Inoculation of the Leishmania infantum HSP70-II null mutant induces long-term protection against L. amazonensis infection in BALB/c mice

Leishmania amazonensis parasites are etiological agents of cutaneous leishmaniasis in the New World. BALB/c mice are highly susceptible to L. amazonensis challenge due to their inability to mount parasite-dependent IFN-γ-mediated responses. Here, we analyzed the capacity of a single administration of the LiΔHSP70-II genetically-modified attenuated L. infantum line in preventing cutaneous leishmaniasis in mice challenged with L. amazonensis virulent parasites. In previous studies, this live attenuated vaccine has demonstrated to induce long-protection against murine leishmaniasis due to Old World Leishmania species. Vaccinated mice showed a reduction in the disease evolution due to L. amazonensis challenge, namely reduction in cutaneous lesions and parasite burdens. In contrast to control animals, after the challenge, protected mice showed anti-Leishmania IgG2a circulating antibodies accompanied to the induction of Leishmania-driven specific IFN-γ systemic response. An analysis performed in the lymph node draining the site of infection revealed an increase of the parasite-specific IFN-ϒ production by CD4+ and CD8+ T cells and a decrease in the secretion of IL-10 against leishmanial antigens. Since the immunity caused by the inoculation of this live vaccine generates protection against different forms of murine leishmaniasis, we postulate LiΔHSP70-II as a candidate for the development of human vaccines.This research was funded by grants from Ministerio de Ciencia e Innovación FISPI11/00095 and FISPI14/00366 (FEDER FUNDING) to M.S. and RYC-2016-19463 and RTI2018-343 to S.I. J.M.R. and M.S. are funded by the Fondo de Investigaciones Sanitarias (ISCIII-RETICRD16/0027/008-FEDER). E.H.G. is supported by a FPI grant from the Spanish Ministerio de Ciencia e Innovación. Institutional grants from the Fundación Ramón Areces and Banco de Santander to the CBMSO are also acknowledged. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.Peer reviewe

Projected increases in potential groundwater recharge and reduced evapotranspiration under future climate conditions in West Africa

Study region West Africa, with a focus between 5°W and 5°E. Study focus The effects of changing climate and CO2 concentration (RCP8.5 between 2000 and 2100) on the West African monsoon are examined using the UPSCALE high-resolution (25 km) global climate model ensembles for present and future climate, combined with the JULES land-surface model. New hydrological insights Future climate is predicted to have an enhanced summertime Saharan heat low, changing large-scale circulation, causing monsoon rainfall generally to increase. The monsoon progresses further inland and occurs later in the year. UPSCALE rainfall projections indicate that the eastern Sahel becomes wetter (+ 12.2%) but the western Sahel drier (− 13.5%). Future evapotranspiration is reduced across most of West Africa due to the CO2 fertilisation effect causing lower transpiration. Potential groundwater recharge (soil drainage at the bottom of a 3 m deep soil column), is predicted to increase from 0% to 16% of rainfall under present climate, to 1–20% in the future, doubling from ~ 5% to ~ 10% in northern Ghana and the eastern Sahel. Potential recharge increases largely due to increased soil hydraulic conductivity, caused by higher soil moisture resulting from increased rainfall and reduced transpiration. Other factors have only a minor influence on the water balance and potential recharge, including rainfall intensity and land use type. A predicted increase in future potential groundwater recharge is significant as development of groundwater resources is seen as a key means to meet growing water demand in West Africa

Fine-tuning protein recycling to control cholesterol homeostasis

Intracellular levels of cholesterol are paramount to regulating cholesterol levels in blood. The Ubiquitin Proteasome System (UPS) can regulate the expression and activity of the master regulators of cholesterol levels in the cell: SREBP2 and LXR. The UPS, its E2 and E3 ligases and deubiquitylating enzymes (DUBs) can also fine-tune the expression, degradation and activity enzymes involved in the synthesis, uptake and efflux of cholesterol. Using molecular techniques, in this thesis we focus on the identification and description of new pathways that regulate intracellular cholesterol pools through the UPS. Two new E3 ligases involved in the regulation of intracellular cholesterol homeostasis were identified: MARCH6 and RNF145. Both E3 ligases respond to high cholesterol levels. MARCH6 degrades SM, an enzyme involved in cholesterol synthesis when intracellular cholesterol is high. RNF145's transcription is responsive to LXR, a transcription factor activated in the presence of certain cholesterol derivatives. We also look at a feedback mechanism in cholesterol homeostasis regulated by two E3 ligases: MARCH6 and IDOL. This feedback mechanism regulates which cholesterol source is preferentially used by the cell: either uptake or synthesis. The E2 ligases involved in the cholesterol-mediated degradation of HMGCR and SM were identified and serve as another mechanism to differentiate their breakdown. Furthermore, we identify a novel regulation of IDOL by DUBs, independent of its regulation by LXR