Biology subjects

Schroeder, T.

Publications and source records attributed to Schroeder, T..

At least 19 recordsLinked to original sources

bioRxiv2026

Spatial Transcriptomics Reveals Compartment-Specific Immune Activation Signatures in Ileal and Lymph Node Tissue in Treated HIV Infection

People with HIV (PWH) on long-term antiretroviral therapy (ART) continue to experience elevated rates of morbidities and mortality driven by persistent immune activation despite viral suppression. Known contributors include low-level HIV provirus activity, microbial translocation in part from epithelial barrier dysfunction, microbiome dysfunction, and co-infections. However, how these interact and where they predominate across tissue compartments remains incompletely defined. Here, we applied spatial transcriptomics to characterize compartment-specific transcriptional programs in ileum (epithelium, Peyer's patches, lamina propria) and inguinal lymph nodes (B Cell follicles and T cell zone) from ten PWH on long-term ART, stratified by CD4/CD8 ratio into low-ratio and high-ratio groups, with low-ratio as a proxy for immune activation and increased risk for non-AIDS related serious event. Comparison of global expression found significant differences between groups in four of five compartments. Differential expression analysis identified 483 differentially expressed genes across four of five compartments, with the greatest burden in the T-cell zone and none in the lamina propria. Gene set enrichment analysis identified 116 enriched pathways predominantly in the low-ratio group, spanning immune activation, infection-associated, and metabolic programs, with Peyer's patches showing the broadest transcriptional divergence of any compartment. Cross-compartment signals included higher expression of ORMDL3 and ARL17B in the low-ratio group implicating mitochondrial stress and inflammasome activation, lower expression of CCL3L3 and FCMR in the low-ratio group suggesting impaired immune execution, and divergent ribosomal protein programs between B-cell follicles and the T-cell zone. Cell deconvolution identified compartment-specific differences in estimated immune cell proportions, and T-cell zone gene expression showed significant associations with HIV reservoir measures and plasma markers of microbial translocation and immune activation. Together these findings support spatially heterogeneous immune activation as a feature of persistent immune dysregulation in treated HIV infection and provide compartment-resolved, hypothesis-generating evidence for the tissue-specific mechanisms driving inflammation in this population.

bioinformatics↗

bioRxiv2026

Plasma metabolomics reveals lipid-predominant metabolic disruptions in virologically suppressed people with HIV

People with HIV (PWH) on antiretroviral therapy (ART) experience excess morbidity and mortality from comorbidities including cardiovascular and metabolic disease, yet the biological mechanisms underlying these outcomes in virally suppressed PWH (VS-PWH) remain incompletely understood. We applied high-dimensional targeted plasma metabolomics to quantify 254 small molecules and 750 lipids across 49 classes in viremic PWH (Vi-PWH), VS-PWH, and people without HIV (PWoH), analyzed alongside multiple T cell metrics and plasma cytokine concentrations. Globally, the plasma metabolome of VS-PWH was indistinguishable from PWoH, while Vi-PWH exhibited substantial metabolic disruption characterized by depletion of phosphatidylcholines, sphingomyelins, and hexosylceramides alongside triglyceride accumulation, dysregulation of the tryptophan-kynurenine and arginine-citrulline axes, and elevations in diacetylated polyamines and N4-acetylcytidine. Ordinal trend analysis identified subtle but consistent residual alterations in VS-PWH, particularly within phosphatidylcholine and sphingomyelin classes, that correlated with elevated TNF and reduced CD4+ T cell counts and CD4/CD8 ratio. Together, these findings indicate that residual TNF-associated inflammation and incomplete T cell recovery continue to shape the plasma metabolome in treated HIV, identifying candidate biomarkers for further mechanistic and clinical investigation.

microbiology↗

bioRxiv2026

Midbody inheritance predicts re-entry into quiescence, but not lineage potential, in mouse hematopoietic stem cells

