BCG vaccination-induced acquired control of mycobacterial growth differs from growth control preexisting to BCG vaccination

Bacillus Calmette-Guèrin - vaccination induces not only protection in infants and young children against severe forms of tuberculosis, but also against nontuberculosis related all-cause mortality. To delineate different factors influencing mycobacterial growth control, here we first investigate the effects of BCG-vaccination in healthy Dutch adults. About a quarter of individuals already control BCG-growth prior to vaccination, whereas a quarter of the vaccinees acquires the capacity to control BCG upon vaccination. This leaves half of the population incapable to control BCG-growth. Single cell RNA sequencing identifies multiple processes associated with mycobacterial growth control. These data suggest (i) that already controllers employ different mechanisms to control BCG-growth than acquired controllers, and (ii) that half of the individuals fail to develop measurable growth control irrespective of BCG-vaccination. These results shed important new light on the variable immune responses to mycobacteria in humans and may impact on improved vaccination against tuberculosis and other diseases.Immunogenetics and cellular immunology of bacterial infectious disease

Circulating Mycobacterium tuberculosis DosR latency antigen-specific, polyfunctional, regulatory IL10(+) Th17 CD4 T-cells differentiate latent from active tuberculosis

Immunogenetics and cellular immunology of bacterial infectious disease

Monocytes Contribute to Differential Immune Pressure on R5 versus X4 HIV through the Adipocytokine Visfatin/NAMPT

Background: The immune system exerts a diversifying selection pressure on HIV through cellular, humoral and innate mechanisms. This pressure drives viral evolution throughout infection. A better understanding of the natural immune pressure on the virus during infection is warranted, given the clinical interest in eliciting and sustaining an immune response to HIV which can help to control the infection. We undertook to evaluate the potential of the novel HIV-induced, monocyte-derived factor visfatin to modulate viral infection, as part of the innate immune pressure on viral populations. Results: We show that visfatin is capable of selectively inhibiting infection by R5 HIV strains in macrophages and resting PBMC in vitro, while at the same time remaining indifferent to or even favouring infection by X4 strains. Furthermore, visfatin exerts a direct effect on the relative fitness of R5 versus X4 infections in a viral competition setup. Direct interaction of visfatin with the CCR5 receptor is proposed as a putative mechanism for this differential effect. Possible in vivo relevance of visfatin induction is illustrated by its association with the dominance of CXCR4-using HIV in the plasma. Conclusions: As an innate factor produced by monocytes, visfatin is capable of inhibiting infections by R5 but not X4 strains, reflecting a potential selective pressure against R5 viruses. © 2012 Van den Bergh et al.SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pleural Tuberculosis in Patients with Early HIV Infection Is Associated with Increased TNF-Alpha Expression and Necrosis in Granulomas

Although granulomas may be an essential host response against persistent antigens, they are also associated with immunopathology. We investigated whether HIV co-infection affects histopathological appearance and cytokine profiles of pleural granulomas in patients with active pleural tuberculosis (TB). Granulomas were investigated in pleural biopsies from HIV positive and negative TB pleuritis patients. Granulomas were characterised as necrotic or non-necrotic, graded histologically and investigated for the mRNA expression of IL-12, IFN-γ, TNF-α and IL-4 by in situ hybridisation. In all TB patients a mixed Th1/Th2 profile was noted. Necrotic granulomas were more evident in HIV positive patients with a clear association between TNF-α and necrosis. This study demonstrates immune dysregulation which may include TNF-α-mediated immunopathology at the site of disease in HIV infected pleural TB patients

Innate immunity against HIV: a priority target for HIV prevention research

This review summarizes recent advances and current gaps in understanding of innate immunity to human immunodeficiency virus (HIV) infection, and identifies key scientific priorities to enable application of this knowledge to the development of novel prevention strategies (vaccines and microbicides). It builds on productive discussion and new data arising out of a workshop on innate immunity against HIV held at the European Commission in Brussels, together with recent observations from the literature

Galectin-1 is required for the regulatory function of B cells

Galectin-1 (Gal-1) is required for the development of B cells in the bone marrow (BM), however very little is known about the contribution of Gal-1 to the development of B cell regulatory function. Here, we report an important role for Gal-1 in the induction of B cells regulatory function. Mice deficient of Gal-1 (Gal-1−/−) showed significant loss of Transitional-2 (T2) B cells, previously reported to include IL-10+ regulatory B cells. Gal-1−/− B cells stimulated in vitro via CD40 molecules have impaired IL-10 and Tim-1 expression, the latter reported to be required for IL-10 production in regulatory B cells, and increased TNF-α expression compared to wild type (WT) B cells. Unlike their WT counterparts, T2 and T1 Gal-1−/− B cells did not suppress TNF-α expression by CD4+ T cells activated in vitro with allogenic DCs (allo-DCs), nor were they suppressive in vivo, being unable to delay MHC-class I mismatched skin allograft rejection following adoptive transfer. Moreover, T cells stimulated with allo-DCs show an increase in their survival when co-cultured with Gal-1−/− T2 and MZ B cells compared to WT T2 and MZ B cells. Collectively, these data suggest that Gal-1 contributes to the induction of B cells regulatory function

Learning and Educational Programs for Entrepreneurs

This chapter summarizes the latest studies in entrepreneurial learning in order to highlight their implications for the design of educational programs (Pittaway & Thorpe, 2012). It examines in detail the latest thinking on the subject, summarizes the key concepts and empirical contributions with a particular focus on expanding understanding of ‘situated’, social and contextual learning (Lave & Wenger, 1991). The chapter stems from Pittaway and Thorpe’s (2012: 850) summary of Cope’s framework. Here it highlights critical concepts, such as dynamic temporal phases, forms and characteristics of learning (Cope, 2010) and lays out the underlying principles of each concept. Following this initial framework recent contributions to the subject of entrepreneurial learning, both conceptual and empirical, are presented to provide an up-to-date picture of thinking in the field. The latter part of the chapter highlights implications of current thinking on the design of development programs for entrepreneurs. It focuses on how concepts in this field can be used to enhance efforts to consider, design and deliver educational programs for entrepreneurs. A number of forms of educational practice are recommended based on this analysis. The chapter closes by considering future developments and lines of inquiry in entrepreneurial learnin