Abstract
Mycobacterium tuberculosis (Mtb), the etiological agent of tuberculosis, kills 1.5 to 1.7 million people every year. Macrophages are Mtb’s main host cells and their inflammatory response is an essential component of the host defense against Mtb. However, Mtb is able to circumvent the macrophages’ defenses by triggering an inappropriate inflammatory response. The ability of Mtb to hinder phagolysosome maturation and acidification, and to escape the phagosome into the cytosol, is closely linked to its virulence. The modulation of the host inflammatory response relies on Mtb virulence factors, but remains poorly studied. Understanding macrophage interactions with Mtb is crucial to develop strategies to control tuberculosis. The present study aims to determine the inflammatory response transcriptome and miRNome of human macrophages infected with the virulent H37Rv Mtb strain, to identify macrophage genetic networks specifically modulated by Mtb virulence. Using human macrophages infected with two different live strains of mycobacteria (live or heat-inactivated Mtb H37Rv and M. marinum), we quantified and analyzed 184 inflammatory mRNAs and 765 micro(mi)RNAs. Transcripts and miRNAs differently modulated by H37Rv in comparison with the two other conditions were analyzed using in silico approaches. We identified 30 host inflammatory response genes and 37 miRNAs specific for H37Rv virulence, and highlight evidence suggesting that Mtb intracellular-linked virulence depends on the inhibition of IL-1β-dependent pro-inflammatory response, the repression of apoptosis and the delay of the recruitment and activation of adaptive immune cells. Our findings provide new potential targets for the development of macrophage-based therapeutic strategies against TB.
Highlights
Tuberculosis is one of the top 10 causes of death [1] and, right after COVID-19 [2], is the world’s deadliest infection caused by a single infectious agent: Mycobacterium tuberculosis (Mtb) [3]
Infection With Virulent Mycobacterium tuberculosis Leads to a Specific Deregulation of Macrophage Host Response-Related Genes
To compare the host inflammatory response induced by macrophages upon infection with a virulent or non-virulent mycobacterial strain, we used phorbol 12-myristate 13-acetate (PMA)-differentiated THP-1 cells as a human macrophage model and infected them with either the virulent H37Rv strain, or the occasional human pathogen M. marinum and the avirulent heat killed Mtb (HKMT)
Summary
Tuberculosis is one of the top 10 causes of death [1] and, right after COVID-19 [2], is the world’s deadliest infection caused by a single infectious agent: Mycobacterium tuberculosis (Mtb) [3]. For the remaining 30%, the immune system is only able to contain, but not to eradicate the bacteria [5]. These people develop LTBI that can persist for their entire lifetime [6]. Approximately 5 to 10% of LTBIs evolve into ATBIs when the immune system is no longer able to constrain Mtb [5]. The ability of Mtb to persist for so long in the host is due to its ability to hijack host defense mechanisms by converting macrophages into a permissive cellular niche [7, 8]
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