Hematopoietic stem cells (HSCs) give rise to all blood cell lineages and possess long-term self-renewal potential. HSCs undergo symmetric division for their expansion and asymmetric division to generate one HSCs and one progenitor cells which contribute to production of mature blood cells. The midbody is a structure which is formed in the center of the intercellular bridge during cytokinesis. However, the midbody is either asymmetrically inherited by one daughter cell or symmetrically released after cell division, whether these distinct patterns of midbody inheritance influence HSC fate remain poorly understood. In this study, we designed a fusion protein hmKO2 and MgcRacGAP which is a component of midbody. We then traced the midbody inheritance during cell division and the future cell fates of HSC daughters after division by time-lapse imaging. As a result, we found that the midbody release correlated with the delay of the time to the next division but not to the lineage potential of HSCs, indicating the possibility that midbody remnant plays some roles in cell cycle progression. HighlightHematopoietic stem cells exhibit a low frequency of midbody inheritance. Midbody inheritance does not affect the lineage potential of daughter cells. Midbody loss is associated with delayed entry into the next cell cycle.

cell biology↗

bioRxiv2026

Resolving Sub-Microsecond Conformational Dynamics of Vertical Nucleic Acids on Graphene

The function of nucleic acids is governed not only by their structure but also by their dynamics. At the molecular scale, transitions between functional structural states are superimposed on rapid thermal fluctuations, resulting in an intricate interplay that is challenging to resolve experimentally, particularly at the single-molecule level. Here, we introduce a novel approach for unraveling sub-microsecond dynamics in oligonucleotides, enabling direct observation of fluctuations in single DNA molecules. By immobilizing nucleic acids vertically on graphene and exploiting distance-dependent graphene energy transfer of fluorescent molecules attached to the DNA, we relate fluctuations in fluorescence intensity to biomolecular dynamics. We show that ionic strength modulates the fluctuations and that structural defects in DNA, such as nucleotide gaps or mismatches, alter the measured dynamics. The experimental findings are complemented by atomistic molecular dynamics simulations and kinetic Monte Carlo simulations, establishing a direct link between theoretical predictions of structure and dynamics and experimentally accessible fluctuation timescales. Overall, our findings advance the understanding of how thermal fluctuations affect oligonucleotides and are modulated by both external and internal stimuli.

biophysics↗

bioRxiv2026

BaSiCPy: Scalable and Robust Shading Correction for Optical Microscopy Images

Quantitative fluorescence microscopy is frequently confounded by spatially varying illumination and temporal intensity drift. Although BaSiC is a widely adopted retrospective correction method, it can fail when foreground content is strongly correlated across images--a common regime in time-lapse, tiled and volumetric acquisitions--and its application often requires manual parameter tuning that limits reproducibility and scalability. We introduce BaSiCPy, a foreground-aware implementation of BaSiC that improves illumination profile estimation under correlated foreground structures, provides automatic hyperparameter selection and accelerates large-scale processing through GPU support. BaSiCPy is distributed as an open-source Python package with graphical and programmatic interfaces, facilitating integration into contemporary bioimage analysis workflows.

bioengineering↗

bioRxiv2026

Multi-omics links microbial dysbiosis, systemic inflammation and metabolomic disruptions to SNAE risk in treated HIV

Serious non-AIDS events (SNAEs), including non-AIDS malignancies, cardiovascular disease, and hepatic complications, remain major causes of mortality in treated HIV infection. These outcomes are driven by persistent immune activation, systemic inflammation, and metabolic dysfunction despite effective viral suppression with antiretroviral therapy (ART). To investigate mechanisms underlying SNAE pathogenesis, we performed a cross-site multi-omic analysis integrating plasma proteins, plasma metabolites, and mucosal microbiomes (ileum and rectum) in 82 ART-treated people with HIV (PWH) and 10 people without HIV (PWoH) from the United States and Mexico. Geography was the dominant source of variation, particularly across lipid classes. However, individuals at high risk for SNAEs, defined by low CD4 T cell counts and low CD4/CD8 ratios, shared a consistent signature of systemic inflammation, mitochondrial dysfunction, and microbial dysbiosis including elevated plasma IL-6, {omega}-oxidation products (adipic and suberic acids), and depletion of short-chain fatty acid-producing commensals in the gut mucosa, including Akkermansia muciniphila, Bacteroides uniformis, and Ruminococcus. Notably, A. muciniphila abundance correlated with lower IL-6 levels, fewer HIV RNA-producing cells in lymph nodes, and higher CD4/CD8 ratios. Together, these findings identify a shared inflammatory and metabolic phenotype in PWH and implicate A. muciniphila as a potential microbiome-based target to mitigate immune activation and SNAE risk in treated HIV.

