Evidence for the Contribution of the Hemozoin Synthesis Pathway of the Murine Plasmodium yoelii to the Resistance to Artemisinin-Related Drugs

Plasmodium falciparum malaria is a major global health problem, causing approximately 780,000 deaths each year. In response to the spreading of P. falciparum drug resistance, WHO recommended in 2001 to use artemisinin derivatives in combination with a partner drug (called ACT) as first-line treatment for uncomplicated falciparum malaria, and most malaria-endemic countries have since changed their treatment policies accordingly. Currently, ACT are often the last treatments that can effectively and rapidly cure P. falciparum infections permitting to significantly decrease the mortality and the morbidity due to malaria. However, alarming signs of emerging resistance to artemisinin derivatives along the Thai-Cambodian border are of major concern. Through long-term in vivo pressures, we have been able to select a murine malaria model resistant to artemisinins. We demonstrated that the resistance of Plasmodium to artemisinin-based compounds depends on alterations of heme metabolism and on a loss of hemozoin formation linked to the down-expression of the recently identified Heme Detoxification Protein (HDP). These artemisinins resistant strains could be able to detoxify the free heme by an alternative catabolism pathway involving glutathione (GSH)-mediation. Finally, we confirmed that artemisinins act also like quinolines against Plasmodium via hemozoin production inhibition. The work proposed here described the mechanism of action of this class of molecules and the resistance to artemisinins of this model. These results should help both to reinforce the artemisinins activity and avoid emergence and spread of endoperoxides resistance by focusing in adequate drug partners design. Such considerations appear crucial in the current context of early artemisinin resistance in Asia

Ground deformation monitoring of the eruption offshore Mayotte

In May 2018, the Mayotte island, located in the Indian Ocean, was affected by an unprecedented seismic crisis, followed by anomalous on-land surface displacements in July 2018. Cumulatively from July 1, 2018 to December 31, 2021, the horizontal displacements were approximately 21 to 25 cm eastward, and subsidence was approximately 10 to 19 cm. The study of data recorded by the on-land GNSS network, and their modeling coupled with data from ocean bottom pressure gauges, allowed us to propose a magmatic origin of the seismic crisis with the deflation of a deep source east of Mayotte, that was confirmed in May 2019 by the discovery of a submarine eruption, 50 km offshore of Mayotte ([Feuillet et al., 2021]). Despite a non-optimal network geometry and receivers located far from the source, the GNSS data allowed following the deep dynamics of magma transfer, via the volume flow monitoring, throughout the eruption

Edifice strength and magma transfer modulation at Piton de la Fournaise volcano

International audience2003 to 2007, eruptive activity at Piton de la Fournaise was shown to follow cycles, comprising many summit/proximal eruptions and finishing by a distal eruption. GPS measurements evidenced striking asymmetric deformation between its western and eastern flanks. Horizontal displacements recorded during interdistal periods showed a characteristic amplitude at the top of the eastern flank. Displacements recorded at the base of the summit cone showed a bimodal distribution, with low amplitudes during interdistal periods and large ones during distal eruptions. To account for displacement asymmetry, characteristic amplitude, and large flank displacement, we modeled the volcanic edifice using a Drücker-Prager elastoplastic rheology. Friction angles of 15° and >30° were needed to model the displacements respectively during distal eruptions and interdistal periods; this change shows that strain weakening occurred during distal events. Large plastic displacement that occurred in the eastern flank during distal eruptions relaxed the horizontal elastic stress accumulated during interdistal periods; it triggered summit deflation, horizontal magma transfer, and distal flank eruption and reset the eruptive cycle. Our elastoplastic models also show that simple source geometries may induce large eastern flank displacements that would be explained by a complex geometry in a linear elastic edifice. Magma supply is often thought to control volcano's eruptive activity, with surface deformation reflecting changes in magma supply rate, the volcano's response being linear. Our results bring some evidences that on Piton de la Fournaise time-space discretization of magma transfer may be the result of the edifice's nonlinear response, rather than changes in magma supply

Implementation of a multistation approach for automated event classification at Piton de la Fournaise volcano

