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bioRxiv2024

Dynamic Control of Argonautes by a Rapidly Evolving Immunological Switch

Small RNAs, coupled with Argonuate proteins (AGOs), regulate diverse biological processes, including immunity against nucleic acid parasites. C. elegans possesses an expanded repertoire of at least 19 AGOs functioning in an intricate gene regulatory network. Despite their crucial roles, little is known about the regulation of AGOs, and whether their expression levels, tissue specificity, and functions change in response to genetic perturbations or environmental triggers. Here, we report that PALS-22, a member of an unusually expanded protein family in C. elegans, acts as a negative regulator of antiviral RNAi involving the RIG-I homolog. The loss of pals-22 leads to enhanced silencing of transgenes and endogenous dsRNAs. We found that PALS-22 normally suppresses the expression of two AGOs, VSRA-1 and SAGO-2, which are activated by bZIP transcription factor ZIP-1. When pals-22 is eliminated, vsra-1 and sago-2 are upregulated. These AGOs in turn play key roles in defense against foreign genetic elements and intracellular pathogens, respectively. Surprisingly, while in pals-22 mutants immune genes functioning in the intracellular pathogen response (IPR) are upregulated, removing SAGO-2 or the RNA-dependent RNA polymerase RRF-3 in these mutants leads to the downregulation of these genes. This observation contrasts with the typical gene-silencing role of siRNAs. Finally, by analyzing C. elegans wild isolates and lab reference strains, we demonstrate that PALS-22 regulates the expression of several germline AGOs, affecting germline mortality and transgenerational epigenetic inheritance. In summary, PALS-22 is a key genetic node that balances the trade-off between immunity and germline health by modulating the functions of different AGOs, thereby shaping the outputs of the RNAi machinery and the dynamics of epigenetic inheritance.

genetics↗

bioRxiv2024

Vaccines for immunological defense against traumatic brain injury

Traumatic brain injury (TBI) and subsequent neurodegeneration is partially driven by chronic inflammation both locally and systemically. Yet, current clinical intervention strategies do not mitigate inflammation sequalae necessitating the development of innovative approaches to reduce inflammation and minimize deleterious effects of TBI. Herein, a subcutaneous formulation based on polymer of alpha-ketoglutarate (paKG) delivering glycolytic inhibitor PFK15 (PFKFB3 inhibitor, a rate limiting step in glycolysis), alpha-ketoglutarate (to fuel Krebs cycle) and peptide antigen from myelin proteolipid protein (PLP139-151) was utilized as the prophylactic immunosuppressive formulation in a mouse model of TBI. In vitro, the paKG(PFK15+PLP) vaccine formulation stimulated proliferation of immunosuppressive regulatory T cells and induced generation of T helper-2 cells. When given subcutaneously in the periphery to two weeks prior to mice sustaining a TBI, the active vaccine formulation increased frequency of immunosuppressive macrophages and dendritic cells in the periphery and the brain at day 7 post- TBI and by 28 days post-TBI enhanced PLP-specific immunosuppressive cells infiltrated the brain. While immunohistology measurements of neuroinflammation were not altered 28 days post-TBI, the vaccine formulation improved motor function and enhanced autophagy mediated genes in a spatial manner in the brain. Overall, these data suggest that the TBI vaccine formulation successfully induced an anti-inflammatory profile and decreased TBI-associated inflammation. TeaserIn this study, a vaccine formulation was generated to develop central nervous specific immunosuppressive responses for TBI.

bioengineering↗

bioRxiv2025

Spatially-divergent metabolic impact of experimental toxoplasmosis: immunological and microbial correlates

