SET1B is required for sustained HIF2-dependent activity in ccRCC. A, High expression of SETD1B (SET1B gene name) in kidney cancer is associated with poor outcomes. Kaplan–Meier survival analysis of TCGA data for ccRCC, comparing tumors in the highest and lowest quartiles of SETD1B mRNA expression. n = 130 patients for each group. Log-rank test. B, VEGFA ELISA in control, SET1B depletion, SET1B KO, and HIF2α KO 786-0 cells. Cells were incubated for 48 hours and before supernatants were collected. The graph is representative of 3 biological replicates. Two-way ANOVA. C, Graphs showing the percentage engraftment of control, HIF1β, and SET1B KO cells in the CAM assay. D, Representative images of 786-O parental (n = 17), SET1B KO (n = 16), and HIF1β KO (n = 15) CAM assay. The xenografts and surrounding CAM was fixed in ovo to preserve blood in the vessels and then imaged from the underneath after dissection. Scale bars, 1 mm. Vessel density was calculated as total vessel length (pixels)/total area analyzed (pixels2) per ROI. Brown–Forsythe ANOVA test, F(2,33.38) = 7.156, P = 0.0026. Dunnett T3 multiple comparison test; parental (P) vs. SET1B KO (S), P = 0.0076; parental vs. HIF1β KO (H), P = 0.4873; SET1B KO vs. HIF1β KO, P = 0.0136. D, Branching points relative to area analyzed (mm2). Ordinary one-way ANOVA, F(2, 45) 4.019, P = 0.0248. Tukey multiple comparison test; parental vs. SET1B P = 0.0076; parental vs. HIF1β P = 0.4873; SET1B vs. HIF1β P = 0.0136. E, IHC of SET1B was performed on a ccRCC tissue microarray (TMA). Samples were assessed and graded 1–4 with 1 being the least aggressive and grade 4 being the most aggressive. SET1B staining intensity across the tumor was calculated as an H score which accounts for the staining intensity and the % of positive cells detected. Samples were subdivided based on grade, and SET1B intensity was plotted. Significance was assessed using a two-way ANOVA. F, Control, HIF2α KO, and SET1B KO 786-0 cells were embedded in Matrigel, and cellular invasion was measured over indicated time using Incucyte. Graphs are representative for 3 biological replicates and depict the mean ± SD. Two-way ANOVA. G, qPCR of HIF targets associated with metastasis (MAFF, AKAP12, and ANGPTL4) in 786-0 cells depleted of HIF1β and SET1B using CRISPR (n = 3 biologically independent samples, mean ± SD). H, ccRCC mouse xenograft model. WT, HIF1β, and SET1B-depleted 786-0 cells expressing luciferase were injected into the tail vein of nude mice. Bioluminescence was measured and quantified from the lungs on day 40 and day 54 (control = 5; HIF1β KO = 6; and SET1B KO = 6). Mean ± SD. Two-way ANOVA. ROI, region of interest; siSET1B, SET1B siRNA.

Abstract Background Shigellosis morbidity and mortality, combined with the increase in multidrug-resistant infections make Shigella vaccine development a global imperative. Glycoconjugate vaccines that couple immunogenic O-antigen to protein derived from Shigella may provide broader protection across Shigella species and serogroups. Such an approach also circumvents immunotolerance arising from repeated use of the same carrier. Here we use bioconjugation, exploiting an oligosaccharyltransferase (OST) enzyme to couple O-antigen and carrier protein in vivo , to generate a “double-hit” Shigella glycoconjugate vaccine. Method Glycoconjugates were synthesised in E. coli SDB1 cells expressing S. sonnei O-antigen, the OST PglS, and one of two Shigella carrier proteins. Recombinant glycoconjugate was purified using anion exchange chromatography and then used to immunise mice. Antibody responses were measured and compared by ELISA. Results When co-produced in E. coli , PglS was able to transfer the cloned S. sonnei O-antigen onto three carrier proteins, modified to accept glycans from the PglS transferase enzymes- the standard bioconjugate carrier ExoA and two immunogenic Shigella -specific outer membrane proteins, EmrK and MdtA. Production of MdtA or ExoA glycoconjugates for immunisation studies utilised successive rounds of anion exchange chromatography, to remove unglycosylated material and obtain highly purified glycoconjugate proteins for us in vaccination. Analysis of murine sera following immunisation revealed an IgG response was raised against both carrier protein and the S. sonnei O-antigen for each glycoconjugate. Conclusion A novel, conserved Shigella protein can be utilised as an effective carrier for the generation of a “double-hit”, immunogenic Shigella glycoconjugate vaccine that elicits IgG responses to both carrier protein and S. sonnei O-antigen.

