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62 Publications visible to you, out of a total of 62
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

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

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

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

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

Antibody-Fab and -Fc features promote Mycobacterium tuberculosis restriction.

Abstract (Expand)

Mycobacterium tuberculosis, the causative agent of tuberculosis (TB), a leading cause of death by an infectious disease globally, has no efficacious vaccine. Antibodies are implicated in M. tuberculosis … control, but the mechanisms of action remain poorly understood. We assembled a library of monoclonal antibodies (mAb) and screened for M. tuberculosis-restrictive activity in mice, identifying protective antibodies targeting diverse antigens. To dissect the mechanism of mAb-mediated M. tuberculosis restriction, we optimized a protective lipoarabinomannan-specific mAb, generating Fc variants. In vivo analysis of these Fc variants revealed a role for Fc-effector function in M. tuberculosis restriction. Restrictive Fc variants altered distribution of M. tuberculosis across innate immune cells. Single-cell transcriptomics highlighted distinctly activated pathways within innate immune cell subpopulations, identifying early activation of neutrophils as a key signature of mAb-mediated M. tuberculosis restriction. Therefore, antibody-mediated restriction of M. tuberculosis is associated with reorganization of the tissue-level immune response to infection and depends on the collaboration of antibody Fab and Fc.

Authors: P. S. Grace, J. M. Peters, J. Sixsmith, R. Lu, E. B. Irvine, C. Luedeman, B. A. Fenderson, A. Vickers, M. D. Slein, T. McKitrick, M. H. Wei, R. D. Cummings, A. Wallace, L. A. Cavacini, A. Choudhary, M. K. Proulx, C. Sundling, G. Kallenius, R. Reljic, J. D. Ernst, A. Casadevall, C. Locht, A. Pinter, C. M. Sassetti, B. D. Bryson, S. M. Fortune, G. Alter

Date Published: 10th Jun 2025

Publication Type: Journal

Structural and systems characterization of phosphorylation on metabolic enzymes identifies sex-specific metabolic reprogramming in obesity.

Abstract (Expand)

Coordination of adaptive metabolism through signaling networks is essential for cellular bioenergetics and homeostasis. Phosphorylation of metabolic enzymes provides a rapid, efficient, and dynamic … mechanism to regulate metabolic networks. Our structural analysis stratified phosphosites on metabolic enzymes based on proximity to functional and dimerization domains. Most phosphosites occur on oxidoreductases and are enriched near substrate, cofactor, active sites, or dimer interfaces. Despite low stoichiometry, phosphotyrosine (pY) is overrepresented in functional domains. Using high-fat diet (HFD)-induced obesity in C57BL/6J mice and multiomics, we measured HFD-induced sex-specific dysregulation of pY and metabolites, which was reversible with the antioxidant butylated hydroxyanisole (BHA). Computational modeling revealed predictive pY sites for HFD- or BHA-induced metabolite changes. We characterized functional roles for predictive pY sites on glutathione S-transferase pi 1 (GSTP1), isocitrate dehydrogenase 1 (IDH1), and uridine monophosphate synthase (UMPS) using CRISPR interference (CRISPRi) rescue and stable isotope tracing. Our findings reveal mechanisms whereby cellular signaling fine-tunes enzyme activity and metabolism.

Authors: T. Y. Tamir, S. Chaudhary, A. X. Li, S. E. Trojan, C. T. Flower, P. Vo, Y. Cui, J. C. Davis, R. Mukkamala, F. N. Venditti, A. L. Hillis, A. Toker, M. G. Vander Heiden, J. B. Spinelli, N. J. Kennedy, R. J. Davis, F. M. White

Date Published: 5th Jun 2025

Publication Type: Journal

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