Maladaptive host metabolic responses to infection are emerging as major determinants of infectious disease pathogenesis. However, the factors regulating these metabolic changes within tissues remain poorly understood. In this study, we used toxoplasmosis, as a prototypical example of a disease regulated by strong type I immune responses, to assess the relative roles of local parasite burden, local tissue inflammation and the microbiome in shaping local tissue metabolism during acute and chronic infection. Toxoplasmosis is a zoonotic disease caused by the parasite Toxoplasma gondii. This protozoan infects the small intestine and then disseminates to nearly every organ in the acute stage of infection, before establishing chronic infection in the skeletal muscle, cardiac muscle and brain. We compared metabolism in eleven sampling sites in C57BL/6 mice during the acute and chronic stage of T. gondii infection. Strikingly, significant metabolic changes were observed in the large intestine and colon during chronic infection, organs not associated with T. gondii persistence. Overall, major spatial mismatches were observed between metabolic perturbation and local parasite burden for both disease stages. In contrast, a stronger association with indicators of type I immune responses was observed, indicating a tighter relationship between metabolic perturbation and local immunity, than with local parasite burden. In addition, we observed significant changes in microbiota composition with infection, and candidate microbial origins for multiple metabolites impacted by infection. These findings highlight the metabolic consequences of toxoplasmosis across different organs, and their regulators. ImportanceInflammation is a major driver of tissue perturbation. However, the signals driving these changes on a tissue-intrinsic and molecular level are poorly understood. This study evaluated tissue-specific metabolic perturbations across eleven sampling sites following systemic murine infection with the parasite Toxoplasma gondii. Results revealed relationships between differential metabolite enrichment and variables including inflammatory signals, pathogen burden and commensal microbial communities. These data will inform hypotheses about the signals driving specific metabolic adaptation in acute and chronic protozoan infection, with broader implications for infection and inflammation in general.

microbiology↗

bioRxiv2025

Immunologic insights into the critical epitopes of HIV-1 and structure-based characterization of cross-reactive antibodies

HIV-1 escape from neutralizing antibodies even in the presence of strong host immunity is associated with variations in envelope proteins that drive antigenic diversification. The virus exploits the error-prone nature of reverse transcriptase and the high mutation rate as key survival strategies. However, the rate of production of new variations occurs at relatively slow pace. Interestingly, the immune system often produces cross-reactive antibodies, with anticipated role in neutralizing point mutations in HIV surface proteins by cross-reacting with mutants and tolerating them. In light of this paradox, we explored the mystery of immune evasion and antibody promiscuity by screening single chain variable fragment (scFvs) antibodies against several crucial HIV-1 gp41 epitopes using a phage display library. These findings underscore the broader significance of cross-reactive antibodies. Here, high-affinity cross-reactive scFvs showed physiologically relevant affinities with peptide epitopes, their analogs, and the native HIV-1 gp41 protein. We determined the crystal structure of a high-affinity cross-reactive scFv, DE94, and obtained insights into the molecular interactions of scFv antibodies with peptide epitopes and its natural mutants using molecular docking studies. This analysis of cross-reactive antibodies could contribute to the therapeutic development against immune-evading pathogens and paves the way for innovative strategies for combating viral infections, including emerging global threats.

biophysics↗

bioRxiv2025

A Microphysiologic Model of the Cervical Epithelium Recapitulates Microbial, Immunologic, and Pathogenic Properties of Sexually Transmitted Infections

Sexually transmitted infections (STIs) of the cervicovaginal mucosa are among the most common global infections. Clinical studies have revealed that susceptibility to STIs and the subsequent host responses they elicit are frequently associated with vaginal microbiota compositions that facilitate infection. Current monolayer cell culture and animal models fail to reproduce the multilevel complexity required to investigate these relationships simultaneously and/or with sufficient physiological relevance. To address this limitation, we have developed a microphysiologic system (MPS) that models human cervical tissue, its microbiota, and is susceptible to infection by two prominent genital pathogens, Chlamydia trachomatis and Neisseria gonorrhoeae. Significantly, this MPS platform recapitulates essential dynamic, polymicrobial, immune, and pathogenic features of chlamydial and gonococcal infections as they occur in humans. The lowcost MPS device requires no specialized equipment or specific expertise and was experimentally validated for both chlamydial and gonococcal infections across multiple nonengineering, remotely located laboratories, demonstrating its transferability and reproducibility. The MPS platform described herein provides a novel tool for expanded research into genital infections in a reconstituted system that closely mimics the cervical epithelium, a significant advance over existing models.

bioengineering↗

bioRxiv2025

Ancestry-Dependent Immunologic and Prognostic Effects Characterize the Prostate Cancer Urinary Proteome