immunology↗

bioRxiv2025

Cell-stereotyped DNA repair outcomes are widespread during genome editing

Genome editing outcomes are governed by DNA repair pathways that vary with cell type and state. We developed scOUT-seq (single-cell Outcomes Using Transcript sequencing), a scalable approach that jointly profiles transcriptomes and matched multi-allelic editing outcomes ranging from homology directed repair (HDR) to inter-chromosomal translocations. We mapped editing outcomes in human CD34 hematopoietic stem and progenitor cells (HSPCs), mouse LSK HSPC equivalents, human upper airway organoids, and mouse multi-organ in vivo editing. Profiling 500,000 alleles across 74 cell types, scOUT-seq revealed that outcomes in most cell subtypes differ markedly from the bulk average. Various cell types shifted major repair classes, preferred different molecular sequences, and even enriched large structural variants, with distinctive patterns of allelic co-occurrence. Surprisingly, rare stem subtypes diverged from prevalent progenitors, and inhibitory neuron subtypes efficiently incorporated HDR alleles. These data suggest the potential for tailored therapeutic editing that may have been missed by bulk measurements.

genomics↗

bioRxiv2025

Pre-treatment Microbiome Diversity and Function is associated with Expansion of Cytotoxic and Regulatory Immune Populations after N-803 treatment in People with HIV

BackgroundN-803, an IL-15 superagonist, is currently being studied in clinical trials as a treatment to reverse HIV latency. However, its effects on the gut microbiome are not well understood. MethodsIn this longitudinal metagenomic study, we analyzed fecal microbiomes from ART-suppressed people with HIV at four different timepoints before, during, and after N-803 treatment. ResultsOverall taxonomic and functional diversity did not change significantly, yet beneficial microbial taxa and pathways were enriched after N-803. Specifically, the relative abundance of Faecalibacterium prausnitzii increased significantly after N-803, whereas histidine degradation pathways, often associated with pro-inflammatory mucosal state, decreased. A higher baseline microbial diversity correlated with stronger CD8+ and natural killer (NK) cells activation and reduced frequency of rectal HIV RNA+ cells. MaAsLin2 analyses further associated short-chain fatty acid (SCFA)-producing taxa and pathways with increased immune activation markers. ConclusionsThese results indicate that gut microbiome diversity prior to immunotherapy influences host response and suggest that microbiome-based strategies could improve efforts to cure HIV.

microbiology↗

bioRxiv2025

Gut barrier integrity biomarkers are associated with increased inflammation and predict disease status in hospitalized COVID-19 patients

The COVID-19 global pandemic persists as an endemic disease with frequent case spikes and a significant continued burden on public health. Although most COVID-19 cases are asymptomatic or mild, severe infections requiring hospitalization have resulted in likely more than 14 million cumulative deaths to date. One hallmark of severe COVID-19 is a dysregulated immune response that leads to systemic inflammation and contributes to disease severity and mortality but is not explained by viral replication alone. Severe COVID-19 has been shown to disrupt the gut microbiome and increase intestinal permeability which may contribute to immune dysregulation and systemic inflammation. In this study, we investigated the differences in plasma biomarkers for microbial translocation and gut barrier damage as well as circulating cytokines between healthy volunteers and patients hospitalized with COVID-19. We then performed a correlation analysis to understand how the relationships between these plasma biomarkers differed and used a random forest model to assess their accuracy in distinguishing between these two groups. Our results demonstrated that hospitalized COVID-19 patients have elevated concentrations of pro-inflammatory cytokines and markers of microbial translocation, and that the relationships between these biomarkers were significantly altered compared to healthy volunteers, especially those related to the mucosal associated homeostatic cytokines IL-17A and IL-23. Furthermore, IL-6 and LBP were the top biomarkers for prediction accuracy in our random forest model, highlighting the importance of managing microbial translocation in COVID-19 and its potential utility as a biomarker for disease severity. IMPORTANCECOVID-19 continues to be a burden on public health. Understanding how plasma biomarkers differ between healthy and acutely infected individuals can help in understanding pathogenesis and predict disease severity. It has been demonstrated that COVID-19 disrupts the gut microbiome and intestinal permeability, which contributes to systemic inflammation. Our study highlights the link between gut barrier integrity and inflammation in hospitalized SARS-CoV-2 cases, demonstrating the usefulness of gut barrier integrity biomarkers in predicting disease severity, and offers insights for therapeutic interventions in acute COVID-19 infection.

