Chemical synthesis of phosphatidylinositol mannoside glycans from Mycobacterium tuberculosis

The efficient synthesis of phosphatidylinositol mono- to hexa-mannoside (PIM1 to PIM6) is reported. The invention relates to these phosphatidylinositol mono- to hexa-mannosides carrying a linker and a reactive functional group, e.g. the sulfhydryl group, a protein, a fluorescent probe, or a solid phase. The invention further relates to vaccines comprising the PIMs linked to a carrier protein or an antigen

Lectin-mediated bacterial modulation by the intestinal nematode Ascaris suum

Ascariasis is a global health problem for humans and animals. Adult Ascaris nematodes are long-lived in the host intestine where they interact with host cells as well as members of the microbiota resulting in chronic infections. Nematode interactions with host cells and the microbial environment are prominently mediated by parasite-secreted proteins and peptides possessing immunomodulatory and antimicrobial activities. Previously, we discovered the C-type lectin protein AsCTL-42 in the secreted products of adult Ascaris worms. Here we tested recombinant AsCTL-42 for its ability to interact with bacterial and host cells. We found that AsCTL-42 lacks bactericidal activity but neutralized bacterial cells without killing them. Treatment of bacterial cells with AsCTL-42 reduced invasion of intestinal epithelial cells by Salmonella. Furthermore, AsCTL-42 interacted with host myeloid C-type lectin receptors. Thus, AsCTL-42 is a parasite protein involved in the triad relationship between Ascaris, host cells, and the microbiota

Dectin-1 binding to annexins on apoptotic cells induces peripheral immune tolerance via NADPH oxidase-2

Summary Uptake of apoptotic cells (ACs) by dendritic cells (DCs) and induction of a tolerogenic DC phenotype is an important mechanism for establishing peripheral tolerance to self-antigens. The receptors involved and underlying signaling pathways are not fully understood. Here, we identify Dectin-1 as a crucial tolerogenic receptor binding with nanomolar affinity to the core domain of several annexins (annexin A1, A5, and A13) exposed on ACs. Annexins bind to Dectin-1 on a site distinct from the interaction site of pathogen-derived β-glucans. Subsequent tolerogenic signaling induces selective phosphorylation of spleen tyrosine kinase (SYK), causing activation of NADPH oxidase-2 and moderate production of reactive oxygen species. Thus, mice deficient for Dectin-1 develop autoimmune pathologies (autoantibodies and splenomegaly) and generate stronger immune responses (cytotoxic T cells) against ACs. Our data describe an important immunological checkpoint system and provide a link between immunosuppressive signals of ACs and maintenance of peripheral immune tolerance

Becoming Sociological: Disciplinarity and a Sense of ‘Home’

This short reflective piece uses the concept of ‘home’ to explore sociology as an intellectual and disciplinary pursuit. Drawing on autobiographical reflections and ethnographic study of sociology writing, I consider some of the trajectories of academics into sociology and what these tell us about the discipline itself. In light of increasing incursions by audit culture and marketisation of academia, Holmwood has drawn attention to a lack of clear internal identity as being ‘sociology’s misfortune’ – that sociology loses out, and is weakened by lacking theories and methodologies specific to the discipline. This essay takes a more optimistic view of sociology’s position, and instead argues that it is this very ambiguity which keeps the discipline a lively and vital space for explorations of the social

Immunological evaluation of synthetic glycosylphosphatidylinositol glycoconjugates as vaccine candidates against malaria

Glycosylphosphatidylinositols (GPIs) are complex glycolipids present on the surfaces of Plasmodium parasites that may act as toxins during the progression of malaria. GPIs can activate the immune system during infection and induce the formation of anti-GPI antibodies that neutralize their activity. Therefore, an anti-toxic vaccine based on GPI glycoconjugates may prevent malaria pathogenesis. To evaluate the role of three key modifications on Plasmodium GPI glycan in the activity of these glycolipids, we synthesized and investigated six structurally distinct GPI fragments from P. falciparum. The synthetic glycans were conjugated to the CRM197 carrier protein and were tested for immunogenicity and efficacy as antimalarial vaccine candidates in an experimental cerebral malaria (ECM) model using C57BL/6JRj mice. Protection may be dependent on both, the antibody and cellular immune response to GPIs, and the elicited immune response depends on the orientation of the glycan, the number of mannoses in the structure and the presence of the phosphoethanolamine and inositol units. This study provides insights into the epitopes in GPIs and contributes to the development of GPI-based anti-toxin vaccine candidates against cerebral malaria