A New Name for Pneumocystis from Humans and New Perspectives on the Host-Pathogen Relationship

The disease known as Pneumocystis carinii pneumonia (PCP) is a major cause of illness and death in persons with impaired immune systems. While the genus Pneumocystis has been known to science for nearly a century, understanding of its members remained rudimentary until DNA analysis showed its extensive diversity. Pneumocystis organisms from different host species have very different DNA sequences, indicating multiple species. In recognition of its genetic and functional distinctness, the organism that causes human PCP is now named Pneumocystis jiroveci Frenkel 1999. Changing the organism’s name does not preclude the use of the acronym PCP because it can be read “Pneumocystis pneumonia.” DNA varies in samples of P. jiroveci, a feature that allows reexamination of the relationships between host and pathogen. Instead of lifelong latency, transient colonization may be the rule

Positional Cloning of “Lisch-like”, a Candidate Modifier of Susceptibility to Type 2 Diabetes in Mice

In 404 Lepob/ob F2 progeny of a C57BL/6J (B6) x DBA/2J (DBA) intercross, we mapped a DBA-related quantitative trait locus (QTL) to distal Chr1 at 169.6 Mb, centered about D1Mit110, for diabetes-related phenotypes that included blood glucose, HbA1c, and pancreatic islet histology. The interval was refined to 1.8 Mb in a series of B6.DBA congenic/subcongenic lines also segregating for Lepob. The phenotypes of B6.DBA congenic mice include reduced β-cell replication rates accompanied by reduced β-cell mass, reduced insulin/glucose ratio in blood, reduced glucose tolerance, and persistent mild hypoinsulinemic hyperglycemia. Nucleotide sequence and expression analysis of 14 genes in this interval identified a predicted gene that we have designated “Lisch-like” (Ll) as the most likely candidate. The gene spans 62.7 kb on Chr1qH2.3, encoding a 10-exon, 646–amino acid polypeptide, homologous to Lsr on Chr7qB1 and to Ildr1 on Chr16qB3. The largest isoform of Ll is predicted to be a transmembrane molecule with an immunoglobulin-like extracellular domain and a serine/threonine-rich intracellular domain that contains a 14-3-3 binding domain. Morpholino knockdown of the zebrafish paralog of Ll resulted in a generalized delay in endodermal development in the gut region and dispersion of insulin-positive cells. Mice segregating for an ENU-induced null allele of Ll have phenotypes comparable to the B.D congenic lines. The human ortholog, C1orf32, is in the middle of a 30-Mb region of Chr1q23-25 that has been repeatedly associated with type 2 diabetes

Synchronization of mothers and offspring promotes tolerance and limits allergy

Allergic disorders, characterized by Th2 immune responses to environmental substances, are increasingly common in children in Western societies. Multiple studies indicate that breastfeeding, early complementary introduction of food allergens, and antibiotic avoidance in the first year of life reduces allergic outcomes in at-risk children. Why the benefit of these practices is restricted to early life is largely unknown. We identified a preweaning interval during which dietary antigens are assimilated by the colonic immune system. This interval is under maternal control via temporal changes in breast milk, coincides with an influx of naive T cells into the colon, and is followed by the development of a long-lived population of colonic peripherally derived Tregs (pTregs) that can be specific for dietary antigens encountered during this interval. Desynchronization of mothers and offspring produced durable deficits in these pTregs, impaired tolerance to dietary antigens introduced during and after this preweaning interval, and resulted in spontaneous Th2 responses. These effects could be rescued by pTregs from the periweaning colon or by Tregs generated in vitro using periweaning colonic antigen-presenting cells. These findings demonstrate that mothers and their offspring are synchronized for the development of a balanced immune system

Tumor cell-driven extracellular matrix remodeling enables haptotaxis during metastatic progression

Fibronectin (FN) is a major component of the tumor microenvironment, but its role in promoting metastasis is incompletely understood. Here we show that FN gradients elicit directional movement of breast cancer cells, in vitro and in vivo. Haptotaxis on FN gradients requires direct interaction between α5β1 integrin and Mena, an actin regulator, and involves increases in focal complex signaling and tumor-cell-mediated extracellular matrix (ECM) remodeling. Compared to Mena, higher levels of the pro-metastatic MenaINV isoform associate with α5, which enables 3D haptotaxis of tumor cells towards the high FN concentrations typically present in perivascular space and in the periphery of breast tumor tissue. MenaINV and FN levels were correlated in two breast cancer cohorts, and high levels of MenaINV were significantly associated with increased tumor recurrence as well as decreased patient survival. Our results identify a novel tumor-cell-intrinsic mechanism that promotes metastasis through ECM remodeling and ECM guided directional migration.Ludwig Center for Molecular OncologyBreast Cancer Research Program (U.S.) (post-doctoral fellowship, W81-XWH-12-1-0031)National Institutes of Health (U.S.) (NIH grant U54-CA112967)National Institutes of Health (U.S.) (NIH grant R01 CA142833)Howard Hughes Medical InstituteNational Institutes of Health (U.S.) (NIH grant U01 CA143069)Kathy and Curt Marble Cancer Research Fund (Koch Institute Frontier Award)Prostate Cancer FoundationDavid H. Koch Institute for Integrative Cancer Research at MIT (NCI core grant P30-CA14051

Sépultures privilégiées dans la cité des Pictons : l’espace funéraire de Jaunay-Clan (Vienne)

International audienceA rescue excavation undertaken in 2011-2012 in Jaunay-Clan (Vienne) revealed a Late Antique funerary area consisting of a pyre, a mausoleum and a large masonry building. The pyre yielded significant accompanying goods, and is associated with a large deposit of broken vases. The surrounding enclosure and the stone pedestal undoubtedly correspond to the final construction of the burial. In the mausoleum, the embalming of bodies and the use of precious textiles (some of which are dyed Tyrian purple) provide evidence of elite funerary practices in the Pictons civitas in the 3rd-4th c. AD.La fouille préventive réalisée en 2011-2012 à Jaunay-Clan (Vienne) a révélé un espace funéraire de la fin de l’Antiquité constitué d’un bûcher, d’un mausolée et d’un vaste bâtiment dont la fonction reste indéterminée. Le bûcher contient un mobilier d’accompagnement fourni et est associé à un important dépôt de vases brisés. L’enclos qui l’entoure et le socle maçonné correspondent sans doute à l’aménagement définitif de la sépulture. Dans le mausolée, qui a livré deux inhumations, l’embaumement des corps et l’usage de textiles précieux (dont certains teints à la pourpre) apportent un témoignage des pratiques funéraires des élites de la cité pictonne aux IIIe-IVe s. apr. J.-C