immunology↗

bioRxiv2024

Monitoring the Coating of Single DNA Origami Nanostructures with a Molecular Fluorescence Lifetime Sensor

The high functionality of DNA nanostructures makes them a promising tool for biomedical applications, their intrinsic instability under application-relevant conditions, still remains challenging. Protective coating of DNA nanostructures with materials like silica or cationic polymers has evolved as a simple, yet powerful strategy to improve their stability even under extreme conditions. While over time, various materials and protocols have been developed, the characterization and quality assessment of the coating is either time consuming, highly invasive or lacks detailed insights on single nanostructures. Here, we introduce a cyanine dye based molecular sensor designed to non-invasively probe the coating of DNA origami by either a cationic polymer or by silica, in real-time and on a single nanostructure level. The cyanine dye reports changes in its local environment upon coating via increased fluorescence lifetime induced by steric restriction and water exclusion. Exploiting the addressability of DNA origami, the molecular sensor can be placed at selected positions to probe the coating layer with nanometer precision. We demonstrate the reversibility of the sensor and use it to study the stability of the different coatings in degrading conditions. To showcase the potential for correlative studies, we combine the molecular fluorescence lifetime sensor with DNA PAINT super-resolution imaging to investigate coating and structural integrity as well as preserved addressability of DNA nanostructures. The reported sensor presents a valuable tool to probe the coating of DNA nanodevices in complex biochemical environments in real-time and at the single nanosensor level and aids the development of novel stabilization strategies.

biophysics↗

bioRxiv2024

The TD drive - A parametric, open-source implant for multi-area electrophysiological recordings in behaving and sleeping rats

Intricate interactions between multiple brain areas underlie most functions attributed to the brain. The process of learning, as well as formation and consolidation of memories are two examples that rely heavily on functional connectivity across the brain. In addition, investigating hemispheric similarities and/or differences goes hand in hand with these multi-area interactions. Electrophysiological studies trying to further elucidate these complex processes thus depend on recording brain activity at multiple locations simultaneously and often in a bilateral fashion. Presented here is a 3D-printable implant for rats, named TD drive, capable of symmetric, bilateral wire electrode recordings, currently in up to ten distributed brain areas simultaneously. The open-source design was created employing parametric design principles, allowing prospective users to easily adapt the drive design to their needs by simply adjusting high-level parameters, such as anterior-posterior and medio-lateral coordinates of the recording electrode locations. The implant design was validated in n = 20 Lister Hooded rats that performed different tasks. The implant was compatible with tethered sleep recordings and open field recordings (Object Exploration) as well as wireless recording in a large maze (HexMaze 9x5 m) using two different commercial recording systems and headstages. In sum, presented here is the adaptable design and assembly of a new electrophysiological implant facilitating fast preparation and implantation.

neuroscience↗

bioRxiv2024

The DREAM implant: A Lightweight, Modular and Cost-Effective Implant System for Chronic Electrophysiology in Head-fixed and Freely Behaving Mice

