therefore, it is unlikely that the enhancing effect of PT on B. parapertussis infection is due to its suppressive activity on AM. Bordetella parapertussis differs from B. pertussis in the structure of their lipopolysaccharides. While they have some shared structural elements, B. pertussis lipooligosaccharide lacks the O antigen that is present on B. parapertussis lipopolysaccharides (Di Fabio et al., 1992; Allen et al., 1998; Caroff et al., 2001). In vitro, purified B. parapertussis lipopolysaccharides is a stronger activator of the innate immune response than purified B. pertussis lipooligosaccharide with regard to maturation of human dendritic cells and cytokine production (Fedele et al., 2008).