Science Translational Medicine

BackgroundPrimary amoebic meningoencephalitis (PAM) is a rapidly progressive and often fatal central nervous system infection caused by Naegleria fowleri. Despite widespread environmental exposure to this free-living amoeba, clinical disease is rare, suggesting that it requires not only exposure to the amoeba but also a host vulnerability. Yet, the immune mechanisms controlling protection vs. susceptibility to N. fowleri remain poorly understood. MethodsWe conducted comprehensive clinical, immu...

BackgroundIn lung transplantation, de novo immunodominant donor-specific anti-HLA antibodies recognizing HLA-DQ antigens (dn-iDSA-DQ) are predominant and can induce chronic lung allograft dysfunction (CLAD). We previously developed a method to measure the active concentration of dn-iDSA-DQ. We aimed to determine whether this new quantitative biomarker is associated with transplantation outcomes. MethodsThis retrospective multicentre cohort study included 90 lung transplant recipients (LTRs) dev...

Plant-based dietary strategies may offer a tractable approach to mitigating microbiome disruption and improving outcomes in patients undergoing autologous hematopoietic cell transplantation (auto-HCT) for multiple myeloma, a population in whom intestinal dysbiosis has been linked to infectious complications and inferior survival. We conducted a single-arm study to test the feasibility and biological activity of a high-fiber, plant-based, whole-food meal delivery intervention during the peri-tran...

The host response to Neisseria gonorrhoeae is variable, and understanding its systemic and local components is critical to understanding anti-gonococcal immunity for vaccine development. We used a controlled human infection model of male gonococcal urethritis in naive volunteers in combination with multiplex cytokine analyte analysis of blood and urine specimens taken before infection, at the time of acute symptoms, and after curative treatment of N. gonorrhoeae to study responses to early infec...

Kidney transplantation faces a critical paradox: while thousands await organs, approximately 30% of potential deceased donor kidneys are discarded for various reasons, including subjective assessments due to the lack of an objective molecular biomarker of preservation quality. Here, we applied novel "top-down" proteoform imaging mass spectrometry across living donor (LD), deceased donor (brain death or cardiac death), and discarded human kidneys to quantify proteoforms correlating with post-tran...

BackgroundIron metabolism disorder is highly prevalent before and after heart transplantation (HTx). The impact of pretransplant and posttransplant iron disorder on posttransplant outcomes is unclear. ObjectivePretransplant serum levels of key regulator proteins of iron metabolism (hepcidin, interleukin-6, erythroferrone) were tested for prediction of the composite outcome 1-year posttransplant all-cause mortality (ACM) or [≥]moderate acute cellular rejection (ACR). Furthermore, serum levels...

Immune imprinting, also known as immune history, is a core aspect of adaptive immunity that influences antibody responses to future antigen exposures. Nevertheless, the impact of sequential flavivirus vaccinations on epitope targeting and antibody activity in humans remains incompletely understood. This question is particularly important in regions where the inactivated Japanese encephalitis virus (JEV) vaccines and the live-attenuated dengue virus (DENV) vaccines are used, as both have been ass...

BackgroundWhile antimicrobial resistance is an increasingly urgent problem, with Escherichia coli infections representing a major priority, the development of effective vaccines has proven both challenging and largely unsuccessful. Given accumulating evidence supporting the immunosuppressive role of extracellular bacterial glyceraldehyde-3-phosphate dehydrogenase (GAPDH), we aimed to characterize individual susceptibility to E. coli infections based on the presence of naturally induced antibodie...

BackgroundInfluenza vaccination and bacterial colonization both shape immunity in the respiratory tract, yet their combined impact on the human lung mucosa remains poorly understood. Secondary bacterial pneumonia following influenza infection is a leading cause of mortality, underscoring the need to define how vaccines and microbes intersect at the airway interface. MethodsUsing the Experimental Human Pneumococcal Challenge (EHPC) model, we examined how intramuscular inactivated (TIV) and nasal...

Ethiopian cutaneous leishmaniasis (CL) shows remarkably heterogeneous clinical presentations, but the underlying immunopathological mechanisms driving this heterogeneity in disease presentation remains poorly understood. To characterise the local immune response in Ethiopian CL, we performed spatial transcriptomics on paired lesional and non-lesional skin punch biopsies from five Ethiopian CL patients. We used reference-free deconvolution, morphology-guided regional analyses, and immunohistochem...