Model for the role of SET1B in ccRCC. In ccRCC, HIF2 is constitutively active because of the loss of VHL protein. SET1B is recruited to HIF target genes by the HIF complex, in which it plays a critical role in initiating and sustaining HIF transcription. This is achieved through its H3K4me3 activity and its interaction with the RNA Pol II complex. The enhanced HIF2 transcription leads to increased angiogenesis, metastasis, and disease progression.

SET1B interacts with the RNA Pol II complex and requires multiple functional domains to coordinate HIF activity.

Oncogenes such as KRAS display marked tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved1-5. Here, to address these questions, we developed the Mouse Cancer Cell line Atlas, a broad-utility resource of 590 comprehensively characterized models across a wide range of entities ( www.mcca.tum.de ). Comparative and functional studies using this platform, human cohorts and mice identified core principles underlying tissue-specific evolution of KRAS-initiated cancers. First, we show that mutant KRAS dosage gain through allelic imbalance exerts cell-type-specific effects, defining its timing across entities, as exemplified by dosage-sensitive developmental reprogramming during pancreatic cancer initiation. Second, we highlight how tissue- and stage-specific evolutionary requirements, such as block of differentiation in the intestine, select for KRAS-collaborating alterations. Third, we identified context-dependent epistatic KRAS-tumour suppressor interactions and show that reciprocal dosage sensitivities dictate the entity-specific patterns of cancer gene alterations, explaining their frequency, zygosity and acquisition chronology. These findings highlight how intrinsic and acquired determinants instruct cancer evolution in different tissues, with predictable molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes.

Abstract Oncogenes like KRAS display striking tissue specificity in their oncogenic potential, genetic interactions and phenotypic effects, but the underlying determinants remain largely unresolved. To address such fundamental questions, we developed the Mouse Cancer Cell line Atlas (MCCA), a broad utility resource encompassing 590 comprehensively characterized models from a wide spectrum of entities. Comparative and functional studies using the MCCA resource, human cohorts and mouse models uncovered general principles guiding KRAS-initiated cancer evolution. We describe how tissue context affects diverse aspects of evolution, including the role of mutant KRAS gene dosage variation, the relevance of collaborating cancer pathways, or the sequential order of genetic alterations. Mechanisms governing tissue-specific evolution transpired at different levels: First, we show that mutant KRAS dosage increase through allelic imbalance exerts cell type-specific effects, such as reactivation of developmental programs in the pancreas. Selection of such dosage-sensitive processes defines the timing of KRAS imbalance and its phenotypic outcomes in individual entities. Second, we highlight how tissue- and stage-specific evolutionary requirements, such as block of differentiation in the intestine, select for KRAS-collaborating alterations. Third, we uncovered tissue-specific epistatic interactions between KRAS imbalance and tumor suppression - as demonstrated for CDKN2A, which displays distinct levels of chromatin repression in different cell types. We show that resulting reciprocal dosage sensitivities dictate the entity-specific patterns of tumor suppressor alterations in human cancers, explaining their frequency, extent/zygosity and acquisition chronology. These findings thus highlight how the interplay of pre-existing and acquired determinants instructs cancer evolution along deterministic trajectories in different tissues - with predictable quantitative molecular patterns, temporal dynamics and phenotypic outcomes. Our study provides major advances towards a mechanistic understanding of cancer genomes. Citation Format: Sebastian Mueller, Niklas de Andrade Krätzig, Markus Tschurtschenthaler, Miguel G. Silva, Chiara Thordsen, Riccardo Trozzo, Perrine Simon, Frederic Saab, Thorsten Kaltenbacher, Magdalena Zukowska, Daniele Lucarelli, Rupert Öllinger, Joscha Griger, Nina Groß, Tanja Groll, Linus R. Schömig, Stefanie Baerthel, Chiara Falcomatà, Alexander Strong, Cordelia Brandt, Mulham Najajreh, Aristeidis Papargyriou, Roman Maresch, Ute Jungwirth, Maximilian Reichert, George S. Vassiliou, Daniel F. Alonso, Pier-Luigi Lollini, Jean J. Zhao, Louis Chesler, Clare M. Isacke, Angela Riedel, Marc Schmidt-Supprian, Günter Schneider, Trevor D. Lawley, Gordon Dougan, Katja Steiger, Nathalie Conte, Allan Bradley, Lena Rad, Dieter Saur, Roland Rad. The mouse cancer cell line atlas reveals core principles of tissue-specific cancer evolution [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2026; Part 1 (Regular Abstracts); 2026 Apr 17-22; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2026;86(7 Suppl):Abstract nr 6794.

