Dual transcriptomic analysis unraveling the immune landscape and host-pathogen interactions during Mycobacterium tuberculosis infection

TL;DR

This study uses dual RNA sequencing to explore how immune cells and tuberculosis bacteria interact during infection, revealing key differences in immune responses and bacterial survival strategies.

Contribution

The study introduces a dual transcriptomic approach to simultaneously analyze host and pathogen gene activity during Mycobacterium tuberculosis infection.

Findings

Macrophages with dead Mtb show strong immune activation, including antigen presentation and lysosomal function.

Live Mtb manipulates host defenses through DNA repair and lipid binding pathways, supporting bacterial adaptation.

Cross-species analysis links Mtb metabolism to host lipid transport and steroid biosynthesis.

Abstract

Elucidating the host-pathogen interactions is critical for uncovering the mechanisms controlling Mycobacterium tuberculosis (Mtb) infection. Using dual RNA-seq with fluorescent Mtb, we simultaneously profiled macrophage and bacterial transcriptomes to resolve dynamic intracellular responses. Macrophages containing dead Mtb exhibited strong immune activation, including enhanced antigen presentation and lysosomal function, whereas macrophages harboring live Mtb showed persistent NF-κB signaling and metabolic reprogramming. Mtb counteracted host defenses through upregulation of DNA repair genes and manipulation of extracellular matrix signaling via SPP1 and integrins, alongside tryptophan catabolism and lipid binding pathways supporting adaptation. Cross-species correlation analysis revealed coordinated transcriptional programs, notably a strong inverse association between Mtb aromatic compound catabolism and host receptor tyrosine kinase signaling. Additional correlations linked bacterial metabolism with host lipid transport and steroid biosynthesis. Together, these results provide a high resolution view of macrophage and Mtb transcriptional interplay defining bacterial persistence versus immune clearance.

•Dual RNA-seq maps coordinated transcriptional programs in macrophage-Mtb interplay•Lysosomal activation and antigen presentation drive effective macrophage control•Macrophages harboring live Mtb show persistent inflammation and metabolic shift•Cross-species correlations couple host RTK signaling to Mtb aromatic catabolism

Dual RNA-seq maps coordinated transcriptional programs in macrophage-Mtb interplay

Lysosomal activation and antigen presentation drive effective macrophage control

Macrophages harboring live Mtb show persistent inflammation and metabolic shift

Cross-species correlations couple host RTK signaling to Mtb aromatic catabolism

Immunology; Microbiology; Transcriptomics

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