Biomedical subjects

David M Tobin

Publications and source records attributed to David M Tobin.

4 recordsLinked to original sources

PubMed2026

Host eicosanoid signals define a granuloma fibroblast population that coordinates mycobacterial containment.

Genetic variation at the leukotriene A4 hydrolase (LTA4H) locus is associated with tuberculosis (TB) severity and outcome. Here, we define a unique population of peripheral fibroblasts at the mycobacterial granuloma, the central immune structure in TB, whose recruitment and functions are coordinated by lta4h-dependent signals. Using single-cell profiling of zebrafish mycobacterial infections, we identify a layer of lta4h-dependent recruited fibroblasts at the granuloma's edge with mesenchymal and stem-like expression signatures, including aldh1a3 expression. Ablation of these cells compromises bacterial containment at the structure's periphery. Similarly, genetic disruption of apolipoprotein D, produced specifically in granuloma-associated fibroblasts, results in an altered eicosanoid balance, decreased inflammation, and increased dissemination of infection. In humans, this granuloma-associated fibroblast population is distinct from myofibroblasts, interacts with LTA4H-expressing macrophages, and is prominent across diverse TB granuloma types. These results link a host genetic susceptibility locus to the recruitment and function of a specialized fibroblast population that limits bacterial dissemination.

Animals↗

PubMed2026

Granuloma dual RNA-seq reveals composite transcriptional programs driven by neutrophils and necrosis within tuberculous granulomas.

Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive under nutrient-restricted conditions and in the face of a host immune response. The granuloma's necrotic core, where bacteria reside extracellularly in humans, is difficult to assess in many experimentally tractable models. Here, using necrotic mycobacterial granulomas in adult zebrafish, we develop dual RNA sequencing (RNA-seq) across different host genotypes to identify the transcriptional alterations that enable bacteria to survive within this key microenvironment. Using pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through up-regulation of the bacterial devR regulon. We identify conserved suites of bacterial transcriptional programs induced only in the context of this unique necrotic extracellular niche, including bacterial modules related to K+ transport and rpf genes. Analysis of Mycobacterium tuberculosis strains across diverse lineages and human populations suggests that granuloma-specific transcriptional modules are targets for bacterial genetic adaptation in the context of human infection.

Animals↗

PubMed2025

Cathepsin Z is a conserved susceptibility factor underlying tuberculosis severity.

Tuberculosis (TB) outcomes vary widely, from asymptomatic infection to mortality, yet most animal models do not recapitulate human phenotypic and genotypic variation. The genetically diverse Collaborative Cross mouse panel models distinct facets of TB disease that occur in humans and allows identification of genomic loci underlying clinical outcomes. We previously mapped a TB susceptibility locus on mouse chromosome 2. Here, we identify cathepsin Z (Ctsz) as a lead candidate underlying this TB susceptibility and show that Ctsz ablation leads to increased bacterial burden, pulmonary inflammation and decreased survival in mice. Ctsz disturbance within murine macrophages enhances production of chemokine (C-X-C motif) ligand 1 (CXCL1), a known biomarker of TB severity. From a Ugandan household contact study, we identify significant associations between CTSZ variants and TB disease severity. Finally, we examine patient-derived TB granulomas and report CTSZ localization within granuloma-associated macrophages, placing human CTSZ at the host-pathogen interface. These findings implicate a conserved CTSZ-CXCL1 axis in humans and genetically diverse mice that mediates TB disease severity.

Animals↗

PubMed2025

Understanding Mycobacterium tuberculosis through its genomic diversity and evolution.

Pathogen evolution and genomic diversity are shaped by specific host immune pressures and therapeutic interventions. Analysis of the extant genomes of circulating strains of Mycobacterium tuberculosis, a leading cause of infectious mortality that has co-evolved with humans for thousands of years, can provide new insights into host-pathogen interactions that underlie specific aspects of pathogenesis and onward transmission. With the explosion in the number of fully sequenced M. tuberculosis strains that are now paired with detailed clinical data, there are new opportunities to understand the evolutionary basis for and consequences of M. tuberculosis strain diversity. This review examines mechanistic findings that have emerged from pairing whole genome sequencing data and evolutionary analysis with functional dissection of specific bacterial variants. These include improved understanding of secreted effectors that modulate the properties and migratory behavior of infected macrophages as well as bacterial genetic alterations important for survival within hypoxic microenvironments. Genomic, evolutionary, and functional analyses across diverse M. tuberculosis strains will identify prominent bacterial adaptations to their human hosts and shape our understanding of TB disease biology and the host immune response.

Mycobacterium tuberculosis↗