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Background Asthma is a heterogeneous disease characterized by overlapping clinical and inflammatory features. Objective This study aimed to provide insight into the systemic inflammatory profile in asthma, greater understanding of asthma endotypes and the contribution of genetic risk factors to both. Methods 4205 patients with asthma aged 16–60 were recruited from UK centers; serum cytokines were quantified from 708, including cytokines associated with Type 1, 2 and 17 inflammation. 3037 patients were genotyped for 25 single nucleotide polymorphisms associated with moderate‐severe asthma. Results Serum cytokines associated with Th2 inflammation showed high coordinated expression for example, IL‐4/IL‐5 (R2 = 0.513). The upper quartile of the serum cytokine data identified 43.7% of patients had high levels for multiple Th2 cytokines. However, the groups defined by serum cytokine profile were not clinically different. Childhood‐onset asthma was characterized by elevated total IgE, allergic rhinitis and dermatitis. Exacerbation prone patients had a higher BMI, smoking pack‐years, asthma control questionnaire score and reduced lung function. Patients with blood eosinophils of > 300 cells/µL had elevated total IgE and lower smoking pack‐years. None of these groups had a differential serum cytokine profile. Asthma risk alleles for; rs61816764 (FLG) and rs9303277 (IKFZ3) were associated with childhood onset disease (p = 2.67 × 10−4 and 2.20 × 10−7; retrospectively). No genetic variant was associated with cytokine levels. Conclusion Systemic inflammation in asthma is complex. Patients had multiple overlapping inflammatory profiles suggesting several disease mechanisms. Genetic risk factors for moderate‐severe asthma confirmed previous associations with childhood onset of asthma. Asthma patients showed a heterogeneous systemic inflammation profile with overlapping inflammatory profile. Additionally, The cytokines demonstrated high coordinated expression.\" Summary A large proportion of asthma patients showed a complex systemic inflammation with multiple overlapping inflammatory profiles suggesting several disease mechanisms spanning Type 1, 2 and 17 inflammation. Nearly half of asthma patients showed elevated levels of mediators that are current biological drug targets suggesting these patients may be amenable to these drugs or even combination monoclonal antibody therapy. Our data also confirms and extends previous findings on childhood versus adult onset, exacerbation prone asthma and eosinophilic driven asthma subgroups.

[...]a RNA sequencing-based approach was used byHeravi et al., to depict the whole transcriptomic profile in diabetic foot infection (DFI) tissues, contributing to clarify the role of the host inflammatory status in the progression of DFIs. In the second paper,Trikha et al.demonstrated that angiotensin-converting enzyme inhibitors (ACEi), often utilized for treating hypertension, increases S. aureus burden and impairs immune responses in a preclinical model of implant-associated infections, raising the intriguing issue that commonly used drugs may negatively impact the immune response to microbial biofilms. Conflict of Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. 1BatoniGMaisettaGEsinS.Antimicrobial Peptides and Their Interaction With Biofilms of Medically Relevant Bacteria.Biochim Biophys Acta(2016)1858(5):1044–60. doi:10.1016/j.bbamem.2015.10.013 2DonlanRMCostertonJW.Biofilms:

Ber e 1, a major Brazil nut allergen, has been successfully produced in the yeast Pichia pastoris expression system as homogenous recombinant Ber e 1 (rBer e 1) with similar physicochemical properties and identical immunoreactivity to its native counterpart, nBer e 1. However, O -linked glycans was detected on the P . pastoris -derived rBer e 1, which is not naturally present in nBer e 1, and may contribute to the allergic sensitisation. In this study, we addressed the glycosylation differences between P . pastoris -derived recombinant Ber e 1 and its native counterparts. We also determined whether this fungal glycosylation could affect the antigenicity and immunogenicity of the rBer e 1 by using dendritic cells (DC) as an immune cell model due to their role in modulating the immune response. We identified that the glycosylation occurs at Ser96, Ser101 and Ser110 on the large chain and Ser19 on the small polypeptide chain of rBer e 1 only. The glycosylation on rBer e 1 was shown to elicit varying degree of antigenicity by binding to different combination of human leukocyte antigens (HLA) at different frequencies compared to nBer e 1 when tested using human DC-T cell assay. However, both forms of Ber e 1 are weak immunogens based from their low response indexes (RI). Glycans present on rBer e 1 were shown to increase the efficiency of the protein recognition and internalization by murine bone marrow-derived dendritic cells (bmDC) via C-type lectin receptors, particularly the mannose receptor (MR), compared to the non-glycosylated nBer e 1 and SFA8, a weak allergenic 2S albumin protein from sunflower seed. Binding of glycosylated rBer e 1 to MR alone was found to not induce the production of IL-10 that modulates bmDC to polarise Th2 cell response by suppressing IL-12 production and DC maturation. Our findings suggest that the O -linked glycosylation by P . pastoris has a small but measurable effect on the in vitro antigenicity of the rBer e 1 compared to its non-glycosylated counterpart, nBer e 1, and thus may influence its applications in diagnostics and immunotherapy.