Urine is an attractive biomarker analyte for non-invasive longitudinal monitoring of health and disease, particularly for diseases of the genitourinary tract, like prostate and bladder cancer. The composition of an individuals urine reflects both genetic and lifestyle characteristics that differ across geographies and populations, like diet, hydration and other socio-economic factors. While men of African ancestry have elevated prostate cancer risk, it is unclear to what extent this influences urinary biomarkers. We therefore quantified the urinary proteomes of 329 localized prostate cancer patients: 135 self-identifying as White and 194 self-identifying as Black. We identified 110 proteins that significantly differed between these groups after controlling for age, PSA, and cISUP. Immune pathways were particularly dysregulated. The urinary proteome of Black patients harboured more features of aggressive cancers than those of grade- and PSA-matched White patients. These observations highlight the importance of controlling for race- and ancestry-associated differences in the development of urinary biomarkers.

cancer biology↗

bioRxiv2025

Streptococcus pneumoniae vaccine serotype persistence following 13-valent pneumococcal conjugate vaccine introduction in Mongolia: investigating changes in epidemiology, immunology and virulence

BackgroundStreptococcus pneumoniae is a leading cause of pneumonia globally. Vaccine serotypes can persist despite pneumococcal conjugate vaccine (PCV) introduction. To examine serotype persistence, we leveraged 6,545 nasopharyngeal swabs collected from children hospitalised with pneumonia before and after PCV13 introduction in Mongolia and undertook molecular, epidemiological and experimental analyses. MethodsSerotype, genetic lineage and antimicrobial resistance genes were inferred from DNA microarray. Patients carrying lineages that were predominant pre- and post-PCV introduction were examined for differences in disease severity. We also compared the pre- and post-PCV lineages by bacterial adhesion to hydrocarbon (BATH) and enzyme-linked immunosorbent (ELISA) assays. Capsule gene expression was measured by quantitative reverse transcription polymerase chain reaction (qRT-PCR), capsule thickness by transmission electron microscopy, and virulence using an infant mouse model. FindingsChanges in lineage composition were observed within serotypes 6A, 6B, 14, 19F and 23F over the six-year surveillance period. Children carrying pre-PCV lineages were more likely to have severe pneumonia than those carrying post-PCV lineages (serotypes 6B, 14 and 19F). Pre-PCV lineages were more likely to be multi-drug resistant than post-PCV lineages (serotypes 6A, 6B and 23F). For serotype 6B the post-PCV lineage had higher cell surface hydrophobicity, lower IgG, lower expression of capsule genes and evidence of thinner capsule than the pre-PCV lineage. Notably, the post-PCV 6B lineage was also less virulent in mice than the pre-PCV 6B lineage. InterpretationDespite persistence of vaccine serotypes in highly vaccinated populations, vaccination may select for lineages with differences in capsule and antibody binding and that are less virulent. When evaluating the true value of vaccination, it is important to consider factors beyond serotype alone. FundingNational Health and Medical Research Council, Murdoch Childrens Research Institute, GAVI, the Vaccine Alliance.

microbiology↗

bioRxiv2018

Natural selection contributed to immunological differences between human hunter-gatherers and agriculturalists

The shift from a hunter-gatherer (HG) to an agricultural (AG) mode of subsistence is believed to have been associated with profound changes in the burden and diversity of pathogens across human populations. Yet, the extent to which the advent of agriculture may have impacted the evolution of the human immune system remains unknown. Here we present a comparative study of variation in the transcriptional responses of peripheral blood mononuclear cells to bacterial and viral stimuli between Batwa rainforest hunter-gatherers and Bakiga agriculturalists from Uganda. We observed increased divergence between hunter-gatherers and agriculturalists in the transcriptional response to viruses compared to that for bacterial stimuli. We demonstrate that a significant fraction of these transcriptional differences are under genetic control, and we show that positive natural selection has helped to shape population differences in immune regulation. Across the set of genetic variants underlying inter-population immune response differences, however, the signatures of positive selection were disproportionately observed in the rainforest hunter-gatherers. This result is counter to expectations based on the popularized notion that shifts in pathogen exposure due to the advent of agriculture imposed radically heightened selective pressures in agriculturalist populations.

evolutionary biology↗

bioRxiv2019

The response of genes and pathways of immunological system induced by irradiation

