Biology subjects

Yacoub, S.

Publications and source records attributed to Yacoub, S..

5 recordsLinked to original sources

bioRxiv2026

Impact of temperature on patient-derived dengue virus breakthrough infections in wMel-infected Aedes aegypti.

The wMel strain of the insect endosymbiont Wolbachia reduces the potential for Aedes aegypti to transmit mosquito-borne viruses such as dengue (DENV). Field trials that have introgressed wMel into Ae. aegypti populations have shown this approach significantly reduces dengue incidence. In a laboratory setting some wMel-Ae. aegypti develop infectious saliva following a viremic blood meal. Additionally, studies have demonstrated that exposing wMel-Ae. aegypti to heat treatment, particularly during the larval stage, reduces wMel density in key tissues such as the ovaries, midgut and salivary glands. Here we build on these studies, using viremic blood collected from 13 dengue inpatients at the Hospital for Tropical Diseases in Ho Chi Minh City (Viet Nam), to assess how temperature affects the protection afforded to Ae. aegypti by wMel. We found that, compared to wMel-Ae. aegypti reared at 28 {+/-} 4{degrees}C, those reared at 31 {+/-} 4{degrees}C developed infectious saliva more frequently, but the risk of this occurring was still reduced compared to WT mosquitoes reared at the same temperature. Heat treatment reduced the density of wMel in all tissues tested, decreased the magnitude of wMels protection against DENV replication in the head/thorax, and significantly increased the amount of DENV replication in wMel-Ae. aegypti. When comparing cohorts of wMel-Ae. aegypti that did or did not develop infectious saliva, DENV levels in the head/thorax were associated with increased odds of mosquitoes developing infectious saliva, but wMel density was not. Overall, these findings show that elevated rearing temperatures increase the risk of patient-derived DENV breakthrough infections in wMel-Ae. aegypti, potentially due to increased DENV replication in these mosquitoes. This limitation suggests it would be prudent to increase surveillance in regions using wMel for dengue control when daily mean temperatures remain above 30{degrees}C for multiday periods. Author SummaryThe mosquito species Ae. aegypti can be infected with the bacterium Wolbachia (wMel strain), reducing its capacity to transmit viruses like dengue (DENV). Wolbachia is now being used as a biocontrol tool to reduce the burden of dengue in communities. However, some mosquitoes with Wolbachia can still transmit DENV. Here we utilised a natural infection model using dengue patient-derived blood to examine how temperature may increase the risk of DENV transmission occurrence in mosquitoes with wMel. Mosquitoes with wMel were more likely to transmit virus when reared at an average temperature of 31{degrees}C compared to those reared at an average temperature of 28{degrees}C but these mosquitoes still had a lower risk of developing infectious saliva compared to their wMel-free counterparts. Higher temperatures reduced the amount of wMel in mosquito tissues and increased the amount of DENV replicating in the head/thorax. Increasing levels of DENV RNA in these tissues were found to be associated with increased risk of mosquitoes with wMel developing infectious saliva. This finding indicates surveillance is warranted in high temperature settings or during heat waves, to monitor for changes in wMel frequency and DENV infection in Ae. aegypti.

microbiology↗

bioRxiv2025

Langerhans Cells Regulate Tongue Intraepithelial Innervation in a Microbiota- and Age-Dependent Manner

Oral Langerhans cells (LCs) are well recognized for their immunological roles, but their involvement in other physiological processes remains poorly understood. This study identifies a novel function of oral LCs in regulating tongue epithelial innervation. Postnatal LC development coincides with the establishment of local innervation, and LC depletion impairs innervation and alters nociceptive responses, underscoring their neuroimmune function. This function is driven by LC-derived IL-1{beta}, which stimulates basal epithelial cells to produce nerve growth factor (NGF), thereby promoting sensory nerve growth. Transcriptomic analyses revealed neuronal-related pathways enriched in LCs. Aging reduces LC frequency, NGF expression, and epithelial innervation, linking neuroimmune regulation to epithelial aging. While LC frequencies in the tongue remain unaffected in germ-free mice, the microbiota is essential for optimal LC function and NGF production. These findings expand our understanding of oral LCs, revealing their pivotal role in epithelial innervation beyond immune surveillance.

immunology↗

bioRxiv2025

Genetic and pharmacological correction of impaired mitophagy in retinal ganglion cells rescues glaucomatous neurodegeneration