Promoting resistance to enteric pathogen infection is a core function of the gut microbiota; however, many of the specific host–commensal interactions that mediate this protection remain uncharacterised. To address this knowledge gap, we monocolonised germ-free mice with mouse-derived commensal microbes to screen for microbiota-induced resistance to Salmonella Typhimurium infection. We identified Enterocloster clostridioformis as a protective species against S. Typhimurium infection. E. clostridioformis selectively upregulates resistin-like molecule β and cell cycle pathway expression at the level of caecal epithelial cells and increases T-regulatory cells in the underlying mucosal immune system, potentially contributing to reduced infection-induced pathology. We highlight novel mechanisms of host–microbe interactions that can mediate microbiota-induced resistance to acute salmonellosis. In the backdrop of increasing antibiotic resistance, this study identifies novel potential avenues for further research into protective host responses against enteric infections and could lead to new therapeutic approaches.

Long-term whipworm-host co-evolution has resulted in tropism for the caecum of specific hosts, an organ with the densest microbial population in the body. Here, we demonstrate that the host specificity of human whipworms (Trichuris trichiura) is host microbiome-driven. We successfully establish a T. trichiura infection in a non-primate host using a humanised-microbiota mouse model. We further show, in vitro , that hatching of T. trichiura was triggered by mucosal scrapings of the caecum of human microbiota-associated mice, but not from wild-type mice, which only induced T. muris hatching. Comparative metagenomic analysis of the murine versus humanised microbiomes directly implicated specific bacterial species in T. trichiura egg hatching. Additionally, we demonstrate that host tissue does not directly determine host specificity, as T. trichiura readily infected mouse caecaloids. Our findings indicate that host-microbiome-whipworm co-evolution has resulted in exquisite bacterial-whipworm egg interactions critical for hatching and development of these parasites in their definitive hosts. ### Competing Interest Statement The authors have declared no competing interest. Wellcome Trust, 222546/Z/21/Z, 206194, 203151/Z/16/Z, 203151/A/16/Z Medical Research Council, MC\_PC\_17230