Current studies have shown that ionizing radiation (IR) could increase the efficiency of radiation therapy by the stimulation of the immune system. This occurs in low-dose radiation as well as doses within hypofractionated range usually used in radiotherapy. However, the elucidation of the mechanisms of immunogenic modulation reported at these doses remain an issue. In this study, we analyzed transcriptome data available in Gene Expression Omnibus (GEO) database related to B cells isolated from whole blood of 95 donors and then irradiated with 10 Gy. The aim of this study is to investigate the regulation of genes and pathways of the immune system considering the B7-CD28/CTLA4 superfamily, CD40-CD40LG molecules, and cytokines expressed by B cells irradiated. The connection between genes and pathways is established by the Reactome database. Relative activity and diversity of pathways were calculated to determine the modulation of the immune system response to irradiation. Analysis of variance (ANOVA) with repeated measures and Bonferronis method were used to determine differentially expressed genes. It was observed that IR up-modulates the response of pathways and genes considered in this study, which indicates that 10 Gy can enhance antitumor immune responses.

biophysics↗

bioRxiv2019

Single cell transcriptomics identifies immunologic priming related to extra corporeal life support survival.

BackgroundDespite being a lifesaving intervention for the most critically ill and circulatory compromised patients, veno-arterial extra-corporeal life support (VA-ECLS) is associated with a mortality rate of nearly 60%. Understanding how the immune response to VA-ECLS either promotes or impedes survival would both enhance risk stratification and uncover new therapeutic strategies for these patients. However, conventional enumeration of peripheral blood mononuclear cells (PBMCs) and their subsets have failed to identify determinants of outcome among these cells. MethodsFlow cytometry and plasma cytokine measurement was combined with single cell RNASeq analysis of PBMCs from patients in circulatory shock being started on VA-ECLS to identify clinical, laboratory, and cellular features associated with 72 hour survival. ResultsNon-surviving patients exhibited higher plasma levels of the tissue aggressive inflammatory cytokines IL-1, IL-6, IL-12 and TNF-. Distribution of cells between conventional PBMC subtypes was not predictive of survival. Single cell RNASeq analysis of discriminatory markers within each PBMC subtype revealed that the proportion of CD8+ Natural Killer T-cells (NKT) that expressed CD52, a known immune-modulator, was associated with improved survival. This cell population correlated inversely with IL-6 production. CD8+/CD52+ NKT cells were quantified by flow cytometry in a second, validation cohort. Those patients with a high proportion of CD52+ cells among all CD8+ NKT cells had more severe disease relative to the low CD52+ group, but nevertheless were nearly 5 time less likely to die in the first 72 hours of VA-ECLS (p=0.043 by log rank test). ConclusionsCD8+/CD52+ NKT cells are associated with survival in patients undergoing VA-ECLS. Fluidics based scRNASeq can reveal important aspects of pathophysiology in complex disease states such as circulatory collapse and VA-ECLS. Further studies in animal models will be required to determine if stimulation of CD8+/CD52+ NKT cell expansion may be an effective therapeutic strategy in this patient population.

genomics↗

bioRxiv2019

Immune and environment-driven gene expression during invasion: An eco-immunological application of RNA-Seq

Host-pathogen dynamics change rapidly during a biological invasion and are predicted to impose strong selection on immune function. The invader may experience an abrupt reduction in pathogen-mediated selection ( enemy release), thereby favoring decreased investment into costly immune responses, and the extent of this reduction may depend on factors such as propagule size. Across plants and animals, there is mixed support for this prediction. Pathogens are not the only form of selection imposed on invaders; differences in abiotic environmental conditions between native and introduced ranges are also expected to drive rapid evolution. Here, we assess the expression patterns of immune and environmentally-associated genes in the cane toad (Rhinella marina) across its invasive Australian range. Transcripts encoding mediators of costly immune responses (inflammation, cytotoxicity) showed a curvilinear relationship with invasion history, with highest expression in toads from oldest and newest colonized areas. This pattern is surprising given theoretical expectations of density dynamics in invasive species, and may be because density influences both intraspecific competition and parasite transmission, generating conflicting effects on the strength of immune responses. Alternatively, this expression pattern may be the result of other evolutionary forces, such as spatial sorting and genetic drift, working simultaneously with natural selection. Our findings do not support predictions about immune function based on the enemy release hypothesis, and suggest instead that the effects of enemy release are difficult to isolate in wild populations. Additionally, expression patterns of genes underlying putatively environmentally-associated traits are consistent with previous genetic studies, providing further support that Australian cane toads have adapted to novel abiotic challenges.

