Biology subjects

Jurado, K. A.

Publications and source records attributed to Jurado, K. A..

8 recordsLinked to original sources

bioRxiv2026

Fetal-intrinsic antiviral mechanisms emerge over the course of gestation

Congenital viral infections have variable effects on pregnancy outcomes with implications for maternal and fetal health. However, the maternal and fetal immune mechanisms that emerge over the course of gestation to determine protective or pathological outcomes remain poorly understood. Here, we use the emerging congenital pathogen Oropouche virus (OROV) to examine gestational stage-dependent differences in maternal and fetal outcomes in a mouse model of congenital infection. Pregnant mice (dams) infected during early gestation resist severe OROV disease, whereas mid-gestation-infected dams succumb to infection. In contrast, fetal pathology is substantial following early gestation infection but limited following infection during mid-gestation, revealing discordant maternal and fetal susceptibility across gestation. Mid-gestation fetal tissues effectively restricted vertical transmission compared to early gestation fetal tissues, corresponding with reduced fetal pathology. Moreover, both placental and fetal tissue cleared OROV RNA over the course of infection, independent of gestational stage, and failure to clear viral RNA was associated with severe fetal pathology. Spatial analysis of early gestation implantation sites further revealed distinct regional susceptibility to OROV infection across the maternal-fetal interface. We identified potential instances of placental-independent vertical transmission via direct fetal contact with highly infected regions of the contralateral maternal uterus. Finally, we uncovered an unexpected mechanism by which type I interferon signaling contributes to inter-fetal immune crosstalk to restrict both OROV vertical transmission and pathology. Together, these findings establish the fetus as an active participant in antiviral defense and reveal previously unrecognized mechanisms by which fetal-intrinsic antiviral immune responses limit congenital viral infection and disease.

immunology↗

bioRxiv2025

Neutral lipid processing in glia is sexually dimorphic and promotes sleep through diacylglycerol catabolism

Sleep is thought to have a protective role in clearing toxic waste from the brain, which may include processing of damaged lipids. We recently showed that blocking endocytosis in glia increases sleep and report here that this block is associated with an increase in peroxidized lipids and glial lipid droplet accumulation, raising the possibility that accumulation of these lipids increases the need to sleep. Sleep gain induced by blocking glial transport is exaggerated by knockout of the lipid droplet coat protein, Lipid Storage Droplet 2 (Lsd2), suggesting that sleep-promoting lipids are not contained in lipid droplets. To identify lipids regulated by sleep state, we performed global, targeted lipidomics analysis on Drosophila neurons and glia, screening nearly 3,000 lipids across 11 major classes. This revealed that sex influences lipid composition in both cell types and lipid homeostasis following extended wakefulness. Female neurons and glia are enriched in ultra-long chain fatty acids, triacylglycerols, and diacylglycerols, with glial diacylglycerol enrichment correlating with elevated sleep need. Based on manipulations of neutral lipid metabolic pathways, we propose that monoacylglycerols, products of glial diacylglycerol catabolism, promote sleep.

neuroscience↗

bioRxiv2024

Antiviral immunity within neural stem cells distinguishes viral strain differences in forebrain organoids

Neural stem cells have intact innate immune responses that protect them from virus infection and cell death. Yet, viruses can antagonize such responses to establish neuropathogenesis. Using a forebrain organoid model system at two developmental time points, we identified that neural stem cells, in particular radial glia, are basally primed to respond to virus infection by upregulating several antiviral interferon-stimulated genes. Infection of these organoids with a neuropathogenic Enterovirus-D68 strain, demonstrated the ability of this virus to impede immune activation by blocking interferon responses. Together, our data highlight immune gene signatures present in different types of neural stem cells and differential viral capacity to block neural-specific immune induction.

immunology↗

bioRxiv2024

Human erythroid progenitors express antigen presentation machinery

Early-life immune exposures can profoundly impact lifelong health. However, functional mechanisms underlying fetal immune development remain incomplete. Erythrocytes are not typically considered active immune mediators, primarily because erythroid precursors discard their organelles as they mature, thus losing the ability to alter gene expression in response to stimuli. Erythroid progenitors and precursors circulate in human fetuses and neonates. Although there is limited evidence that erythroid precursors are immunomodulatory, our understanding of the underlying mechanisms remains inadequate. To define the immunobiological role of fetal and perinatal erythroid progenitors and precursors, we analyzed single cell RNA-sequencing data and found that transcriptomics support erythroid progenitors as putative immune mediators. Unexpectedly, we discovered that human erythroid progenitors constitutively express Major Histocompatibility Complex (MHC) class II antigen processing and presentation machinery, which are hallmarks of specialized antigen presenting immune cells. Furthermore, we demonstrate that erythroid progenitors internalize and cleave foreign proteins into peptide antigens. Unlike conventional antigen presenting cells, erythroid progenitors express atypical costimulatory molecules and immunoregulatory cytokines that direct the development of regulatory T cells, which are critical for establishing maternal-fetal tolerance. Expression of MHC II in definitive erythroid progenitors begins during the second trimester, coinciding with the appearance of mature T cells in the fetus, and is absent in primitive progenitors. Lastly, we demonstrate physical and molecular interaction potential of erythroid progenitors and T cells in the fetal liver. Our findings shed light on a unique orchestrator of fetal immunity and provide insight into the mechanisms by which erythroid cells contribute to host defense.