Enteropathogenic infections cause pathophysiological changes in the host but their effects beyond the gastrointestinal tract are undefined. Here, using Citrobacter rodentium infection in mouse, which mimics human diarrheal enteropathogenic Escherichia coli, we show that gastrointestinal infection negatively affects bone remodeling, leading to compromised bone architecture. Transmission of infection through fecal-oral route from Citrobacter rodentium-infected to non-infected mice caused bone loss in non-infected cage mates. Mice with B cell deficiency (Igh6-/- mice) failed to clear C. rodentium infection and exhibited more severe and long-term bone loss compared to WT mice. Unbiased cytokine profiling showed an increase in circulating tumor necrosis factor a (TNFa) levels following Citrobacter rodentium infection, and immunoneutralization of TNFa prevented infection-induced bone loss completely in WT and immunocompromised mice. These findings reveal rapid, relaying, and modifiable effects of enteropathogenic infections on an extraintestinal organ-bone, and provide insights into the mechanism(s) through which these infections affect extraintestinal organ homeostasis.

Animal African trypanosomiasis (AAT) is an infectious wasting disease of economically important livestock caused by Trypanosoma spp. parasites. The disease is primarily caused by two species: Trypanosoma congolense and Trypanosoma vivax, which are endemic in many African countries. AAT is managed by therapeutic and prophylactic drugs; however, resistance is now widely reported, and the development of new drugs has been impeded due to a chronic lack of investment. Recently, we identified an invariant flagellar-associated cell surface protein (IFX) that could elicit protective immune responses when used as a vaccine against T. vivax. We showed that a complement-recruiting anti-IFX monoclonal antibody can prevent infection when used prophylactically. Here, we show that this same unmodified antibody can be used to cure T. vivax infections in a murine experimental model. Importantly, we show that infections can be treated with a single dose and demonstrate full cure by the lack of detectable parasites in peripheral tissues even after immunosuppression. Using structural modeling and site-directed mutagenesis, we localize the protective antibody epitope, thereby identifying targetable regions on IFX to improve vaccine design. Together, these findings validate IFX as both a prophylactic and curative drug target that could be useful in the management of AAT.IMPORTANCETrypanosoma vivax is a parasite that causes animal African trypanosomiasis (AAT), a chronic wasting disease that infects economically important livestock animals, which is a particular problem in African countries south of the Sahara. The impact of this disease is significant: it is responsible for over 3 million cattle deaths and an estimated $4.5 billion of annual lost productivity. There is a desperate need to develop new control measures because resistance is now widely reported to the drugs commonly used to treat this infection. We show here that a single dose of an unmodified monoclonal antibody that recognizes IFX—a parasite cell surface protein localized to the flagellum—is sufficient to cure an established T. vivax infection with no parasite reservoirs detectable in peripheral tissues. Our finding validates IFX as a new drug target and provides a rationale route to the development of new drugs to target AAT.

The cellular response to hypoxia is driven by hypoxia-inducible factors (HIFs), which regulate genes involved in glycolysis, angiogenesis, and cell proliferation, as well as inflammation and tumour progression. HIF activation is well-characterised and is primarily regulated by oxygen-dependent prolyl hydroxylation and subsequent degradation. However, how transcription of individual HIF target genes is regulated at the chromatin level is less clear. SET1B, a histone H3 lysine 4 (H3K4) methyltransferase, has emerged as a key modulator of HIF target gene transcription. Our study reveals that SET1B interacts with RNA Polymerase II to coordinate sustained HIF-mediated transcriptional activity through multiple functional domains. We also show that in clear cell renal cell carcinoma (ccRCC), SET1B is critical for sustained HIF activity, and SET1B expression correlates with disease progression and metastasis in patient samples. Moreover, SET1B depletion enhances the efficacy of HIF-2 inhibitors, establishing SET1B as a potential therapeutic target in ccRCC. ### Competing Interest Statement GDS has received educational grants from Pfizer and AstraZeneca; consultancy fees from Evinova; travel expenses from MSD; he is Clinical lead (urology) National Kidney Cancer Audit and Topic Advisor for the NICE kidney cancer guideline. All other authors declare that they have no competing interests