ecology↗

bioRxiv2019

Immunological efficacy of self-assembled nanoparticle anti-mite vaccine

This report demonstrates the effects of self-assembled nanoparticle anti-caries vaccine Glu-FTH and Glu+ Poly(I:C) (in combination with adjuvant Poly(I:C) and antigen Glu) on specific humoral and mucosal immunity in mice. Mice were randomly divided into 6 groups, and Glu-FTH, Glu, Glu-FTH + Poly (I: C), Glu+Poly (I: C), FTH, and PBS were injected into mice via nasal mucosa. Enzyme-linked immunosorbent assay (ELISA) to detect specific antibody levels in serum and saliva. Results indicate that Glu-FTH, Glu, Glu-FTH+Poly(I:C), Glu+Poly(I:C) can effectively increase anti-Glu IgG levels in mouse serum; Glu+Poly(I:C) and Glu It can effectively increase the level of anti-GlusIgA in mouse saliva. Therefore, we demonstrate that Glu-FTH has a certain immune effect. The combination of adjuvant Poly(I:C) and antigen Glu can induce strong immune response.

bioengineering↗

bioRxiv2019

Sequence and immunologic conservation of Anaplasma marginale OmpA within strains from Ghana as compared to the predominant OmpA variant

A primary challenge in developing effective vaccines against obligate, intracellular, bacterial tick-borne pathogens that establish persistent infection is the identification of antigens that cross protect against multiple strains. In the case of Anaplasma marginale, the most prevalent tick-borne pathogen of cattle found worldwide, OmpA is an adhesin and thus a promising vaccine candidate. We sequenced ompA from cattle throughout Ghana naturally infected with A. marginale in order to determine the degree of variation in this gene in an area of suspected high genetic diversity. We compared the Ghanaian sequences with those available from N. America, Mexico, Australia and Puerto Rico. When considering only amino acid changes, three unique Ghanaian OmpA variants were identified. In comparison, strains from all other geographic regions, except one, shared a single OmpA variant, Variant 1, which differed from the Ghanaian variants. Next, using recombinant OmpA based on Variant 1, we determined that amino acid differences in OmpA in Ghanaian cattle as compared to OmpA Variant 1 did not alter the binding capacity of antibody directed against OmpA Variant 1, supporting the value of OmpA as a highly conserved vaccine candidate.

microbiology↗

bioRxiv2019

Overcoming Immunological Resistance Enhances the Efficacy of a Novel anti-tMUC1 CAR T Cell Treatment Against Pancreatic Ductal Adenocarcinoma

Chimeric antigen receptor engineered T cells (CAR T cells) have shown remarkable success in treating hematologic cancers. However, this efficacy has yet to translate to treatment in solid tumors. Pancreatic ductal adenocarcinoma (PDA) is a fatal malignancy with poor prognosis. Treatment options are limited and commonly associated with severe side effects. We have developed and characterized a second generation CAR engineered T cell using the light and heavy chain sequence derived from a novel monoclonal antibody, TAB004, that specifically binds the tumor associated antigen, tMUC1. tMUC1 is overexpressed in varying levels on ~85% of all human PDA. We present data showing that the TAB004 derived CAR T cells (tMUC1-CAR T cells) specifically bind to tMUC1 on PDA cells and is cytotoxic against the majority of the PDA cell lines. The tMUC1-CAR T cells do not bind or kill normal epithelial cells. We further demonstrate that the tMUC1-CAR T cells control the growth of orthotopic pancreatic tumors in vivo. PDAs are generally cold tumors with resistance to many standard treatment modalities, thus, it was not surprising that some of the PDA cell lines were refractory to CAR T cell treatment. qPCR analysis of several genes known to be associated with immune resistance revealed overexpression of indoleamine 2, 3-dioxygenases-1 (IDO1), Cyclooxygenase 1 and 2 (COX1 and COX2), Adenosine deaminases acting on RNA (ADAR1) and galectin-9 (Gal-9). We treated resistant PDA cells with a combination of CAR T cells and biological inhibitors of IDO1, COX1/2, ADAR1, and Gal-9. Results showed a significant enhancement of CAR T cell cytotoxicity against PDA cells when inhibiting IDO1, COX1/2, and Gal-9 but not ADAR1 or COX2. Overcoming CAR T cell resistance in PDA is a significant advancement in the field and may lead to future combination therapies that are less toxic but more efficient against this deadly disease.

