High Prevalence of Both Humoral and Cellular Immunity to Zaire ebolavirus among Rural Populations in Gabon

To better understand Zaire ebolavirus (ZEBOV) circulation and transmission to humans, we conducted a large serological survey of rural populations in Gabon, a country characterized by both epidemic and non epidemic regions. The survey lasted three years and covered 4,349 individuals from 220 randomly selected villages, representing 10.7% of all villages in Gabon. Using a sensitive and specific ELISA method, we found a ZEBOV-specific IgG seroprevalence of 15.3% overall, the highest ever reported. The seroprevalence rate was significantly higher in forested areas (19.4%) than in other ecosystems, namely grassland (12.4%), savannah (10.5%), and lakeland (2.7%). No other risk factors for seropositivity were found. The specificity of anti-ZEBOV IgG was confirmed by Western blot in 138 individuals, and CD8 T cells from seven IgG+ individuals were shown to produce IFN-γ after ZEBOV stimulation. Together, these findings show that a large fraction of the human population living in forested areas of Gabon has both humoral and cellular immunity to ZEBOV. In the absence of identified risk factors, the high prevalence of “immune” persons suggests a common source of human exposure such as fruits contaminated by bat saliva. These findings provide significant new insights into ZEBOV circulation and human exposure, and raise important questions as to the human pathogenicity of ZEBOV and the existence of natural protective immunization.     

Pathocenosis: A Holistic Approach to Disease Ecology

The History of medicine describes the emergence and recognition of infectious diseases, and human attempts to stem them. It also throws light on the role of changing environmental conditions on disease emergence/re-emergence, establishment and, sometimes, disappearance. However, the dynamics of infectious diseases is also influenced by the relationships between the community of interacting infectious agents present at a given time in a given territory, a concept that Mirko Grmek, an historian of medicine, conceptualized with the word “pathocenosis”. The spatial and temporal evolution of diseases, when observed at the appropriate scales, illustrates how a change in the pathocenosis, whether of “natural” or anthropic origin, can lead to the emergence and spread of diseases.     

Once-daily administration of CJC-1295, a long-acting growth hormone-releasing hormone (GHRH) analog, normalizes growth in the GHRH knockout mouse

Although the majority of children with isolated growth hormone (GH) deficiency have a good growth response to GH-releasing hormone (GHRH), the use of this therapeutic agent is limited by its very short half-life. Indeed, we have shown that, in mice with GHRH gene ablation (GHRH knockout; GHRHKO), even twice-daily injections of a GHRH analog are unable to normalize growth. CJC-1295 is a synthetic GHRH analog that selectively and covalently binds to endogenous albumin after injection, thereby extending its half-life and duration of action. We report the effects of CJC-1295 administration in GHRHKO animals. Three groups of 1-wk-old GHRHKO mice were treated for 5 wk with 2 microg of CJC-1295 at intervals of 24, 48, and 72 h. Placebo-treated GHRHKO mice and mice heterozygous for the GHRHKO allele served as controls. GHRHKO animals receiving daily doses of CJC-1295 exhibited normal body weight and length. Mice treated every 48 and 72 h reached higher body weight and length than placebo-treated animals, without full growth normalization. Femur and tibia length remained normal in animals treated every 24 and 48 h. Relative lean mass and subcutaneous fat mass were normal in all treated groups. CJC-1295 caused an increase in total pituitary RNA and GH mRNA, suggesting that proliferation of somatotroph cells had occurred, as confirmed by immunohistochemistry images. These findings demonstrate that treatment with once-daily administration of CJC-1295 is able to maintain normal body composition and growth in GHRHKO mice. The same dose is less effective when administered every 48 or 72 h.     

Maturation by LctT Is Required for Biosynthesis of Full-Length Lantibiotic Lacticin 481

In lantibiotic lacticin 481 biosynthesis, LctT cleaves the precursor peptide and exports mature lantibiotic. Matrix-assisted laser desorption ionization-time of flight mass spectrometry revealed that a truncated form of lacticin 481 is produced in the absence of LctT or after cleavage site inactivation. Production of truncated lacticin 481 is 4-fold less efficient, and its specific activity is about 10-fold lower.     