immunology↗

bioRxiv2024

Neuronal interactions in forebrain organoids lead to protective antiviral responses

Neurotropic viruses are the most common cause of infectious encephalitis and largely target neurons for infection. Our understanding of intrinsic neuronal innate immune response capacity to mediate protective antiviral responses remains incomplete. Here, we evaluated the role of intercellular crosstalk in mediating intrinsic neuronal immunity and its contribution to limiting viral infection. We found that in the absence of viral antagonism, neurons transcriptionally induce robust interferon signaling and can effectively signal to neighboring uninfected bystander neurons. Yet, in two-dimensional cultures, this dynamic response did not restrict viral spread. Interestingly, this differed in the context of viral infection in three-dimensional forebrain organoids with complex neuronal interactions, where we observed protective capacity. We show antiviral crosstalk between infected neurons and bystander neural progenitors is mediated by type I interferon signaling. Using spatial transcriptomics, we then uncover distinct regions of bystander progenitor interactions that reveal critical underpinnings of protective antiviral responses, including expression of distinct antiviral genes. These findings underscore the importance of intercellular communication in protective antiviral immunity in the brain and implicate key contributions to protective antiviral signaling.

immunology↗

bioRxiv2024

Type I interferon alters invasive extravillous trophoblast function.

Inappropriate type I interferon (IFN) signaling during embryo implantation and placentation is linked to poor pregnancy outcomes. Here, we evaluated the consequence of elevated type I IFN exposure on implantation using a biomimetic model of human implantation in an organ-on-a-chip device. We found that type I IFN reduced extravillous trophoblast (EVT) invasion capacity. Analyzing single-cell transcriptomes, we uncovered that IFN truncated endovascular EVT emergence in the implantation-on-a-chip device by stunting EVT epithelial-to-mesenchymal transition. Disruptions to the epithelial-to-mesenchymal transition is associated with the pathogenesis of preeclampsia, a life-threatening hypertensive disorder of pregnancy. Strikingly, unwarranted IFN stimulation induced genes associated with increased preeclampsia risk and a preeclamptic gene-like signature in EVTs. These dysregulated EVT phenotypes ultimately reduced EVT-mediated endothelial cell vascular remodeling in the implantation-on-a-chip device. Overall, our work indicates IFN signaling can alter EVT epithelial-to-mesenchymal transition progression which results in diminished EVT-mediated spiral artery remodeling and a preeclampsia gene signature upon sustained stimulation. Our work implicates unwarranted type I IFN as a maternal disturbance that can result in abnormal EVT function that could trigger preeclampsia.

immunology↗

bioRxiv2022

An alpaca-derived nanobody neutralizes the SARS-CoV-2 omicron variant

The SARS-CoV2 Omicron variant sub-lineages spread rapidly through the world, mostly due to their immune-evasive properties. This has put a significant part of the population at risk for severe disease and underscores the need for anti-SARS-CoV-2 agents that are effective against emergent strains in vulnerable patients. Camelid nanobodies are attractive therapeutic candidates due to their high stability, ease of large-scale production and potential for delivery via inhalation. Here, we characterize the RBD-specific nanobody W25, which we previously isolated from an alpaca, and show superior neutralization activity towards Omicron lineage BA.1 in comparison to all other SARS-CoV2 variants. Structure analysis of W25 in complex with the SARS-CoV2 spike surface glycoprotein shows that W25 engages an RBD epitope not covered by any of the antibodies previously approved for emergency use. Furthermore, we show that W25 also binds the spike protein from the emerging, more infectious Omicron BA.2 lineage with picomolar affinity. In vivo evaluation of W25 prophylactic and therapeutic treatments across multiple SARS-CoV-2 variant infection models, together with W25 biodistribution analysis in mice, demonstrates favorable pre-clinical properties. Together, these data endorse prioritization of W25 for further clinical development.

microbiology↗

bioRxiv2022

Human red blood cells express the RNA sensor TLR7 and bind viral RNA

Red blood cells (RBCs) express the nucleic acid-sensing toll-like receptor 9 (TLR9) and bind CpG-containing DNA. However, whether human RBCs express other nucleic acid-sensing TLRs and bind RNA is unknown. Here we show that human RBCs express the RNA sensor, TLR7. TLR7 is present on the red cell membrane and associates with the RBC membrane protein Band 3. RBCs bind synthetic single-stranded RNA and RNA from pathogenic single-stranded RNA viruses. RNA acquisition by RBCs is attenuated by recombinant TLR7 and inhibitory oligonucleotides. Thus, RBCs may represent a previously unrecognized reservoir for RNA, although how RNA-binding by RBCs modulates the immune response has yet to be elucidated. These findings add to the growing list of non-gas exchanging RBC immune functions. SignificanceRed blood cells interact with pathogens, cytokines, and CpG-containing DNA; however, their immune functions remain largely unexplored. Here, we report that RBCs can bind synthetic or viral RNA and express TLR7. TLR7 interacts with the RBC membrane protein Band 3 and this interaction is increased during acute infection with SARS-CoV-2. Our study suggests that RBCs may have immune functions mediated by viral RNA, and RNA-carrying RBCs can potentially be a reservoir for RNA-based diagnostics.

immunology↗