cancer biology↗

bioRxiv2019

Food supplementation affects gut microbiota and immunological resistance to parasites in a wild bird species

O_LISupplemental feeding can increase the overall health of animals but also can have varying consequences for animals dealing with parasites. Furthermore, the mechanism mediating the effect of food supplementation on host-parasite interactions remains poorly understood. C_LIO_LIThe goal of the study was to determine the effect of food supplementation on host defenses against parasitic nest flies and whether host gut microbiota, which can affect immunity, potentially mediates these relationships. In a fully crossed design, I experimentally manipulated the abundance of parasitic nest flies (Protocalliphora sialia) and food availability then characterized the gut microbiota, immune responses, and nest parasite abundance of nestling eastern bluebirds (Sialia sialis). C_LIO_LIFood supplemented birds had 75% fewer parasites than unsupplemented birds. Parasite abundance decreased throughout the breeding season for unsupplemented birds, but abundance did not change throughout the season for supplemented birds. Food supplementation increased overall fledging success. Parasitism had a sublethal effects on blood loss, but food supplementation mitigated these effects by increasing parasite resistance via the nestling IgY antibody response. C_LIO_LIFood supplementation increased the gut bacterial diversity in nestlings, which was negatively related to parasite abundance. Food supplementation also increased the relative abundance of Clostridium spp. in nestlings, which was positively related to their antibody response and negatively related to parasite abundance. C_LIO_LISynthesis and applications. Overall, these results suggest that food supplementation, especially early in the breeding season, increases resistance to parasitism during the early life stage of the host, which could be mediated by the effect of supplementation on the gut microbiota. Wildlife food supplementation is a common pastime for humans worldwide and therefore it is important to determine the consequences of this activity on animal health. Furthermore, supplemental feeding could induce resistance to detrimental parasites (e.g. invasive parasites) in hosts when management of the parasite is not immediately possible. C_LI

ecology↗

bioRxiv2019

The evolution of dengue-2 viruses in Malindi, Kenya and greater East Africa: epidemiological and immunological implications

Kenya experiences a substantial burden of dengue, yet there are very few DENV-2 sequence data available from this country and indeed the entire continent of Africa. We therefore undertook whole genome sequencing and evolutionary analysis of fourteen dengue virus (DENV)-2 strains sampled from Malindi sub-County Hospital during the 2017 DENV-2 outbreak in the Kenyan coast. We further performed an extended East African phylogenetic analysis, which leveraged 26 complete African env genes. Maximum likelihood analysis showed that the 2017 outbreak was due to the Cosmopolitan genotype, indicating that this has been the only confirmed human DENV-2 genotype circulating in Africa to date. Phylogeographic analyses indicated transmission of DENV-2 viruses between East Africa and South/South-West Asia. Time-scaled genealogies show that DENV-2 viruses are spatially structured within Kenya, with a time-to-most-common-recent ancestor analysis indicating that these DENV-2 strains were circulating for up to 5.38 years in Kenya before detection in the 2017 Malindi outbreak. Selection pressure analyses indicated sampled Kenyan DENV strains uniquely being under positive selection at 6 sites, predominantly across the non-structural genes, and epitope prediction analyses showed that one of these sites corresponds to a putative predicted MHC-I CD8+ DENV-2 Cosmopolitan virus epitope only evident in a sampled Kenyan virus. Taken together, our findings indicate that the 2017 Malindi DENV-2 outbreak arose from a strain which had circulated for several years in Kenya before recent detection, has experienced diversifying selection pressure, and may contain new putative immunogens relevant to vaccine design. These findings prompt further genomic epidemiology studies in this and other Kenyan locations to further elucidate the transmission dynamics of DENV in this region. Author summary (non-technical)Kenya experiences a substantial burden of dengue, yet the patterns of dengue spread in this region are unclear. Evolutionary analyses of dengue virus strain sequences could offer major insights into the spread of dengue viruses in this region, but there are very few DENV-2 sequence data available from this country and indeed the entire continent of Africa. We therefore undertook whole genome sequencing and evolutionary analysis of fourteen dengue virus (DENV)-2 strains sampled from Malindi sub-County Hospital during the 2017 DENV-2 outbreak in the Kenyan coast. We further performed an extended East African phylogenetic analysis, which leveraged 26 complete African env genes. Our results indicated transmission of DENV-2 viruses between East Africa and South/South-West Asia, that there is localized spread of DENV-2 viruses within Kenya, and that Kenyan DENV-2 strains were circulating for up to 5.38 years in Kenya before detection in the 2017 Coastal outbreak. We further performed selection pressure analyses and identified possible new markers of DENV-2 immune recognition specific to this population, with relevance to vaccine design.

