Biomedical subjects

Thomas R Hawn

Publications and source records attributed to Thomas R Hawn.

3 recordsLinked to original sources

PubMed2026

Human genetic variation associates with infection by derived Ugandan M. tuberculosis lineage.

BACKGROUND: Several studies have examined host and pathogen genetic influences on tuberculosis (TB) susceptibility separately, but relatively few studied their combined effects. However, host-pathogen interactions or co-evolution may explain the inability to replicate many reported human genetic effects across global populations and provide additional insight into TB risk. In this study, we address such possible interactions by focusing on the outcome of infection with the L4-Uganda M. tuberculosis sub-lineage and human genetic variants as independent variables. This is possible because the L4-Uganda sub-lineage is both restricted to Uganda and nearby locations and is recent there, compared to other more ancestral L4 lineages. METHODS: Our study consisted of 276 culture-confirmed adult TB cases from a long-standing household contact study. We conducted a genome-wide association study, with infection with L4-Uganda versus L4-NonUganda as the outcome. RESULTS: Multiple loci with results suggestive of association (p<10-5) also demonstrated convergent relevant evidence for strain specific infection via: evidence of gene expression in relevant cells and lung tissue, signatures of natural selection, eQTL expression, and CRISPR screens for immunity-related genes. We also replicated previously published host-pathogen interaction effects, demonstrating that effects seen for other sub-lineages were also present for L4-Uganda. CONCLUSIONS: These results provide evidence for host-pathogen co-evolution in TB, consistent with our previous work, and indicate these interactions involve genes highly relevant to the host immune response to Mycobacterium infection.

GWAS↗

PubMed2026

Human iPSC-derived alveolar macrophages reveal macrophage subtype functions of itaconate in M. tuberculosis defense.

Mycobacterium tuberculosis (Mtb) survives within multiple macrophage populations during infection, including alveolar macrophages (AMs) and recruited inflammatory macrophages. In mice, itaconate, produced in macrophages by ACOD1-mediated decarboxylation of aconitate, has direct antimicrobial activity, modulates inflammatory cytokines, and is required for resistance to Mtb infection. The role of itaconate in human macrophages is less clear, and it is unknown whether itaconate mediates distinct effects in macrophage subtypes. Here, we investigated the role of itaconate in macrophages derived from human induced pluripotent stem cells (iPSCs), induced by either GM-CSF to resemble AMs (AM-like cells, hereafter ipAM-Ls) or M-CSF to resemble monocyte-derived macrophages (MDM-like cells, hereafter ipMDM-Ls). Both human macrophage types produced substantially less itaconate than mouse macrophages, and ipAM-Ls produced 4-fold less itaconate than ipMDM-Ls. Surprisingly, ACOD1-deficient ipAM-Ls, but not ipMDM-Ls, were permissive for Mtb growth. Moreover, itaconate functioned to dampen the Mtb-induced inflammatory response in ipMDM-Ls, but not ipAM-Ls, affecting both the type I IFN and TNF pathways. These results indicate that itaconate is involved in human macrophage responses to tuberculosis, with distinct roles in different macrophage subsets. These results also show that genetically tractable iPSC-derived macrophages are a useful model to dissect cellular host-pathogen interactions in human macrophages.

Humans↗

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↗