The meninges house several innate and adaptive immune cell populations[1][1]–[3][2]. These predominantly localise within the dura mater and include gut-derived IgA-secreting plasma cells[4][3]. Whether T cell adaptive memory in the dura is similarly linked to the gut is currently unknown. Here we show that dural CD4 T cell polarisation to a T helper (Th) 1, Th2 and Th17 state is determined by the nature of the immunological challenge encountered in the gastrointestinal tract. We find that intestinally polarised CD4 T cells seed to the dura in a CXCR6-CXCL16-dependent manner, express tissue-residency markers and are long-lived. Functionally, these orally-primed dural CD4 T are capable of a rapid antigen-specific recall response that limits pathogen spread into the brain following intravenous re-challenge. Our work reveals how linked intestinal and dural immunity enables the central nervous system to accrue immunological memory of gut microbes, the most likely source of life-threatening bloodborne pathogens. ### Competing Interest Statement The authors have declared no competing interest. Wellcome Trust, 102163/B/13/Z, 110199/Z/15/Z, 220268/Z/20/Z, 107057/Z/15/Z, 227890/Z/23/ Medical Research Council, MR/S035842/1 NIHR, RP-2017-08-ST2-002 [1]: #ref-1 [2]: #ref-3 [3]: #ref-4

Host body temperature can define a virus's replicative profile-influenza A viruses (IAVs) adapted to 40° to 42°C in birds are less temperature sensitive in vitro compared with human isolates adapted to 33° to 37°C. In this work, we show that avian-origin PB1 polymerase subunits enable IAV replication at elevated temperatures, including avian-origin PB1s from the 1918, 1957, and 1968 pandemic viruses. Using a model system to ensure biosafety, we show that a small increase in body temperature protects against severe disease in mice and that this protection is overcome by a febrile temperature-resistant PB1. These findings indicate that although elevated temperature itself can be a potent antiviral defense, it may not be effective against all influenza strains. These data inform both the clinical use of antipyretics and IAV surveillance efforts.

Maternal antibodies (MatAbs) are transferred transplacentally during pregnancy and through breast milk after birth to provide protection whilst the neonatal immune response is immature. However, MatAbs also suppress the development of neonatal B cell responses via mechanisms that are not well defined. MatAbs can therefore result in poor vaccine performance in the infant, placing them at risk against potentially life-threatening pathogens such as rotavirus. It is essential we understand the mechanisms by which MatAbs interact with neonatal immunity, so that strategies can be developed to overcome this major vaccine issue. To investigate mechanisms of interference we developed a mouse model of neonatal oral rotavirus vaccination in the presence and absence of MatAbs. Oral vaccination with attenuated murine rotavirus induced robust neonatal antibody responses, whereas vaccination failed to induce seroconversion in the presence of MatAbs. Vaccination with heterologous strains, reduced MatAb titers and vaccination in FcγRIIB knockout mice did not overcome interference. However, live vaccine replication was blocked in the presence of MatAbs and more rapid waning of MatAbs was observed following vaccination. This is indicative of premature vaccine clearance and likely reduced antigen encounter by B cells. Single-cell RNA sequencing of mesenteric lymph nodes revealed diminished plasma and germinal center B cell subpopulations as well as global reduction of interferon-stimulated genes in the presence of MatAbs. Our model has also enabled identification of strategies to reduce the effects of interference. In summary, we have tested multiple hypotheses for MatAb-mediated interference to rotavirus vaccination in a mouse model, and demonstrated that premature FcγRIIB signaling and epitope masking are not the primary mechanisms of vaccine failure. Rather our data supports the conclusion that MatAb-mediated vaccine clearance is a key mechanism of interference to oral rotavirus vaccine. ### Competing Interest Statement The authors have declared no competing interest.