Chronic electrophysiological recordings in rodents have significantly improved our understanding of neuronal dynamics and their behavioral relevance. However, current methods for chronically implanting probes present steep trade-offs between cost, ease of use, size, adaptability and long-term stability. SUMMARYIntroducing a lightweight, cost-effective probe implant system for chronic electrophysiology in rodents, optimized for ease of use, probe recovery, experimental versatility and compatibility with behavior. This protocol introduces a novel chronic probe implant system for mice called the DREAM (Dynamic, Recoverable, Economical, Adaptable and Modular), designed to overcome the trade-offs associated with currently available options. The system provides a lightweight, modular and cost-effective solution with standardized hardware elements that can be combined and implanted in straightforward steps and explanted safely for recovery and multiple re-use of probes, significantly reducing experimental costs. The DREAM implant system integrates three hardware modules: (1) a microdrive that can carry all standard silicon probes, allowing experimenters to adjust recording depth across a travel distance of up to 7mm; (2) a 3D-printable, open-source design for a wearable Faraday cage covered in copper mesh for electrical shielding, impact protection and connector placement, and (3) a miniaturized head-fixation system for improved animal welfare and ease of use. The corresponding surgery protocol was optimized for speed (total duration: 2 hours), probe safety and animal welfare. The resulting implants had minimal impact on animals behavioral repertoire, were easily applicable in freely moving and head-fixed contexts and delivered clearly identifiable spike waveforms and healthy neuronal responses for weeks of data collection post-implant. Infections and other surgery complications were extremely rare. As such, the DREAM implant system is a versatile, cost-effective solution for chronic electrophysiology in mice, enhancing animal well-being, and enabling more ethologically sound experiments. Its design simplifies experimental procedures across various research needs, increasing accessibility of chronic electrophysiology in rodents to a wide range of research labs.

neuroscience↗

bioRxiv2023

Self-renewing Sox9+ osteochondral stem cells in the postnatal skeleton

Postnatal skeletal growth, homeostatic maintenance, and regeneration is driven by skeletal stem cells. In addition, it is well established that skeletal tissues lose their regenerative potential with age, comorbidities, and repeated trauma, possibly through stem cell exhaustion or loss of function. However, it is largely unknown where these cells reside in skeletal tissues, what molecular mechanisms regulate their self-renewal and fate decisions, and how to isolate, purify, and expand them ex vivo. Therefore, there is an urgent need for a deeper understanding of postnatal skeletal stem cells. Here, we used genetic lineage tracing, thymidine analogues retention, whole bone microscopy, imaging cytometry, in vitro assays, and single cell transcriptomics and provide the first experimental evidence for the existence of self-renewing osteochondral stem cells in the postnatal skeleton in both males and females. We also show direct comparisons between adult, fetal, mouse, and human skeletal stem cells at the transcriptome level.

developmental biology↗

bioRxiv2023

SARS-CoV-2 infection is associated with intestinal permeability, systemic inflammation, and microbial dysbiosis in hospitalized COVID-19 patients

Coronavirus disease 2019 (COVID-19) and associated severity has been linked to uncontrolled inflammation and may be associated with changes in the microbiome of mucosal sites including the gastrointestinal tract and oral cavity. These sites play an important role in host-microbe homeostasis and disruption of epithelial barrier integrity during COVID-19 may potentially lead to exacerbated inflammation and immune dysfunction. Outcomes in COVID-19 are highly disparate, ranging from asymptomatic to fatal, and the impact of microbial dysbiosis on disease severity is unclear. Here, we obtained plasma, rectal swabs, oropharyngeal swabs, and nasal swabs from 86 patients hospitalized with COVID-19 and 12 healthy volunteers. We performed 16S rRNA sequencing to characterize the microbial communities in the mucosal swabs and measured circulating cytokines, markers of gut barrier integrity, and fatty acids in the plasma samples. We compared these plasma concentrations and microbiomes between healthy volunteers and the COVID-19 patients who had survived or unfortunately died by the end of study enrollment, and between severe disease and healthy controls, as well as performed a correlation analysis between plasma variables and bacterial abundances. The rectal swabs of COVID-19 patients had reduced abundances of several commensal bacteria including Faecalibacterium prausnitsii, and an increased abundance of the opportunistic pathogens Eggerthella lenta and Hungatella hathewayi. Furthermore, the oral pathogen Scardovia wiggsiae was more abundant in the oropharyngeal swabs of COVID-19 patients who died. The abundance of both H. hathewayi and S. wiggsiae correlated with circulating inflammatory markers including IL-6, highlighting the possible role of the microbiome in COVID-19 severity, and providing potential therapeutic targets for managing COVID-19.

