# Comparative Transcriptomic Analysis of Human Macrophages During Mycobacterium avium Versus Mycobacterium tuberculosis Infection

## TL;DR

This study compares how human macrophages respond to two mycobacterial infections, finding both similarities and key differences in immune responses that could guide new treatments.

## Contribution

The study provides the first comparative transcriptomic analysis of human macrophages infected with Mycobacterium avium and Mycobacterium tuberculosis.

## Key findings

- Mav and Mtb infections share immune pathways like cytokine signaling and GPCR modulation.
- Mav infection more strongly affects phospholipases and GIMAP genes compared to Mtb.
- Immediate early genes and IFN signaling show distinct regulation between the two infections.

## Abstract

The treatment of
Mycobacterium avium
(Mav) infection, responsible for over 80% of nontuberculous mycobacterial pulmonary disease, remains challenging due to rising antibiotic resistance and unsatisfactory success rates. Hence, there is a need for a deeper understanding of host–pathogen interactions to inform the development of alternative therapeutic approaches, like host‐directed therapy (HDT), aimed at improving host antimycobacterial defenses. However, compared to
Mycobacterium tuberculosis
(Mtb) infections, knowledge of host–pathogen interactions for Mav infection is still limited. To address this knowledge gap, we performed a genome‐wide host transcriptomic analysis of Mav‐infected primary human macrophages—the primary host cell—alongside Mtb‐infected macrophages to leverage insights from Mtb research. Our findings show substantial overlap in the gene expression patterns between Mav‐infected and Mtb‐infected macrophages, including induction of cytokine responses and modulation of various G‐protein coupled receptors (GPCRs) involved in (lipid‐mediated) macrophage immune functions. Notable differences were observed in the expression of immediate early genes (IEGs), phospholipases, and genes of the GTPase of immunity‐associated protein (GIMAP) family. This study laid a foundation for identifying both shared and Mav‐specific host response pathways, providing direction for future investigations into host–pathogen interactions during Mav infection and the identification of novel targets for HDT.

Human macrophage transcriptomic responses to
Mycobacterium avium
(Mav), a major cause of nontuberculous lung disease, were compared to
Mycobacterium tuberculosis
(Mtb). Both infections activated overlapping immune pathways, including cytokine signaling and GPCRs involved in lipid metabolism, while phospholipases were more strongly regulated by Mav and IFN signaling by Mtb. Mav also more strongly regulated GIMAP family genes, cytokines, and immediate early genes, revealing differences in host responses and highlighting potential targets to enhance Mav‐specific immunity.