Generational distribution of a Candida glabrata population: Resilient old cells prevail, while younger cells dominate in the vulnerable host.

Similar to other yeasts, the human pathogen Candida glabrata ages when it undergoes asymmetric, finite cell divisions, which determines its replicative lifespan. We sought to investigate if and how aging changes resilience of C. glabrata populations in the host environment. Our data demonstrate that old C. glabrata are more resistant to hydrogen peroxide and neutrophil killing, whereas young cells adhere better to epithelial cell layers. Consequently, virulence of old compared to younger C. glabrata cells is enhanced in the Galleria mellonella infection model. Electron microscopy images of old C. glabrata cells indicate a marked increase in cell wall thickness. Comparison of transcriptomes of old and young C. glabrata cells reveals differential regulation of ergosterol and Hog pathway associated genes as well as adhesion proteins, and suggests that aging is accompanied by remodeling of the fungal cell wall. Biochemical analysis supports this conclusion as older cells exhibit a qualitatively different lipid composition, leading to the observed increased emergence of fluconazole resistance when grown in the presence of fluconazole selection pressure. Older C. glabrata cells accumulate during murine and human infection, which is statistically unlikely without very strong selection. Therefore, we tested the hypothesis that neutrophils constitute the predominant selection pressure in vivo. When we altered experimentally the selection pressure by antibody-mediated removal of neutrophils, we observed a significantly younger pathogen population in mice. Mathematical modeling confirmed that differential selection of older cells is sufficient to cause the observed demographic shift in the fungal population. Hence our data support the concept that pathogenesis is affected by the generational age distribution of the infecting C. glabrata population in a host. We conclude that replicative aging constitutes an emerging trait, which is selected by the host and may even play an unanticipated role in the transition from a commensal to a pathogen state.post-print10768 K

Candida glabrata : a review of its features and resistance

Candida species belong to the normal microbiota of the oral cavity and gastrointestinal and vaginal tracts, and are responsible for several clinical manifestations, from mucocutaneous overgrowth to bloodstream infections. Once believed to be non-pathogenic, Candida glabrata was rapidly blamable for many human diseases. Year after year, these pathological circumstances are more recurrent and problematic to treat, especially when patients reveal any level of immunosuppression. These difficulties arise from the capacity of C. glabrata to form biofilms and also from its high resistance to traditional antifungal therapies. Thus, this review intends to present an excerpt of the biology, epidemiology, and pathology of C. glabrata, and detail an approach to its resistance mechanisms based on studies carried out up to the present.The authors are grateful to strategic project PTDC/SAU-MIC/119069/2010 for the financial support to the research center and for Celia F. Rodrigues' grant

Understanding visibility in Iron Age and Roman southern Spain with exponential random graph models for visibility networks

Long-term changes in visibility patterns between urban settlements are considered an important factor for understanding Iron Age II settlement locations in Southern Spain. From some settlements, the surrounding landscape and other settlements could be visually controlled, and some settlements are argued to be intervisible to allow for communication through visual signals. However, the study of how these visibility patterns changed in the subsequent Roman period in this region is largely ignored. In this paper, we argue that visibility might still have structured interactions between communities in Roman times and should not be dismissed out of hand merely because more and other data sources are available as compared to the Iron Age. However, the way in which it affected human behaviour might have been different in Roman times as compared to the Iron Age. We argue that simulating archaeologists’ hypotheses about the emergence of inter-settlement visibility is a promising way of understanding such differences. To do this, we use exponential random graph modelling (ERGM), a statistical network simulation modelling technique that allows us to simulate hypotheses about the emergence and long-term change of visibility networks. We combine this approach with an exploratory analysis of the observed visibility networks between identified urban settlements, which will reveal similarities and differences in the changing patterns of visibility networks through time. The results of the ERGMs are then compared with the changes in the observed network structure. We conclude that our knowledge of the changes from the Iron Age II to the Roman settlement pattern suggests only gradual changes in the role of visibility in structuring inter-settlement interactions, possibly followed by a disintegration of the visibility network after the Roman Early Imperial period