Signalling and oxidant adaptation in Candida albicans and Aspergillus fumigatus

Candida species and Aspergillus fumigatus were once thought to be relatively benign organisms. However, it is now known that this is not the case - Candida species rank among the top four causes of nosocomial infectious diseases in humans and A. fumigatus is the most deadly mould, often having a 90% mortality rate in immunocompromised transplant recipients. Adaptation to stress, including oxidative stress, is a necessary requisite for survival of these organisms during infection. Here, we describe the latest information on the signalling pathways and target proteins that contribute to oxidant adaptation in C. albicans and A. fumigatus, which has been obtained primarily through the analysis of mutants or inference from genome annotation.     

How does cholesterol affect the way Hedgehog works?

Members of the Hedgehog (Hh) family of proteins are conserved morphogens that spread and modulate cell fates in target tissue. Mature Hh carries two lipid adducts, a palmitoyl group at the N terminus and cholesterol at the C terminus. Recent findings have addressed how these lipid modifications affect the function and transport of Hh in Drosophila. In contrast to the palmitoyl adduct, cholesterol appears not to be essential for signalling. However, the absence of the cholesterol adduct affects the spread of Hh within tissues. As we discuss here, the exact nature of this effect is controversial.     

Normal Pathways: Controlling Isotopes and Building Biomedical Research in Postwar France

During the late 1940s and 1950s, radioisotopes became important resources for biological and medical research. This article explores the strategies used by French researchers to get access to this material, either from the local Atomic Energy Commission (CEA) or from suppliers in the United States or United Kingdom. It focuses on two aspects of this process: the transatlantic circulation of both isotopes and associated instrumentation; the regulation of use and access by the administrative bodies governing research in France. Analyzing the investigations conducted within laboratories associated either with the atomic energy agency or with the local National Institute of Health (INH), the paper discusses the part played by the new tools in the postwar transformation of biomedical research. It contrasts the INH successful development of biological studies and metabolic tracing with the mixed results of CEA in advancing cancer radiotherapy, thus highlighting locally defined “normal paths” to radiobiology.     

P2X7 and phospholipid signalling: the search of the "missing link" in epithelial cells

The purinergic receptor P2X₇ is widely expressed in epithelial cells. This receptor shares in common with the other P2X receptors the ability to form a non-selective cation channel. On the other hand, the COOH terminus of P2X₇ seems to allow this receptor to couple to a spectrum of downstream effectors responsible for the regulation of cell death and pore formation among other functions. However, the coupling of P2X₇ to these downstream effectors, as well as the identity of possible adapters directly interacting with the receptor, remains poorly understood. Here we review the ability of P2X₇ to activate phospholipid signalling pathways in epithelial cells and propose this step as a possible link between the receptor and other downstream effectors. The P2X₇ ability to control the cellular levels of several lipid messengers (PA, AA, DAG, ceramide, etc.) through the modulation of phospholipases (C, A₂, D) and neutral sphingomyelinase is described. These pathways are sometimes regulated independently of the channel function of the receptor. Recent data concerning P2X₇ localization in lipid rafts is also discussed in relation to the coupling to these pathways and dissociation from channel function.     

Surface nucleolin participates in both the binding and endocytosis of lactoferrin in target cells.

Lactoferrin (Lf), a multifunctional molecule present in mammalian secretions and blood, plays important roles in host defense and cancer. Indeed, Lf has been reported to inhibit the proliferation of cancerous mammary gland epithelial cells and manifest a potent antiviral activity against human immunodeficiency virus and human cytomegalovirus. The Lf-binding sites on the cell surface appear to be proteoglycans and other as yet undefined protein(s). Here, we isolated a Lf-binding 105 kDa molecular mass protein from cell extracts and identified it as human nucleolin. Medium-affinity interactions ( approximately 240 nm) between Lf and purified nucleolin were further illustrated by surface plasmon resonance assays. The interaction of Lf with the cell surface-expressed nucleolin was then demonstrated through competitive binding studies between Lf and the anti-human immunodeficiency virus pseudopeptide, HB-19, which binds specifically surface-expressed nucleolin independently of proteoglycans. Interestingly, binding competition studies between HB-19 and various Lf derivatives in proteoglycan-deficient hamster cells suggested that the nucleolin-binding site is located in both the N- and C-terminal lobes of Lf, whereas the basic N-terminal region is dispensable. On intact cells, Lf co-localizes with surface nucleolin and together they become internalized through vesicles of the recycling/degradation pathway by an active process. Morever, a small proportion of Lf appears to translocate in the nucleus of cells. Finally, the observations that endocytosis of Lf is inhibited by the HB-19 pseudopeptide, and the lack of Lf endocytosis in proteoglycan-deficient cells despite Lf binding, point out that both nucleolin and proteoglycans are implicated in the mechanism of Lf endocytosis.