microbiology↗

bioRxiv2023

DNA Origami Vesicle Sensors with Triggered Cargo Transfer

Interacting with living systems typically involves the ability to address lipid membranes of cellular systems. The first step of interaction of a nanorobot with a cell will thus be the detection of binding to a lipid membrane. Leveraging the programmable nature of DNA origami, we engineered a biosensor harnessing single-molecule Fluorescence Resonance Energy Transfer (smFRET) as transduction mechanism for precise lipid vesicle detection. The system hinges on a hydrophobic ATTO647N modified single-stranded DNA (ssDNA) leash, protruding from a rectangular DNA origami. In a vesicle-free environment, the ssDNA adopts a coiled stance, ensuring high FRET efficiency. However, upon lipid vesicle binding to cholesterol anchors on the DNA origami, the hydrophobic ATTO647N induces the ssDNA to stretch towards the lipid bilayer, leading to reduced FRET efficiency. The strategic placement of cholesterol anchors further modulates this interaction, affecting the observed FRET populations. Beyond its role as a vesicle sensor, we show targeted cargo transport of the acceptor dye unit to the vesicle. The cargo transport is initiated by vesicle bound DNA and a strand displacement reaction. Our interaction platform opens pathways for innovative interaction such as biosensing and molecular transport with complex biosystems.

bioengineering↗

bioRxiv2023

Determinants of DDX3X sensitivity uncovered using a helicase activity in translation reporter

DDX3X regulates the translation of a subset of human transcripts containing complex 5' untranslated regions (5' UTRs). In this study we developed the helicase activity reporter for translation (HART) which uses DDX3X-sensitive 5' UTRs to measure DDX3X mediated translational activity in cells. To dissect the structural underpinnings of DDX3X dependent translation, we first used SHAPE-MaP to determine the secondary structures present in DDX3X-sensitive 5' UTRs and then employed HART to investigate how their perturbation impacts DDX3X-sensitivity. Additionally, we identified residues 38-44 as potential mediators of DDX3Xs interaction with the translational machinery. HART revealed that both DDX3Xs association with the ribosome complex as well as its helicase activity are required for its function in promoting the translation of DDX3X-sensitive 5' UTRs. These findings suggest DDX3X plays a crucial role regulating translation through its interaction with the translational machinery during ribosome scanning, and establish the HART reporter as a robust, lentivirally encoded measurement of DDX3X-dependent translation in cells.

molecular biology↗

bioRxiv2023

Elevated peripheral and nervous system inflammation is associated with decreased short-chain fatty acid levels in Zika-virus infected macaques

