Biology subjects

Lefevre, G.

Publications and source records attributed to Lefevre, G..

4 recordsLinked to original sources

bioRxiv2025

AXL mediates mast cell survival and resistance to tyrosine kinase inhibitors in mastocytosis

Mastocytosis is a clonal disorder driven by KIT mutations, but resistance to tyrosine kinase inhibitors (TKIs) remains a major challenge. Following the discovery of an AXL L197M mutation in a patient with congenital aggressive mastocytosis, we demonstrated unexpected wild-type AXL expression in neoplastic mast cells (MCs) across mastocytosis subtypes, challenging current views concerning mastocytosis pathophysiology. AXL was undetectable in steady-state MCs but several factors, including IFN- and IFN-{beta}, induced its expression, consistent with the inflammatory nature of mastocytosis and the high interferon levels in patient plasma. Ectopic expression of WT or L197M AXL in the ROSA KIT D816V cell line enhanced proliferation and survival by upregulating pSTAT5, pSTAT3, pFAK, p-p38, survivin and BCL2. Both AXL forms conferred resistance to the KIT inhibitor PKC412/midostaurin by sustaining BCL2, MCL1, and BCL-XL expression while reducing caspase-3 activation. L197M AXL induced slightly stronger resistance to apoptosis than WT, but this difference was not significant. Combined KIT and AXL targeting (PKC412+R428) restored TKI sensitivity by downregulating BCL-XL, Livin and cIAP1, and activating caspase-3, highlighting the therapeutic potential of dual KIT/AXL pathway inhibition. Importantly, neoplastic MCs from a mast cell leukemia patient harboring the KIT F522C mutation and unresponsive to PKC412 strongly expressed AXL and displayed marked in vitro sensitivity to R428 alone, highlighting AXL as a potential therapeutic target in aggressive mastocytosis not driven by KIT D816V. These findings identify AXL as a previously unrecognized driver of malignant MC survival and TKI resistance, and support AXL inhibition as a promising therapeutic strategy in aggressive mastocytosis. Key Points- AXL is aberrantly expressed in neoplastic mast cells, driving survival and resistance to KIT inhibition in mastocytosis. - Dual KIT and AXL inhibition restores TKI sensitivity in KIT-mutant mastocytosis. Graphical abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=182 SRC="FIGDIR/small/686205v1_ufig1.gif" ALT="Figure 1"> View larger version (40K): org.highwire.dtl.DTLVardef@1569c9eorg.highwire.dtl.DTLVardef@1445b32org.highwire.dtl.DTLVardef@bf3565org.highwire.dtl.DTLVardef@14a94f0_HPS_FORMAT_FIGEXP M_FIG C_FIG

cancer biology↗

bioRxiv2025

Parental exposure to wet and dry conditions shapes the viability and thermotolerance of eggs in Aedes aegypti

Aedes aegypti, a primary vector of dengue, Zika, and chikungunya, displays remarkable adaptability across ecological gradients. Central to this resilience is the egg stage, which must withstand fluctuating moisture and temperature conditions. Environmental transitions, particularly changes in moisture availability, significantly influence egg hatching success in mosquitoes. This study investigates how parental exposure to variable hydration conditions shapes key reproductive traits in Ae. aegypti. Using four environmental regimes, continuous wet, continuous dry, wet-to- dry, and dry-to-wet, we assessed egg output, hatching success, thermotolerance, and egg nutrient composition across three Ae. aegypti populations. Our results show that oviposition timing and egg production are significantly affected by the hydration environment experienced by the parental generation. While the wet, dry, and dry-to-wet groups exhibited a consistent oviposition peak beginning four days post-blood feeding, the wet-to-dry group showed delayed reproductive investment, with peak egg production occurring later. Egg output was highest under continuous wet conditions and significantly reduced in the dry and wet-to-dry treatments across all populations. Interestingly, the wet-to-dry group showed significantly higher egg-thermotolerance than any other group, and this pattern was consistent across all three populations under high- temperature stress conditions (41{degrees}C and 45{degrees}C). Nutritional composition showed an increased glycogen level in eggs when parents were exposed to wet conditions before blood feeding. By integrating physiological and ecological metrics such as hatching rates and thermal stress resilience, we demonstrate how parental environments shape subsequent egg performance, highlighting adaptive responses that enable Ae. aegypti persistence under increasing climate variability.

physiology↗

bioRxiv2024

MAJOR METABOLITES FROM HYPERICUM PERFORATUM L., HYPERFORIN AND HYPERICIN, ARE BOTH ACTIVE AGAINST HUMAN CORONAVIRUSES

COVID-19 pandemic has highlighted the need of antiviral molecules against coronaviruses. Plants are an endless source of active compounds. In the current study, we investigated the potential antiviral effects of Hypericum perforatum L.. Its extract contained two major metabolites belonging to distinct chemical classes, hypericin (HC) and hyperforin (HF). First, we demonstrated that HC inhibited HCoV-229E at the entry step by directly targeting the viral particle in a light-dependent manner. While antiviral properties have already been described for HC, the study here showed for the first time that HF has pan-coronavirus antiviral capacity. Indeed, HF was highly active against Alphacoronavirus HCoV-229E (IC50 value of 1.10 {micro}M), and Betacoronaviruses SARS-CoV-2 (IC50 value of of 0.24 to 0.98 {micro}M), SARS-CoV (IC50 value of 1.01 {micro}M) and MERS-CoV (IC50 value of 2.55 {micro}M). Unlike HC, HF was active at a post-entry step, most likely the replication step. Antiviral activity of HF on HCoV-229E and SARS-CoV-2 was confirmed in primary human respiratory epithelial cells. Furthermore, in vitro combination assay of HF with remdesivir showed that their association was additive, which was encouraging for a potential therapeutical association. As HF was active on both Alpha- and Betacoronaviruses, a cellular target was hypothesized. Heme oxygenase 1 (HO-1) pathway, a potential target of HF, has been investigated but the results showed that HF antiviral activity against HCoV-229E was not dependent on HO-1. Collectively, HF is a promising antiviral candidate in view of our results and pharmacokinetics studies already published in animal models or in human.

microbiology↗

bioRxiv2021

Antibody and T cell memory immune response after two doses of the BNT162b2 mRNA vaccine in older adults with and without prior SARS-CoV-2 infection

We quantified S1-specific IgG, neutralizing antibody titers, specific IFN{gamma} secreting T cells and functionality of specific CD4+ and CD8+ T cells in 130 young adults (median age 44.0 years) and 106 older residents living in a long-term care facility (86.5 years) after 2 doses of BNT162b2. Three months after the first injection, humoral and cellular memory responses were dramatically impaired in the 54 COVID-19-naive older compared to the 121 COVID-19-naive younger adults. Notably, older participants neutralizing antibodies, detected in 76.5% (versus 100% in young adults, P < 0.0001), were ten times lower than the youngers antibody titers (P < 0.0001). Antibody and T cell responses were greater among the 52 COVID-19-recovered than among the 54 COVID-19-naive older adults (P < 0.0001). Our study shows that 2 doses of BNT162b2 does not guarantee long-term protection against SARS-CoV-2 in the older. An additional dose should be considered to boost their specific memory response.

immunology↗