genomics↗

bioRxiv2026

Curation at Scale with EPITOME: Extraction Pipeline for Immunological Texts and Open-Source Multimodal Enquiry

The Immune Epitope Database (IEDB, iedb.org) has manually curated epitope data from over 26,000 publications across two decades. With PubMed adding [~]5,000 articles daily, traditional curation methods face scalability challenges. Given the multimodality of data contained in scientific papers, we have sought to build an open-source vision language model (VLM)-based tool that human curators can use to speed up and automate biological data curation. Here we present a multimodal document ingestion and Question-Answering (QnA) pipeline that ties traditional Optical Character Recognition (OCR) and text matching with Vision-Language Model (VLM) capabilities. The system, which we call EPITOME, implements three-stage processing: regex-based epitope and MHC molecule identification, visual element extraction from PDFs, and contextual indexing that links peptide sequences, MHC molecules, and assays to their locations across text, tables, and figures. This indexing is used to supply context for further VLM QnA. Our preliminary results from EPITOME demonstrate promising zero-shot performance of open-source VLMs that suggest promise for accelerating biocuration through a curator-in-the-loop process, with our evaluation identifying strategic points where curator-in-the-loop intervention can enhance overall system accuracy.

bioinformatics↗

bioRxiv2026

Small extracellular vesicular transfer of MYCN and glycolytic cargo coordinates metabolic and immunological reprogramming in neuroblastoma in vitro

Extracellular vesicles (EVs) are emerging mediators of oncogenic communication within the neuroblastoma (NB) tumour microenvironment (TEM). Here, we investigated how constitutive MYCN overexpression influences the proteomic and functional properties of small EVs (sEVs) derived from SKNAS-MYCN-GFP (SK-M) cells and assessed their impact on non-cancerous immune cells. SK-M cells exhibited robust MYCN upregulation at both the mRNA and protein levels and produced sEVs that were selectively enriched in MYCN. Transwell co-culture revealed transfer of MYCN-GFP to recipient DC2.4 nuclei, indicating intercellular transport of functional transcription factor cargo. LC-MS/MS profiling showed that SK-M sEVs incorporated oncogenic cargo non-randomly, displaying significant enrichment of metabolic and MYC/MYCN-regulated pathways, including glycolysis, mTORC1 signalling, and suppression of oxidative phosphorylation (OXPHOS). These observations are consistent with emerging evidence that MYC family proteins can regulate metabolism through vesicular transfer of glycolytic kinases to neighbouring cells. Functionally, SK-M cells displayed elevated lactate secretion and reduced acetyl-CoA, and their sEVs induced a glycolytic shift in recipient immune cells, increasing lactate output in DC2.4, RAW264.7, BMDCs, and splenocytes. sEV-treated BMDCs and splenocytes acquired immunoregulatory phenotypes characterised by increased IL-10, reduced IL-12, expansion of regulatory T cells (Tregs), and macrophage polarization toward an M2-like state. These findings demonstrate that MYCN-driven NB cells disseminate metabolic and immunosuppressive cues via sEVs, reshaping the local immune landscape to favour tumour tolerance. This study provides mechanistic insight into how MYCN-amplified NB cells exploit EV-based communication to coordinate metabolic rewiring and immune escape.

cancer biology↗