Mounting evidence of the occurrence of direct and indirect interactions between the human blood fluke, Schistosoma mansoni, and the gut microbiota of rodent models raises questions on the potential role(s) of the latter in the pathophysiology of hepatointestinal schistosomiasis. However, substantial differences in both the composition and function between the gut microbiota of laboratory rodents and that of humans hinders an in-depth understanding of the significance of such interactions for human schistosomiasis. Taking advantage of the availability of a human microbiota-associated mouse model (HMA), we have previously highlighted differences in infection-associated changes in gut microbiota composition between HMA and wildtype (WT) mice. To further explore the dynamics of schistosome-microbiota relationships in HMA mice, in this study we (i) characterize qualitative and quantitative changes in gut microbiota composition of a distinct line of HMA mice (D2 HMA) infected with S. mansoni prior to and following the onset of parasite egg production; (ii) profile local and systemic immune responses against the parasite in HMA as well as WT mice and (iii) assess levels of faecal inflammatory markers and occult blood as indirect measures of gut tissue damage. We show that patent S. mansoni infection is associated with reduced bacterial alpha diversity in the gut of D2 HMA mice, alongside expansion of hydrogen sulphide-producing bacteria. Similar systemic humoral responses against S. mansoni in WT and D2 HMA mice, as well as levels of faecal lipocalin and markers of alternatively activated macrophages, suggest that these are independent of baseline gut microbiota composition. Qualitative comparative analyses between faecal microbial profiles of S. mansoni-infected WT and distinct lines of HMA mice reveal that, while infection-induced alterations of the gut microbiota composition are highly dependent on the baseline flora, bile acid composition and metabolism may represent key elements of schistosome-microbiota interactions through the gut-liver axis.

The use of monoclonal antibodies for the control of drug resistant nosocomial bacteria may alleviate a reliance on broad spectrum antimicrobials for treatment of infection. We identify monoclonal antibodies that may prevent infection caused by carbapenem resistant Acinetobacter baumannii. We use human immune repertoire mice (Kymouse platform mice) as a surrogate for human B cell interrogation to establish an unbiased strategy to probe the antibody-accessible target landscape of clinically relevant A. baumannii. After immunisation of the Kymouse platform mice with A. baumannii derived outer membrane vesicles (OMV) we identify 297 antibodies and analyse 26 of these for functional potential. These antibodies target lipooligosaccharide (OCL1), the Oxa-23 protein, and the KL49 capsular polysaccharide. We identify a single monoclonal antibody (mAb1416) recognising KL49 capsular polysaccharide to demonstrate prophylactic in vivo protection against a carbapenem resistant A. baumannii lineage associated with neonatal sepsis mortality in Asia. Our end-to-end approach identifies functional monoclonal antibodies with prophylactic potential against major lineages of drug resistant bacteria accounting for phylogenetic diversity and clinical relevance without existing knowledge of a specific target antigen. Such an approach might be scaled for a additional clinically important bacterial pathogens in the post-antimicrobial era.

Human microbiota assembly commences at birth, seeded by both maternal and environmental microorganisms. Ecological theory postulates that primary colonizers dictate microbial community assembly outcomes, yet such microbial priority effects in the human gut remain underexplored. Here using longitudinal faecal metagenomics, we characterized neonatal microbiota assembly for a cohort of 1,288 neonates from the UK. We show that the pioneering neonatal gut microbiota can be stratified into one of three distinct community states, each dominated by a single microbial species and influenced by clinical and host factors, such as maternal age, ethnicity and parity. A community state dominated by Enterococcus faecalis displayed stochastic microbiota assembly with persistent high pathogen loads into infancy. In contrast, community states dominated by Bifidobacterium, specifically B. longum and particularly B. breve, exhibited a stable assembly trajectory and long-term pathogen colonization resistance, probably due to strain-specific functional adaptions to a breast milk-rich neonatal diet. Consistent with our human cohort observation, B. breve demonstrated priority effects and conferred pathogen colonization resistance in a germ-free mouse model. Our findings solidify the crucial role of Bifidobacteria as primary colonizers in shaping the microbiota assembly and functions in early life. Primary colonization by microbial communities dominated by Bifidobacteria contribute to stable gut microbiota assembly and long-term pathogen resistance in neonates.

