Meta-analysis reveals a core iron-responsive gene signature in Mycobacterium tuberculosis linking siderophore biosynthesis, virulence, and metabolic adaptation.

The meta-analysis integrates transcriptomic data from two independent datasets (GSE8732 and GSE84554) to elucidate Mycobacterium tuberculosis (Mtb)'s transcriptional response to iron limitation, a key host defense mechanism. The study identifies a core set of consistently differentially expressed genes (DEGs) critical for Mtb's survival under iron-restricted conditions. Key upregulated genes include those involved in siderophore biosynthesis (mbtA, mbtB, mbtE, mbtI), which are essential for iron acquisition, and components of the ESX secretion system (esxG, esxH, esxR, esxS), linking iron scavenging to virulence. Additionally, PE/PPE family genes (PPE37, PE5), implicated in immune evasion, were consistently upregulated, suggesting their role in host-pathogen interactions during iron scarcity. Conversely, downregulated genes included iron storage proteins (bfrA), regulatory factors (ideR, sigB, rpoC), and metabolic enzymes (aspC, frdA), reflecting a strategic shift away from iron-dependent processes to conserve resources. Temporal analysis revealed a dynamic adaptation process: early-phase responses prioritized iron acquisition, while prolonged starvation induced metabolic restructuring (e.g., upregulation of fadD33, kasB) and stress responses (grpE). The iron-dependent regulator IdeR emerged as a central player, derepressing iron acquisition genes under low iron but also revealing additional regulatory layers. The consistent DEGs across datasets validate their biological significance and highlight potential therapeutic targets, such as siderophore biosynthesis and ESX systems, to disrupt Mtb's adaptation during infection. This study advances insights into Mtb's pathogenicity and survival strategies under host-imposed iron restriction, offering a framework for novel anti-tuberculosis interventions.