Biology subjects

Reyes, K.

Publications and source records attributed to Reyes, K..

6 recordsLinked to original sources

bioRxiv2026

The Hao-Fountain syndrome gene USP7 restricts neurotropic orthoflavivirus entry through cell intrinsic control of endosomal dynamics

Neurodevelopmental disorders are increasingly associated with immune phenotypes, including autoinflammation, immunodeficiency, and increased susceptibility to severe infection. To determine whether neurodevelopmental disorders-associated genes exert immune functions, we performed an arrayed siRNA screen targeting 28 genes with nonredundant cellular roles and assessed their effects on Zika virus (ZIKV) infection and innate immune pathways. We identified hits that intrinsically restrict ZIKV infection and modulate inflammatory pathways following infection. We further characterized the antiviral activity of the Hao-Fountain syndrome gene USP7, which potently restricts selected neurotropic orthoflaviviruses. USP7 inhibits ZIKV internalization before viral membrane fusion and genome release into the cytoplasm. Because USP7 plays a role in endosomal tubulation and recycling, we investigated whether endosomal recycling pathways restrict ZIKV infection. We identified the USP7-regulated E3 ubiquitin ligase TRIM27, as well as the recycling-associated Rab GTPases RAB11 and RAB35, as potent regulators of ZIKV infection. Infection assays using cell lines expressing pathogenic USP7 variants and primary fibroblasts from individuals with Hao-Fountain syndrome demonstrated that disease-associated USP7 mutations impair its antiviral activity and increase permissivity to ZIKV infection. These findings are consistent with recent case reports of unusually severe viral infection during early life in individuals with Hao-Fountain syndrome. Collectively, our study identifies endosomal recycling pathways as important intrinsic restriction mechanisms against neurotropic orthoflaviviruses and nominates pathogenic USP7 variation as a candidate inborn error of immunity.

microbiology↗

bioRxiv2025

Gangliosides Modulate the Secretion of Extracellular Vesicles and Their Misfolded Protein Cargo

Gangliosides are glycosphingolipids that play an integral role in cell signaling and provide neuroprotection. While present on extracellular vesicles (EVs) - key mediators of intercellular communication - their role in EV biogenesis remains unclear. Here, we identify gangliosides, both endogenously synthesized and exogenously administered, as key modulators of EV biogenesis, with the specific composition of their glycan headgroup and the presence or absence of sialic acid and N-acetyl-D-galactosamine residues dictating whether they promote or inhibit EV biogenesis. We show that GM1 and other complex gangliosides enhance EV secretion, while disruption of ganglioside synthesis impairs it. GM1 supplementation restores EV secretion in Huntingtons disease (HD) fibroblasts and HD cell models that have lower than normal levels of gangliosides, and in cells with a genetic block of ganglioside synthesis that models rare early-onset neurodegenerative diseases. Notably, GM1 also enhances EV-mediated secretion of pathogenic misfolded proteins, including mutant huntingtin (mHTT), -synuclein and tau, reducing intracellular burden and providing mechanistic insight into the mHTT-lowering effects of GM1 treatments in HD models. Our findings shed light on the neuroprotective roles of gangliosides and highlight their potential for therapeutic exploitation in misfolded protein disorders.

cell biology↗

bioRxiv2024

Elevational and Oceanic Barriers Shape the Distribution, Dispersal and Diversity of Aotearoa's Kapokapowai (Uropetala) Dragonflies

Mountains and islands provide an opportunity for studying the biogeography of diversification and population fragmentation. Aotearoa (New Zealand) is an excellent location to investigate both phenomena due to alpine emergence and oceanic separation. While it would be expected that separation across oceanic and elevation gradients are major barriers to gene flow in animals, including aquatic insects, such hypotheses have not been thoroughly tested in these taxa. By integrating population genomic from sub-genomic Anchored-Hybrid Enrichment sequencing, ecological niche modeling, and morphological analyses from scanning-electron microscopy, we show that tectonic uplift and oceanic vicariance are implicated in speciation and population structure in Kapokapowai (Uropetala) dragonflies. Although Te Moana o Raukawa (Cook Strait), is likely responsible for some of the genetic structure observed, speciation has not yet occurred in populations separated by the strait. We find that the altitudinal gradient across K[a] Tiritiri-o-te-Moana (the Southern Alps) is not impervious but it significantly restricts gene flow between aforementioned species. Our data support the hypothesis of an active colonization of K[a] Tiritiri-o-te-Moana by the ancestral population of Kapokapowai, followed by a recolonization of the lowlands. These findings provide key foundations for the study of lineages endemic to Aotearoa.

