Weighted Gene Co-Expression Network Analysis Identifies Key Modules and Hub Genes Associated with Mycobacterial Infection of Human Macrophages.

Lu Lu,Ranlei Wei,Simon J Waddell,Ester Boix,Sanjib Bhakta

doi:10.3390/antibiotics10020097

Abstract

Tuberculosis (TB) is still a leading cause of death worldwide. Treatments remain unsatisfactory due to an incomplete understanding of the underlying host–pathogen interactions during infection. In the present study, weighted gene co-expression network analysis (WGCNA) was conducted to identify key macrophage modules and hub genes associated with mycobacterial infection. WGCNA was performed combining our own transcriptomic results using Mycobacterium aurum-infected human monocytic macrophages (THP1) with publicly accessible datasets obtained from three types of macrophages infected with seven different mycobacterial strains in various one-to-one combinations. A hierarchical clustering tree of 11,533 genes was built from 198 samples, and 47 distinct modules were revealed. We identified a module, consisting of 226 genes, which represented the common response of host macrophages to different mycobacterial infections that showed significant enrichment in innate immune stimulation, bacterial pattern recognition, and leukocyte chemotaxis. Moreover, by network analysis applied to the 74 genes with the best correlation with mycobacteria infection, we identified the top 10 hub-connecting genes: NAMPT, IRAK2, SOCS3, PTGS2, CCL20, IL1B, ZC3H12A, ABTB2, GFPT2, and ELOVL7. Interestingly, apart from the well-known Toll-like receptor and inflammation-associated genes, other genes may serve as novel TB diagnosis markers and potential therapeutic targets.

Highlights

Tuberculosis (TB) is still a global threat and one of the leading infectious diseases according to the World Health Organisation, causing 1.5 million deaths and 10 million new cases in 2018 [1]
By applying the weighted gene co-expression network analysis (WGCNA) methodology to 198 transcriptome profiles, we identified a defined set of core genes consisting of 226 genes that were commonly regulated during host macrophage cell infection with the majority of mycobacterial species
We compared the transcriptomic responses of different types of macrophages infected with seven different mycobacterial strains: four that are pathogenic and survive intracellularly and three that are non-pathogenic surrogates

Summary

Introduction

Tuberculosis (TB) is still a global threat and one of the leading infectious diseases according to the World Health Organisation, causing 1.5 million deaths and 10 million new cases in 2018 [1]. The granuloma prevents dissemination of the mycobacteria but provides a local environment for the infection of immune cells [3]. The formation of granulomas may suppress host immune responses, as macrophages and dendritic cells in the granulomas are unable to present antigen to lymphocytes [4]. The impact of Mtb strain variation on human disease is not well established, and Mtb genomic diversity remains to be unambiguously correlated to the intracellular/lung lesion phenotypic diversity [11]. Understanding this host–pathogen relationship is fundamental to the development of new transformative therapies to prevent TB

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Conclusion