International audienc

Tumor Necrosis Factor-Alpha Targeting Can Protect against Arthritis with Low Sensitization to Infection

Tumor necrosis factor-alpha (TNF-α) blockade is an effective treatment for rheumatoid arthritis (RA) and other inflammatory diseases, but in patients, it is associated with reduced resistance to the infectious agents Mycobacterium tuberculosis and Listeria monocytogenes, among others. Our goal was to model infection and arthritis in mice and to compare etanercept, a currently used anti-TNF-α inhibitor, to an anti-TNF-α vaccine. We developed a murine surrogate of the TNF-α kinoid and produced an anti-murine TNF-α vaccine (TNFKi) composed of keyhole limpet hemocyanin conjugated to TNF-α, which resulted in anti-TNF-α antibody production in mice. We also used etanercept (a soluble receptor of TNF commonly used to treat RA) as a control of TNF neutralization. In a mouse model of collagen-induced arthritis, TNFKi protected against inflammation similar to etanercept. In a mouse model of acute L. monocytogenes infection, all TNFKi-treated mice showed cleared bacterial infection and survived, whereas etanercept-treated mice showed large liver granulomas and quickly died. Moreover, TNFKi mice infected with the virulent H37Rv M. tuberculosis showed resistance to infection, in contrast with etanercept-treated mice or controls. Depending on the TNF-α blockade strategy, treating arthritis with a TNF-α inhibitor could result in a different profile of infection suceptibility. Our TNFKi vaccine allowed for a better remaining host defense than did etanercept

Changes in the Long-Term Geophysical Eruptive Precursors at Piton de la Fournaise: Implications for the Response Management

Anticipating eruptions early enough to give warning to authorities is one of the main goals in volcanology. However, identifying and providing unequivocal identification on volcano reawakening remain challenging issues, mostly when unrests are sudden or undetectable. At the Piton de la Fournaise volcano, a clear increase in both the seismicity and the ground displacements are systematically observed a few days/weeks before eruptions, and appear as clear eruptive precursors. Here a systematic study of these long-term precursors demonstrates the changes in their intensity, duration, and time of appearance during 1998–2017 (43 eruptions), directly linked to the influence of the pre- and post-summit caldera formation (April 2007) and to changes in the deep magma refilling process since 2016. These changes in the precursors were not without consequence on the early alert to the authorities, with some false alerts and late alerts. It is thus of prime importance for crisis management to bear in mind the possibility of these rapid changes and that of sudden volcanic unrest with little warnings, to be able to take the most appropriate decisions, in particular raising the level of alert or lifting it totally. The findings of this study have enabled the relevant authorities to improve the alert chain protocol, and scientists to communicate more efficiently with the decision-makers

A damage model for volcanic edifices: Implications for edifice strength, magma pressure, and eruptive processes

International audienceMonitoring of large basaltic volcanoes, such as Piton de la Fournaise (La Réunion Island, France), has revealed preeruptive accelerations in surface displacements and seismicity rate over a period of between 1 h and several weeks before magma reaches the surface. Such eruptions are attributed to ruptures of pressurized magma reservoirs. Elastic models used to describe surface deformation would assume that accelerations in surface deformation are due to increases in reservoir pressure. This assumption requires changes in magma or pressure conditions at the base of the magma feeding system that are unrealistic over the observed timescale. Another possible cause for these accelerations is magma pressure in the reservoir weakening the volcanic edifice. In the present study, we modeled such weakening by progressive damage to an initially elastic edifice. We used an incremental damage model, with seismicity as a damage variable with daily increments. Elastic moduli decrease linearly with each damage increment. Applied to an initially elastic edifice with constant pressure at the base of the system, this damage model reproduces surface displacement accelerations quite well when damage is sufficient. Process dynamics is controlled by the damage parameter, taken as the ratio between the incremental rupture surface and the surface to be ruptured. In this case, edifice strength and magma reservoir pressure decrease with decreasing elastic moduli, whereas surface displacement accelerates. We discuss the consequences of pressure decreases in magma reservoirs