Zika virus (ZIKV) infection of central nervous system (CNS) tissue is associated with CNS inflammation, which contributes to ZIKV pathology. Similarly, ZIKV infection has been associated with increased vaginal and rectal mucosal inflammation. As mucosal dysfunction may contribute to elevated systemic inflammation, ZIKV-induced mucosal alterations could potentiate CNS disruptions, leading to ZIKV pathogenesis. However, the potential link between mucosal dysfunction, CNS inflammation and the underlying mechanisms causing these disruptions in ZIKV infection has not been well described. Here, we assessed plasma and CSF indicators of inflammation, including neopterin, tryptophan, kynurenine and serotonin by liquid chromatography tandem mass spectrometry. We observed significant increases in neopterin formation, tryptophan catabolism and serotonin levels in the plasma and CSF of ZIKV-infected pigtail macaques (PTM), rhesus macaques (RM) and in the plasma of ZIKV-infected humans. We next examined whether ZIKV infection resulted in microbial translocation across mucosal surfaces by evaluating plasma and cerebrospinal fluid (CSF) levels of soluble CD14 (sCD14) and lipopolysaccharide-binding protein (LBP) by enzyme-linked immunosorbent assay (ELISA). Increased sCD14 was observed in the CSF of PTM and rhesus macaque (RM), while increased LBP was observed in pigtail macaque (PTM) plasma. Finally, to examine whether ZIKV-induced microbial dysbiosis could underlie increased microbial translocation and inflammation, we characterized intestinal microbial communities by 16s rRNA gene sequencing and microbial functional changes by quantifying short-chain fatty acid (SCFA) concentrations by gas chromatography mass spectrometry. We observed that although ZIKV infection of PTM did not result in significant taxonomic shifts in microbial communities, there were significant reductions in SCFA levels. Loss of microbial function in ZIKV infection could cause decreased intestinal integrity, thereby contributing to elevated microbial translocation and systemic and CNS inflammation, providing a possible mechanism underlying ZIKV pathogenesis. Further, this may represent a mechanism underlying inflammation and pathogenesis in other diseases. Author SummaryZika virus (ZIKV) can be transmitted to humans via the bite of an infected mosquito or between humans during sexual intercourse, typically resulting in mild symptoms, which has been linked to elevated inflammation in the CNS and the development of more serious conditions, including severe neurological syndromes. Previous studies have observed that ZIKV infection is associated with increased mucosal dysfunction, including elevated inflammation in rectal and vaginal mucosal tissue. However, the mechanism of ZIKV-induced mucosal dysfunction may contribute to systemic and CNS inflammation has not been previously investigated. Here, we used the non-human primate (NHP) model and clinical specimens from ZIKV-infected humans to examine markers of systemic and CNS inflammation and microbial translocation. We observed elevated markers indicative of microbial translocation and inflammation in the CNS of ZIKV-infected macaques and humans. A potential association with mucosal dysfunction in ZIKV infection is shifts in microbial dysbiosis. We also observed that there were no significant overall taxonomic shifts in microbial communities, but a reduction of bacterial-derived short-chain fatty acid (SCFA) levels. Finally, we observed that the decrease in SCFA levels significantly negatively correlated with the elevated peripheral and CNS inflammatory markers, suggesting a link between ZIKV-driven disease pathology and microbial function. Taken together, our study provides new insight into a previously unconsidered mechanism underlying ZIKV pathogenesis.

microbiology↗

bioRxiv2023

IL-1β promotes MPN disease initiation by favoring early clonal expansion of JAK2-mutant hematopoietic stem cells

JAK2-V617F is the most frequent somatic mutation causing myeloproliferative neoplasm (MPN). However, JAK2-V617F can also be found in healthy individuals with clonal hematopoiesis of indeterminate potential (CHIP) with a frequency much higher than the prevalence of MPN. The factors controlling the conversion of JAK2-V617F CHIP to MPN are largely unknown. We hypothesized that IL-1{beta} mediated inflammation is one of the factors that favors this progression. We examined mono- or oligoclonal evolution of MPN by performing bone marrow transplantations at limiting dilutions with only 1-3 JAK2-mutant HSCs per recipient. Genetic loss of IL-1{beta} in JAK2-mutant hematopoietic cells or inhibition by a neutralizing anti-IL-1{beta} antibody restricted the early clonal expansion of these JAK2-mutant HSCs resulting in a reduced frequency of a CHIP-like state and a lower rate of conversion to MPN. The MPN disease-promoting effects of IL-1{beta} were associated with damage to sympathetic innervation leading to loss of nestin-positive mesenchymal stromal cells and required the presence of IL-1R1 on bone marrow stromal cells. The anti-IL-1{beta} antibody protected these mesenchymal stromal cells from IL-1{beta} mediated damage and limited the expansion of the JAK2-mutant clone. Our results identify IL-1{beta} as a potential therapeutic target for preventing the transition from JAK2-V617F CHIP to MPN. Brief summaryIn a mouse model of oligo-clonal myeloproliferative neoplasm (MPN), IL-1{beta} produced by JAK2-mutant cells favored expansion of sub-clinical JAK2-V617F clones and initiation of MPN disease.

cancer biology↗