The long-term impact of SARS-CoV-2 infection on kidney allograft survival remains incompletely understood, particularly regarding the influence of vaccination, acute kidney injury (AKI), and post-infection immunosuppression. We conducted a retrospective analysis of 129 kidney transplant recipients with confirmed SARS-CoV-2 infection between March 2020 and March 2022 with a median follow-up of 50 months. Among 129 recipients, 106 (82%) received vaccination at any time before or after SARS-CoV-2 i...

Coccidioidomycosis presents clinically as a spectrum ranging from self-limiting Uncomplicated Valley Fever (UVF) in most cases to life-threatening Disseminated Coccidioidomycosis (DCM) in rare individuals. A few patterns of immunologic deficits allowing for dissemination have been identified, though the specific defects in most individuals with DCM remain undefined. We hypothesized that chronic antigen exposure in DCM engenders a state of T cell exhaustion. From a cohort of over 300 subjects wi...

BackgroundTuberculosis (TB) and HIV co-infection cause profound immune dysregulation. Understanding how these infections alter immune cell distribution across systemic and tissue compartments is critical for improving therapeutic and vaccine strategies. MethodsFlow cytometry was used to quantify CD4 and CD8 T cells, B cells, and tissue-resident memory (TRM) T and B cells in peripheral blood mononuclear cells (PBMCs), lung tissue, bronchoalveolar lavage (BAL), spleen, and lung-draining hilar lym...

Accurate identification of unknown pathogens is critical for medicine and public health, yet current metagenomic workflows remain heavily dependent on specialized bioinformatics expertise and manual interpretation, creating substantial bottlenecks in time-sensitive diagnostic settings1. The key challenges lie in achieving precise species identification amidst high background noise and translating complex microbial data into clinically actionable insights2,3. Here we present the Global Pathogen A...

Background & AimsPerihilar cholangiocarcinoma is an aggressive malignancy with clinical heterogeneity and poor long-term outcomes after resection. Current prognostic assessment relies mainly on anatomical staging and pathological features, which incompletely capture the entire postoperative risk. We aimed to determine whether integrative analysis of clinical, surgical, pathological and tumor genomic data could improve time-resolved, individualized recurrence-risk prediction after curative-intent...

Why do some individuals develop mild COVID-19 while others progress to severe disease remains a central challenge in SARS-CoV-2 immunology. In this study, we leveraged the BACO Cohort - a unique historical cohort of immunologically naive, hospitalized COVID-19 patients from the first pandemic wave - to investigate early immune determinants of clinical disease trajectories. Integrating bulk RNA-seq, Olink proteomics, and systems serology, we identified two fundamentally distinct immune trajectori...

Cutaneous leishmaniasis (CL) is a skin disease caused by Leishmania infection, for which no licensed human vaccine exists. Protective immunity is largely T cell-mediated and depends on antigen presentation by MHC molecules, yet the naturally presented epitopes during human disease remain poorly defined. To address this gap, we performed mass spectrometry-based immunopeptidomics on lesional biopsies from 27 Ethiopian CL patients spanning the full clinical spectrum. We newly identified 333 MHC-I a...

BackgroundThe hyperpolymorphic nature and structural complexity of the human leukocyte antigen (HLA) genomic region present challenges for accurate and scalable typing across diverse sample types. While wholegenome sequencing (WGS) offers the opportunity to infer HLA genotypes without targeted enrichment, systematic benchmarks across sequencing platforms, biospecimens and coverage levels remain limited. ResultsWe assembled a multi-platform resource of WGS datasets derived from short-read (Illum...

PurposeSepsis-associated immunothrombosis significantly contributes to high mortality, yet the role of N-glycosylation in this process remains poorly understood. This study aimed to comprehensively profile the plasma N-glycosylation landscape in sepsis and elucidate how its specific reprogramming in the complement and coagulation cascades influences immunothrombotic balance and patient outcomes. MethodsWe performed in-depth 4D-DIA proteomic and N-glycomic analyses on plasma from 43 sepsis patie...

An H3N2 variant, named subclade K, continues to circulate widely during the 2025-2026 influenza season. This virus possesses a hemagglutinin (HA) protein that has eleven substitutions relative to the HA of the Northern Hemisphere 2025-2026 H3N2 vaccine strain. Many of these substitutions are in epitopes in well-characterized HA antigenic sites. Despite this, interim vaccine effectiveness studies indicate that the 2025-2026 influenza vaccine provides moderate protection against H3N2 subclade K in...