Surface Ig (sIg) of follicular lymphoma (FL) is vital for tumor cell survival. We found previously that the Ig in FL is unusual, because the variable region genes carry sequence motifs for N-glycan addition. These are introduced by somatic mutation and are tumor specific. Unexpectedly, added glycans terminate at high mannose, suggesting a potentially important interaction of FL cells with mannose-binding lectins of the innate immune system. We have now identified mannosylated IgM at the surface of primary lymphoma cells. Recombinant lectin domains of the mannose receptor (MR) or DC-SIGN bind mannosylated Igs in vitro and bind to FL cells, signaling sIgM-associated increases in intracellular Ca²⁺. Lectins also bind to normal B cells but fail to signal. In contrast, anti-Ig signaled similarly in both FL and normal B cells. Mannosylation patterns were mimicked by FL Ig-derived single-chain Fvs (scFv), providing probes for potential receptors. Mannosylated scFv bound specifically to the lectin domains of the MR and DC-SIGN and blocked signaling. Mannosylated scFv also bound to DC-SIGN on the surface of dendritic cells. This unique lymphoma-specific interaction of sIg with lectins of innate immunity reveals a potential route for microenvironmental support of tumor cells, mediated via the key B-cell receptor.

Vaccines elicit neutralizing antibodies to protect organisms against viral infection. Carroll and colleagues show that medullary lymph node dendritic cells capture influenza virus via SIGN-R1 and are necessary for humoral antiviral immunity. A major pathway for B cell acquisition of lymph-borne particulate antigens relies on antigen capture by subcapsular sinus macrophages of the lymph node. Here we tested whether this mechanism is also important for humoral immunity to inactivated influenza virus. By multiple approaches, including multiphoton intravital imaging, we found that antigen capture by sinus-lining macrophages was important for limiting the systemic spread of virus but not for the generation of influenza-specific humoral immunity. Instead, we found that dendritic cells residing in the lymph node medulla use the lectin receptor SIGN-R1 to capture lymph-borne influenza virus and promote humoral immunity. Thus, our results have important implications for the generation of durable humoral immunity to viral pathogens through vaccination.

Macrophages (MØ) and mononuclear phagocytes are major targets of infection by dengue virus (DV), a mosquito-borne flavivirus that can cause haemorrhagic fever in humans. To our knowledge, we show for the first time that the MØ mannose receptor (MR) binds to all four serotypes of DV and specifically to the envelope glycoprotein. Glycan analysis, ELISA, and blot overlay assays demonstrate that MR binds via its carbohydrate recognition domains to mosquito and human cell-produced DV antigen. This binding is abrogated by deglycosylation of the DV envelope glycoprotein. Surface expression of recombinant MR on NIH3T3 cells confers DV binding. Furthermore, DV infection of primary human MØ can be blocked by anti-MR antibodies. MR is a prototypic marker of alternatively activated MØ, and pre-treatment of human monocytes or MØ with type 2 cytokines (IL-4 or IL-13) enhances their susceptibility to productive DV infection. Our findings indicate a new functional role for the MR in DV infection.

Bacterial septicaemia is a major cause of mortality, but its pathogenesis remains poorly understood. In experimental pneumococcal murine intravenous infection, an initial reduction of bacteria in the blood is followed hours later by a fatal septicaemia. These events represent a population bottleneck driven by efficient clearance of pneumococci by splenic macrophages and neutrophils, but as we show in this study, accompanied by occasional intracellular replication of bacteria that are taken up by a subset of CD169 + splenic macrophages. In this model, proliferation of these sequestered bacteria provides a reservoir for dissemination of pneumococci into the bloodstream, as demonstrated by its prevention using an anti-CD169 monoclonal antibody treatment. Intracellular replication of pneumococci within CD169 + splenic macrophages was also observed in an ex vivo porcine spleen, where the microanatomy is comparable with humans. We also showed that macrolides, which effectively penetrate macrophages, prevented septicaemia, whereas beta-lactams, with inefficient intracellular penetration, failed to prevent dissemination to the blood. Our findings define a shift in our understanding of the pneumococcus from an exclusively extracellular pathogen to one with an intracellular phase. These findings open the door to the development of treatments that target this early, previously unrecognized intracellular phase of bacterial sepsis. Splenic CD169 + macrophages serve as an intracellular reservoir for Streptococcus pneumoniae replication and are a target for cell-penetrant antibiotic therapy to prevent septicaemia.

