Publications

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64 Publications visible to you, out of a total of 64
BCG vaccination elicits protection against Mtb infection mediated by two phases of T cell immunity

Abstract

Not specified

Authors: Abiola F. Ogunsola, Rocky Lai, Kelly Cavallo, Gillian L. Beamer, Samuel M. Behar

Date Published: 30th Oct 2025

Publication Type: Journal Article

Rewiring of cortical glucose metabolism fuels human brain cancer growth.

Abstract (Expand)

The brain avidly consumes glucose to fuel neurophysiology(1). Cancers of the brain, such as glioblastoma, relinquish physiological integrity and gain the ability to proliferate and invade healthy … tissue(2). How brain cancers rewire glucose use to drive aggressive growth remains unclear. Here we infused (13)C-labelled glucose into patients and mice with brain cancer, coupled with quantitative metabolic flux analysis, to map the fates of glucose-derived carbon in tumour versus cortex. Through direct and comprehensive measurements of carbon and nitrogen labelling in both cortex and glioma tissues, we identify profound metabolic transformations. In the human cortex, glucose carbons fuel essential physiological processes, including tricarboxylic acid cycle oxidation and neurotransmitter synthesis. Conversely, gliomas downregulate these processes and scavenge alternative carbon sources such as amino acids from the environment, repurposing glucose-derived carbons to generate molecules needed for proliferation and invasion. Targeting this metabolic rewiring in mice through dietary amino acid modulation selectively alters glioblastoma metabolism, slows tumour growth and augments the efficacy of standard-of-care treatments. These findings illuminate how aggressive brain tumours exploit glucose to suppress normal physiological activity in favour of malignant expansion and offer potential therapeutic strategies to enhance treatment outcomes.

Authors: A. J. Scott, A. Mittal, B. Meghdadi, A. O'Brien, J. Bailleul, P. Sravya, A. Achreja, W. Zhou, J. Xu, A. Lin, K. Wilder-Romans, N. Liang, A. U. Kothari, N. Korimerla, D. M. Edwards, Z. Wu, J. Feng, S. Su, L. Zhang, P. Sajjakulnukit, A. C. Andren, J. O. Park, J. Ten Hoeve, V. Tarnal, K. A. Redic, N. R. Qi, J. L. Fischer, E. Yang, M. S. Regan, S. A. Stopka, G. Baquer, K. Suresh, J. N. Sarkaria, T. S. Lawrence, S. Venneti, N. Y. R. Agar, E. Vlashi, C. A. Lyssiotis, W. N. Al-Holou, D. Nagrath, D. R. Wahl

Date Published: 9th Oct 2025

Publication Type: Journal Article

Targeting infection-specific peptides in immunopeptidomics studies for vaccine target discovery.

Abstract (Expand)

Vaccine-elicited T cell responses can contribute to immune protection against emerging infectious disease risks such as antimicrobial-resistant (AMR) microbial pathogens and viruses with pandemic … potential, but rapidly identifying appropriate targets for T cell priming vaccines remains challenging. Mass spectrometry (MS) analysis of peptides presented on MHCs can identify potential targets for protective T cell responses in a proteome-wide manner. However, pathogen-derived peptides are outnumbered by self-peptides in the MHC repertoire and may be missed in untargeted MS analyses. Here, we present a novel approach, termed PathMHC, that uses computational analysis of untargeted MS data followed by targeted MS to discover novel pathogen-derived MHC peptides more efficiently than untargeted methods alone. We applied this workflow to identify MHC peptides derived from multiple microbes, including potential vaccine targets presented on MHC-I by human dendritic cells infected with Mycobacterium tuberculosis (Mtb), finding that all Mtb peptides detected in the MHC-I repertoire derived from proteins exported by type VII secretion systems. PathMHC will facilitate antigen discovery campaigns for vaccine development.

Authors: O. Leddy, Y. Yuki, M. Carrington, B. D. Bryson, F. M. White

Date Published: 6th Oct 2025

Publication Type: Journal Article

Persistent interferon signaling and clonal expansion mark early events in DNA methylation damage-induced liver cancer.

Abstract (Expand)

N-Nitrosodimethylamine (NDMA), a probable human carcinogen, induces toxic and mutagenic O (6)-methylguanine lesions that are repaired by the O (6)-methylguanine methyltransferase (MGMT). To elucidate … mechanisms of NDMA-induced liver cancer progression, we performed longitudinal analyses of phenomic, transcriptomic, and phosphoproteomic changes in wild-type and MGMT-deficient mice, observing amplified responses in the deficient genotype. Early molecular rewiring indicative of a DNA damage response was detected by phosphoproteomic and transcriptomic profiling within days post-exposure. Transcriptomic analyses identified a persistent and robust interferon response as the dominant activated pathway. This chronic interferon signaling, which remained unresolved, correlated with extensive clonal expansion, an early hallmark of oncogenesis. Spatial transcriptomics further revealed pathway alterations favoring tumorigenesis within clonally expanded cells. These findings delineate the cascade of molecular events triggered by acute early-life NDMA exposure, culminating in cancer development months later. Our study unveils potential predictive biomarkers and strategies for disease mitigation.

