Plasmodium chabaudi limits early Nippostrongylus brasiliensis-induced pulmonary immune activation and Th2 polarization in co-infected mice

<p>Abstract</p> <p>Background</p> <p>Larvae of several common species of parasitic nematodes obligately migrate through, and often damage, host lungs. The larvae induce strong pulmonary Type 2 immune responses, including T-helper (Th)2 cells as well as alternatively activated macrophages (AAMφ) and associated chitinase and Fizz/resistin family members (ChaFFs), which are thought to promote tissue repair processes. Given the prevalence of systemic or lung-resident Type 1-inducing pathogens in geographical areas in which nematodes are endemic, we wished to investigate the impact of concurrent Type 1 responses on the development of these Type 2 responses to nematode larval migration. We therefore infected BALB/c mice with the nematode <it>Nippostrongylus brasiliensis</it>, in the presence or absence of <it>Plasmodium chabaudi chabaudi </it>malaria parasites. Co-infected animals received both infections on the same day, and disease was assessed daily before immunological measurements were taken at 3, 5, 7 or 20 days post-infection.</p> <p>Results</p> <p>We observed that the nematodes themselves caused transient loss of body mass and red blood cell density, but co-infection then slightly ameliorated the severity of malarial anaemia. We also tracked the development of immune responses in the lung and thoracic lymph node. By the time of onset of the adaptive immune response around 7 days post-infection, malaria co-infection had reduced pulmonary expression of ChaFFs. Assessment of the T cell response demonstrated that the Th2 response to the nematode was also significantly impaired by malaria co-infection.</p> <p>Conclusion</p> <p><it>P. c. chabaudi </it>co-infection altered both local and lymph node Type 2 immune activation due to migration of <it>N. brasiliensis </it>larvae. Given recent work from other laboratories showing that <it>N. brasiliensis</it>-induced ChaFFs correlate to the extent of long-term lung damage, our results raise the possibility that co-infection with malaria might alter pulmonary repair processes following nematode migration. Further experimentation in the co-infection model developed here will reveal the longer-term consequences of the presence of both malaria and helminths in the lung.</p

Alternative activation of macrophages by filarial nematodes is MyD88-independent

AbstractAlternative macrophage activation is largely defined by IL-4Rα stimulation but the contribution of Toll-like receptor (TLR) signaling to this phenotype is not currently known. We have investigated macrophage activation status under Th2 conditions in the absence of the core TLR adaptor molecule, MyD88. No impairment was observed in the ability of MyD88-deficient bone marrow derived macrophages to produce or express alternative activation markers, including arginase, RELM-α or Ym1, in response to IL-4 treatment in vitro. Further, we observed no difference in the ability of peritoneal exudate cells from nematode implanted wild type (WT) or MyD88-deficient mice to produce arginase or express the alternative activation markers RELM-α or Ym1. Therefore, MyD88 is not a fundamental requirement for Th2-driven macrophage alternative activation, either in vitro or in vivo

The Same IκBα Mutation in Two Related Individuals Leads to Completely Different Clinical Syndromes

Both innate and adaptive immune responses are dependent on activation of nuclear factor κB (NF-κB), induced upon binding of pathogen-associated molecular patterns to Toll-like receptors (TLRs). In murine models, defects in NF-κB pathway are often lethal and viable knockout mice have severe immune defects. Similarly, defects in the human NF-κB pathway described to date lead to severe clinical disease. Here, we describe a patient with a hyper immunoglobulin M–like immunodeficiency syndrome and ectodermal dysplasia. Monocytes did not produce interleukin 12p40 upon stimulation with various TLR stimuli and nuclear translocation of NF-κB was impaired. T cell receptor–mediated proliferation was also impaired. A heterozygous mutation was found at serine 32 in IκBα. Interestingly, his father has the same mutation but displays complex mosaicism. He does not display features of ectodermal dysplasia and did not suffer from serious infections with the exception of a relapsing Salmonella typhimurium infection. His monocyte function was impaired, whereas T cell function was relatively normal. Consistent with this, his T cells almost exclusively displayed the wild-type allele, whereas both alleles were present in his monocytes. We propose that the T and B cell compartment of the mosaic father arose as a result of selection of wild-type cells and that this underlies the widely different clinical phenotype

Influenza Virus A Infection of Human Monocyte and Macrophage Subpopulations Reveals Increased Susceptibility Associated with Cell Differentiation