Next-generation sequencing technologies have led to the creation of extensive microbial genome sequence databases for several bacterial pathogens. Mining of these databases is now imperative for unlocking the maximum benefits of these resources. We describe a high-throughput methodology for detecting associations between phenotypic variation in multiple disease-relevant traits and a range of genetic determinants for Neisseria meningitidis , a major causative agent of meningitis and septicemia. Phenotypic variation in 11 disease-related traits was determined for 163 isolates of the hypervirulent ST-11 lineage and linked to specific single-nucleotide polymorphisms, short sequence variants, and phase variation states. Application of machine learning algorithms to our data outputs identified combinatorial phenotypic traits and genetic variants predictive of a disease association. This approach overcomes the limitations of generic meta-data, such as disease versus carriage, and provides an avenue to explore the multi-faceted nature of bacterial disease, carriage, and transmissibility traits.

The macrophage mannose receptor (CD206) is expressed predominantly on the surface of M2-type macrophages, which play a role in resolution of inflammation after myocardial injury. The purpose of this study was to evaluate the utility of CD206-targeted PET tracer Al[ F]F-NOTA-D10CM, a fluorinated mannosylated dextran derivative, for imaging immune responses after experimental acute myocardial infarction (MI). Flow cytometry revealed selective binding of Alexa-488-NOTA-D10CM to human M2-polarized macrophages derived from blood monocytes compared to M1 macrophages. The binding affinity of Al[ F]F-NOTA-DCM for CD206-positive Chinese hamster ovary cells was 1.83 ± 0.68 nM. In vivo PET and ex vivo autoradiography experiments in Sprague-Dawley rats studied at 3 and 7 days after permanent ligation of the left coronary artery or a sham-operation, showed significantly higher uptake of Al[ F]F-NOTA-DCM in the MI area than in remote areas, or the myocardium of sham-operated rats. However, there was no difference in uptake in the MI area between day 3 and day 7. Uptake of Al[ F]F-NOTA-DCM in the MI area correlated positively with the area-% of CD206-positive staining of the left ventricular myocardium (r = 0.481, P = 0.006). In vitro competition studies on tissue cryosections using a molar excess of unlabeled D10CM revealed a reduction of approximately 85%, confirming specific tracer binding. Al[ F]F-NOTA-D10CM PET detects overexpression of CD206 after ischemic myocardial injury, and may be a suitable biomarker for detecting M2-type macrophages associated with the inflammatory process post-MI.

Circadian rhythms affect the progression and severity of bacterial infections including those caused by Streptococcus pneumoniae , but the mechanisms responsible for this phenomenon remain largely elusive. Following advances in our understanding of the role of replication of S. pneumoniae within splenic macrophages, we sought to investigate whether events within the spleen correlate with differential outcomes of invasive pneumococcal infection. Utilising murine invasive pneumococcal disease (IPD) models, here we report that infection during the murine active phase (zeitgeber time 15; 15h after start of light cycle, 3h after start of dark cycle) resulted in significantly faster onset of septicaemia compared to rest phase (zeitgeber time 3; 3h after start of light cycle) infection. This correlated with significantly higher pneumococcal burden within the spleen of active phase-infected mice at early time points compared to rest phase-infected mice. Whole-section confocal microscopy analysis of these spleens revealed that the number of pneumococci is significantly higher exclusively within marginal zone metallophilic macrophages (MMMs) known to allow intracellular pneumococcal replication as a prerequisite step to the onset of septicaemia. Pneumococcal clusters within MMMs were more abundant and increased in size over time in active phase-infected mice compared to those in rest phase-infected mice which decreased in size and were present in a lower percentage of MMMs. This phenomenon preceded significantly higher levels of bacteraemia alongside serum IL-6 and TNF-α concentrations in active phase-infected mice following re-seeding of pneumococci into the blood. These data greatly advance our fundamental knowledge of pneumococcal infection by linking susceptibility to invasive pneumococcal infection to variation in the propensity of MMMs to allow persistence and replication of phagocytosed bacteria. These findings also outline a somewhat rare scenario whereby the active phase of an organism’s circadian cycle plays a seemingly counterproductive role in the control of invasive infection.