Visceral leishmaniasis is a deadly infectious disease and is one of the world's major neglected health problems. Because the symptoms of infection are similar to other endemic diseases, accurate diagnosis is crucial for appropriate treatment. Definitive diagnosis using splenic or bone marrow aspirates is highly invasive, and so, serological assays are preferred, including the direct agglutination test (DAT) or rK39 strip test. These tests, however, are either difficult to perform in the field (DAT) or lack specificity in some endemic regions (rK39), making the development of new tests a research priority. The availability of Leishmania spp. genomes presents an opportunity to identify new diagnostic targets. Here, we use genome data and a mammalian protein expression system to create a panel of 93 proteins consisting of the extracellular ectodomains of the Leishmania donovani cell surface and secreted proteins. We use these panel and sera from murine experimental infection models and natural human and canine infections to identify new candidates for serological diagnosis. We observed a concordance between the most immunoreactive antigens in different host species and transmission settings. The antigen encoded by the LdBPK_323600.1 gene can diagnose Leishmania infections with high sensitivity and specificity in patient cohorts from different endemic regions including Bangladesh and Ethiopia. In longitudinal sampling of treated patients, we observed reductions in immunoreactivity to LdBPK_323600.1 suggesting it could be used to diagnose treatment success. In summary, we have identified new antigens that could contribute to improved serological diagnostic tests to help control the impact of this deadly tropical infectious disease. IMPORTANCE:Visceral leishmaniasis is fatal if left untreated with patients often displaying mild and non-specific symptoms during the early stages of infection making accurate diagnosis important. Current methods for diagnosis require highly trained medical staff to perform highly invasive biopsies of the liver or bone marrow which pose risks to the patient. Less invasive molecular tests are available but can suffer from regional variations in their ability to accurately diagnose an infection. To identify new diagnostic markers of visceral leishmaniasis, we produced and tested a panel of 93 proteins identified from the genome of the parasite responsible for this disease. We found that the pattern of host antibody reactivity to these proteins was broadly consistent across naturally acquired infections in both human patients and dogs, as well as experimental rodent infections. We identified a new protein called LdBPK_323600.1 that could accurately diagnose visceral leishmaniasis infections in humans.

B cells play a central role in humoral immunity but also have antibody-independent functions. Studies to date have focused on B cells in blood and secondary lymphoid organs but whether B cells reside in non-lymphoid organs (NLO) in homeostasis is unknown. Here we identify, using intravenous labeling and parabiosis, a bona-fide tissue-resident B cell population in lung, liver, kidney and urinary bladder, a substantial proportion of which are B-1a cells. Tissue-resident B cells are present in neonatal tissues and also in germ-free mice NLOs, albeit in lower numbers than in specific pathogen-free mice and following co-housing with 'pet-store' mice. They spatially co-localise with macrophages and regulate their polarization and function, promoting an anti-inflammatory phenotype, in-part via interleukin-10 production, with effects on bacterial clearance during urinary tract infection. Thus, our data reveal a critical role for tissue-resident B cells in determining the homeostatic 'inflammatory set-point' of myeloid cells, with important consequences for tissue immunity.

Vaccines work by inducing an immunological memory response that protects against infection or disease. More effective adjuvants and vaccines, and an understanding of how they work, are required to protect high risk groups such as the elderly. We screen transcriptional signatures of T cell memory against signatures of repurposable drug responses, validating predicted hits in a phenotypic screen and identifying a subclass of lysine deacetylase inhibitors (KDACi) capable of modulating activated primary human T cells towards a memory precursor phenotype. Leveraging combined acetylomic, metabolomic, transcriptomic and epigenomic analyses, we identify enhanced glutaminolysis as the mechanism responsible with selective inhibition reversing changes induced by treatment. We validate our findings in four murine models of infection and immunisation with the effect reversed by concurrently inhibiting glutaminolysis. To demonstrate the clinical relevance of our findings we undertake a human experimental medicine study, demonstrating increased breadth, magnitude and duration of cellular and humoral responses.