Authors: L. J. Pribyl, J. E. Kay, J. J. Corrigan, L. B. Volk, M. Norales, N. A. Owiti, E. A. Kowal, I. N. Kohale, I. S. Nazari, M. R. Swanson, A. C. Moise, D. Ma, S. S. Levine, E. Michelsen, R. G. Croy, T. Ragan, D. K. Torous, S. L. Avlasevich, S. D. Dertinger, S. E. Carrasco, L. D. Samson, J. M. Essigmann, F. M. White, B. P. Engelward

Date Published: 3rd Oct 2025

Publication Type: Journal Article

Failed cellular surveillance enables pathogenic matrix deposition in a COL2A1-related osteoarthritis.

Abstract (Expand)

Mutations in the COL2A1 gene, encoding procollagen-II, cause various chondrodysplasias, including precocious osteoarthritis with mild spondyloepiphyseal dysplasia engendered by the p.Arg719Cys substitution. … The molecular mechanisms underlying these disorders remain incompletely understood, largely owing to the absence of models faithfully recapitulating the human disease. Here, we developed an in vitro human cartilage model using isogenic induced pluripotent stem cell (iPSC) lines carrying either wild-type or Arg719Cys COL2A1. Directed differentiation into chondrocytes yielded cartilage tissues that were analyzed by immunohistochemistry, electron microscopy, SDS-PAGE, and RNA-sequencing. Tissues derived from Arg719Cys heterozygotes displayed a deficient matrix, closely reflecting the human disease phenotype. Arg719Cys procollagen-II was excessively post-translationally modified and partially retained within the endoplasmic reticulum (ER), leading to ER distention. Notably, despite introduction of an aberrant cysteine residue-expected to engage redox-sensitive folding and quality control pathways-Arg719Cys procollagen-II was not detectably recognized by the ER proteostasis network. The resulting inability to mount a quality control response, including absent activation of the unfolded protein response, indicates a failure in cellular surveillance. As a result, malformed procollagen-II both accumulates intracellularly and is secreted, contributing to the deposition of a structurally compromised extracellular matrix that drives disease pathology. The iPSC-derived cartilage model presented here provides a genetically defined, expandable, and human-based system for dissecting mechanisms of failed proteostasis in collagenopathies. These findings shed light on the types of substitutions in procollagen that cells do or do not recognize, and underscore the therapeutic potential of targeting cellular surveillance and collagen quality control pathways in COL2A1-related disorders and beyond.

Authors: K. M. Yammine, S. Mirda Abularach, M. Xiong, S. Y. Kim, A. A. Bikovtseva, V. L. Butty, R. P. Schiavoni, J. F. Bateman, S. R. Lamande, M. D. Shoulders

Date Published: 3rd Sep 2025

Publication Type: Journal Article

Protection against reinfection with <i>Mycobacterium tuberculosis</i> extends across heterologous Mtb lineages.

Abstract

Not specified

Authors: Andrew W Simonson, Michael C Chao, Luke E Hood, Rachel A Donlan, Forrest Hopkins, Michael R Chase, Andrew J Vickers, Alanna Callendrello, Edwin Klein, H Jacob Borish, Marshall Malin, Pauline Maiello, Charles A Scanga, Philana Ling Lin, Sarah M Fortune, JoAnne L Flynn

Date Published: 31st Jul 2025

Publication Type: Journal Article

Noncanonical T cell responses are associated with protection from tuberculosis in mice and humans.

Abstract (Expand)

While control of Mycobacterium tuberculosis (Mtb) infection is generally understood to require Th1 cells and IFNgamma, infection produces a spectrum of immunological and pathological phenotypes in … diverse human populations. By characterizing Mtb infection in mouse strains that model the genetic heterogeneity of an outbred population, we identified strains that control Mtb comparably to a standard IFNgamma-dependent mouse model but with substantially lower lung IFNgamma levels. We report that these mice have a significantly altered CD4 T cell profile that specifically lacks the terminal effector Th1 subset and that this phenotype is detectable before infection. These mice still require T cells to control bacterial burden but are less dependent on IFNgamma signaling. Instead, noncanonical immune features such as Th17-like CD4 and gammadeltaT cells correlate with low bacterial burden. We find the same Th17 transcriptional programs are associated with resistance to Mtb infection in humans, implicating specific non-Th1 T cell responses as a common feature of Mtb control across species.

Authors: M. K. Proulx, C. D. Wiggins, C. J. Reames, C. Wu, M. C. Kiritsy, P. Xu, J. C. Gallant, P. S. Grace, B. A. Fenderson, C. M. Smith, C. S. Lindestam Arlehamn, G. Alter, D. A. Lauffenburger, C. M. Sassetti

Date Published: 7th Jul 2025

Publication Type: Journal Article

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