Progressive loss of retinal ganglion cells (RGCs) and degeneration of optic nerve axons are the pathological hallmarks of glaucoma. Ocular hypertension (OHT) and mitochondrial dysfunction are linked to neurodegeneration and vision loss in glaucoma. However, the exact mechanism of mitochondrial dysfunction leading to glaucomatous neurodegeneration is poorly understood. Using multiple mouse models of OHT and human eyes from normal and glaucoma donors, we show that OHT induces impaired mitophagy in RGCs, resulting in the accumulation of dysfunctional mitochondria and contributing to glaucomatous neurodegeneration. Using mitophagy reporter mice, we show that impaired mitophagy precedes glaucomatous neurodegeneration. Notably, the pharmacological rescue of impaired mitophagy via Torin-2 or genetic upregulation of RGC-specific Parkin expression restores the structural and functional integrity of RGCs and their axons in mouse models of glaucoma and ex-vivo human retinal-explant cultures. Our study indicates that impaired mitophagy contributes to mitochondrial dysfunction and oxidative stress, leading to glaucomatous neurodegeneration. Enhancing mitophagy in RGCs represents a promising therapeutic strategy to prevent glaucomatous neurodegeneration. O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=140 SRC="FIGDIR/small/638142v1_ufig1.gif" ALT="Figure 1"> View larger version (33K): org.highwire.dtl.DTLVardef@1620793org.highwire.dtl.DTLVardef@df5a25org.highwire.dtl.DTLVardef@1974c34org.highwire.dtl.DTLVardef@bf605_HPS_FORMAT_FIGEXP M_FIG O_FLOATNOGraphical AbstractC_FLOATNO C_FIG

neuroscience↗

bioRxiv2024

Early NK-cell and T-cell dysfunction marks progression to severe dengue in patients with obesity and healthy weight

Dengue is a mosquito-borne virus infection affecting half of the worlds population for which therapies are lacking. The role of T and NK-cells in protection/immunopathogenesis remains unclear for dengue. We performed a longitudinal phenotypic, functional and transcriptional analyses of T and NK-cells in 124 dengue patients using flow cytometry and single-cell RNA-sequencing. We show that T/NK-cell signatures early in infection discriminate patients who will progress to severe dengue (SD) from those who do not. In patients with overweight/obesity these signatures are exacerbated compared to healthy weight patients, supporting their increased susceptibility to SD. In SD, CD4+/CD8+ T-cells and NK-cells display increased co-inhibitory receptor expression and decreased cytotoxic capacity compared to non-SD. Furthermore, type-I Interferon signalling is downregulated in SD, suggesting defective virus-sensing mechanisms may underlie NK/T-cell dysfunction. We propose that dysfunctional "professional killer" T/NK-cells underpin dengue pathogenesis. Our findings pave the way for the evaluation of immunomodulatory therapies for dengue.

immunology↗

bioRxiv2023

Pervasive environmental chemicals impair oligodendrocyte development

Exposure to environmental chemicals can impair neurodevelopment1-4. Oligodendrocytes that wrap around axons to boost neurotransmission may be particularly vulnerable to chemical toxicity as they develop throughout fetal development and into adulthood5,6. However, few environmental chemicals have been assessed for potential risks to oligodendrocyte development. Here, we utilized a high-throughput developmental screen and human cortical brain organoids, which revealed environmental chemicals in two classes that disrupt oligodendrocyte development through distinct mechanisms. Quaternary compounds, ubiquitous in disinfecting agents, hair conditioners, and fabric softeners, were potently and selectively cytotoxic to developing oligodendrocytes through activation of the integrated stress response. Organophosphate flame retardants, commonly found in household items such as furniture and electronics, were non-cytotoxic but prematurely arrested oligodendrocyte maturation. Chemicals from each class impaired human oligodendrocyte development in a 3D organoid model of prenatal cortical development. In analysis of epidemiological data from the CDCs National Health and Nutrition Examination Survey, adverse neurodevelopmental outcomes were associated with childhood exposure to the top organophosphate flame retardant identified by our oligodendrocyte toxicity platform. Collectively, our work identifies toxicological vulnerabilities specific to oligodendrocyte development and highlights common household chemicals with high exposure risk to children that warrant deeper scrutiny for their impact on human health.

neuroscience↗