Influenza virus infection accounts for significant morbidity and mortality world-wide. Interactions of the virus with host cells, particularly those of the macrophage lineage, are thought to contribute to various pathological changes associated with poor patient outcome. Development of new strategies to treat disease therefore requires a detailed understanding of the impact of virus infection upon cellular responses. Here we report that human blood-derived monocytes could be readily infected with the H3N2 influenza virus A/Udorn/72 (Udorn), irrespective of their phenotype (CD14++/CD16−, CD14++/CD16+ or CD14dimCD16++), as determined by multi-colour flow cytometry for viral haemagglutinin (HA) expression and cell surface markers 8–16 hours post infection. Monocytes are relatively resistant to influenza-induced cell death early in infection, as approximately 20% of cells showed influenza-induced caspase-dependent apoptosis. Infection of monocytes with Udorn also induced the release of IL-6, IL-8, TNFα and IP-10, suggesting that NS1 protein of Udorn does not (effectively) inhibit this host defence response in human monocytes. Comparative analysis of human monocyte-derived macrophages (Mph) demonstrated greater susceptibility to human influenza virus than monocytes, with the majority of both pro-inflammatory Mph1 and anti-inflammatory/regulatory Mph2 cells expressing viral HA after infection with Udorn. Influenza infection of macrophages also induced cytokine and chemokine production. However, both Mph1 and Mph2 phenotypes released comparable amounts of TNFα, IL-12p40 and IP-10 after infection with H3N2, in marked contrast to differential responses to LPS-stimulation. In addition, we found that influenza virus infection augmented the capacity of poorly phagocytic Mph1 cells to phagocytose apoptotic cells by a mechanism that was independent of either IL-10 or the Mer receptor tyrosine kinase/Protein S pathway. In summary, our data reveal that influenza virus infection of human macrophages causes functional alterations that may impact on the process of resolution of inflammation, with implications for viral clearance and lung pathology

Rapid establishment of the European Bank for induced Pluripotent Stem Cells (EBiSC):The Hot Start experience

A fast track “Hot Start” process was implemented to launch the European Bank for Induced Pluripotent Stem Cells (EBiSC) to provide early release of a range of established control and disease linked human induced pluripotent stem cell (hiPSC) lines. Established practice amongst consortium members was surveyed to arrive at harmonised and publically accessible Standard Operations Procedures (SOPs) for tissue procurement, bio-sample tracking, iPSC expansion, cryopreservation, qualification and distribution to the research community. These were implemented to create a quality managed foundational collection of lines and associated data made available for distribution. Here we report on the successful outcome of this experience and work flow for banking and facilitating access to an otherwise disparate European resource, with lessons to benefit the international research community. eTOC: The report focuses on the EBiSC experience of rapidly establishing an operational capacity to procure, bank and distribute a foundational collection of established hiPSC lines. It validates the feasibility and defines the challenges of harnessing and integrating the capability and productivity of centres across Europe using commonly available resources currently in the field

Clarifying the role of life cycle assessment in technical research and development projects: Recommendations for project planning.

In technical Research and Development (R&D) projects, such as those funded within the European 7th Framework Programme, there is often a requirement to conduct an environmental Life Cycle Assessment (LCA) of the technology under development. No requirements or recommendations are provided on the role of LCA within different types of projects, consequently the role of LCA tends to be unclear and arbitrary, and LCA work may not be adequately designed for the needs of the project.There is much literature on LCA and its use in R&D, often on case studies, on development of assessment methods or on possibilities and limitations of LCA in the R&D context. There is also more general research on environmental consideration in R&D, often with a focus on intra-organisational projects. However, there is a need to explore the role of LCA in inter-organisational technical R&D projects, in order to improve project planning and enable projects to make use of the full potential of LCA.In this study, we draw on experiences from LCA work in such projects in order to identify project characteristics which are decisive for what the role of the LCA can be. Four specific projects are used to illustrate how these characteristics have practical consequences for project planning, before or early in the project. The purpose is to help project planners and LCA practitioners to characterise their project and, consequently, plan the project in a more deliberate way for efficient use of LCA.The following key project characteristics were identified:Potential influence on environmental performance: whether the technology under development is a major or minor contributor to the environmental impact of a product’s life cycle.Flexibility of development process: to what extent the direction of the project is fixed, which may set limits to the opportunities the LCA has for influencing the project.LCA dependency on project progress: if key variables in the LCA depend on decisions taken or results obtained within the project.Appropriate audience of LCA results: stakeholders within or external to the project that the LCA should be directed towards.Potential influence on environmental performance, flexibility of development process and LCA dependency on project progress, are crucial for whether there is a need for an early screening LCA of the proposed development routes. For example, this could depend on whether life cycle impacts mainly depend on the production processes or the functional properties of the technology under development. Furthermore, flexibility of development process, LCA dependency on project progress and appropriate audience of the LCA results are central for scheduling the time plan for project deliverables and for deciding how and to whom the LCA results are to be communicated. Also, all four characteristics influence to what degree the LCA should be integrated with other parts of the project: whether LCA is to influence technology development, or whether it is sufficient with a stand-alone LCA that is delivered at the end of the project.The LCA practitioner and any project partner with pre-knowledge of the technology’s environmental impact should be engaged in evaluating the above listed key characteristics. In this way, the role of LCA can be clarified, positively contributing to a more efficient use of LCA in the project. This can also help in creating realistic expectations and, thereby, limit disappointment and stress within the project