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Granuloma Dual RNA-Seq Reveals Composite Transcriptional Programs Driven by Neutrophils and Necrosis within Tuberculous Granulomas

ABSTRACT: Mycobacterial granulomas lie at the center of tuberculosis (TB) pathogenesis and represent a unique niche where infecting bacteria survive in 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-seq across different host genotypes to profile transcriptional alterations that enable bacteria to survive and take advantage of host immune responses. Using both pharmacological and genetic interventions, we find that neutrophils within mature, necrotic granulomas promote bacterial growth, in part through upregulation of the bacterial devR regulon. Finally, we identify conserved transcriptional programs related to K+ transport and the rpf genes induced only in the context of this unique necrotic extracellular niche. Analysis of Mycobacterium tuberculosis strains across diverse lineages suggests that these modules represent targets for bacterial genetic adaptation in the context of human infection.

ORGANISM(S): Danio rerio Mycobacterium marinum

PROVIDER: GSE289727 | GEO | 2025/04/26

REPOSITORIES: GEO

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