evolutionary biology↗

bioRxiv2024

IL-21 Shapes the B Cell Response in a Context-Dependent Manner

The cytokine interleukin-21 (IL-21) is a pivotal T cell-derived signal crucial for germinal center (GC) responses, but the precise mechanisms by which IL-21 influences B cell function remain elusive. Here, we investigated the B cell-intrinsic role of IL-21 signaling by employing a novel IL-21 receptor (Il21r) conditional knock-out mouse model and ex vivo culture systems and uncovered a surprising duality of IL-21 signaling in B cells. While IL-21 stimulation of naive B cells led to Bim-dependent apoptosis, it promoted robust proliferation of pre-activated B cells, particularly class-switched IgG1+ B cells ex vivo. Consistent with this, B cell-specific deletion of Il21r led to a severe defect in IgG1 responses in vivo following immunization. Intriguingly, Il21r-deleted B cells are significantly impaired in their ability to transition from a pre-GC to a GC state following immunization. Although Il21r-deficiency did not affect the proportion of IgG1+ B cells among GC B cells, it greatly diminished the proportion of IgG1+ B cells among the plasmablast/plasma cell population. Collectively, our data suggest that IL-21 serves as a critical regulator of B cell fates, influencing B cell apoptosis and proliferation in a context-dependent manner.

immunology↗

bioRxiv2023

Newly Sequenced Genomes Reveal Patterns of Gene Family Expansion in select Dragonflies (Odonata: Anisoptera)

Gene family evolution plays a key role in shaping patterns of biodiversity across the tree of life. In Insecta, adaptive gene family turnover has broadly been tied to vision, diet, pesticide resistance, immune response and survival in extreme environments. Patterns of gene family evolution are of particular interest in Odonata (dragonflies and damselflies), which represents the first lineage to fly, and one of the most exceptional groups of predators. Previous work in Odonata found expansions of opsin genes are correlated with the diversification of the herbivorous insects that Odonata prey upon, but general trends in gene family turnover has not been studied in this order. Here, we show that two families of suborder Anisoptera (dragonflies), Libellulidae and Petaluridae, have expanded gene repertoire related to their unique life history and diversification patterns. These results are an important step towards understanding why Libellulidae is, generally, a species rich family of short lived species that are highly tolerant to poor water quality, while Petaluridae is a species poor family of habitat and behavioral specialists. Specifically, Libellulidae share expanded gene families related to immune response, desiccation response, and processing of free radicals, which all potentially enable many Libellulidae to inhabit low quality water bodies. Likewise, Petaluridae show unique patterns of gene turnover in gene families implicated in sensory perception, which could be tied to the unique semi-terrestrial lifestyle of the nymphs of this family. Furthermore, Odonata as a whole has a gene gene turnover rate that is an order of magnitude smaller than other studied insect orders, potentially contributing to the relatively low species diversity in the order Odonata compared to other insects. These results offer important hypotheses for the consideration of evolutionary drivers across Insecta.

evolutionary biology↗

bioRxiv2018

Experimental Zika Virus Infection in the Pregnant Common Marmoset Induces Spontaneous Fetal Loss and Neurodevelopmental Abnormalities

During its most recent outbreak across the Americas, Zika virus (ZIKV) was surprisingly shown to cause fetal loss and congenital malformations in acutely and chronically infected pregnant women. However, understanding the underlying pathogenesis of ZIKV congenital disease has been hampered by a lack of relevant in vivo experimental models. Here we present a candidate New World monkey model of ZIKV infection in pregnant marmosets that faithfully recapitulates human disease. ZIKV inoculation at the human-equivalent of early gestation caused an asymptomatic seroconversion, induction of type I/II interferon-associated genes and proinflammatory cytokines, and persistent viremia and viruria. Spontaneous pregnancy loss was observed 16-18 days post-infection, with extensive active placental viral replication and fetal neurocellular disorganization similar to that seen in humans. These findings underscore the key role of the placenta as a conduit for fetal infection, and demonstrate the utility of marmosets as a highly relevant model for studying congenital ZIKV disease and pregnancy loss.

microbiology↗