Differential Host Gene Signatures in Response toMycobacterium tuberculosisInfection

• DOI: 10.1101/2020.02.19.955203
• Publication Date: 2020-02-20T11:29:26Z
• Authors: Loubna Tazi; Ping Wang; Myriam Fornage
• Keywords: 0303 health sciences; 03 medical and health sciences; 3. Good health

ABSTRACTTuberculosis (TB) represents a global public health threat and is the leading cause of morbidity and mortality worldwide. Effective control of TB is complicated with the emergence of multidrug resistance. Yet, there is still a fundamental gap in understanding the complex and dynamic interactions between differentMycobacterium tuberculosisstrains and the host. In this project, we investigated the host immune response to differentM. tuberculosisstrains, including avirulent or virulent and rifampin-resistant or isoniazid-resistant strains in THP-1 cells. We identified major differences in the gene response profiles in response to infection with these strains. The expression of IDO1 and IL-1β in the infected cells was stronger in all virulentM. tuberculosisstrains. The most striking result was the overexpression of many interferon-stimulated genes (ISGs) in cells infected with the isoniazid-resistant strain, compared to the rifampin-drug resistant strain and the drug-sensitive strain. A transcription regulation analysis of the differentially expressed genes in infected THP-1 cells implicated two major transcription factors, NF-κB and STAT1. The differentially expressed ISGs in response to the isoniazid-resistantM. tuberculosisstrain were associated with STAT1 signaling, while the expression of many cytokines, such IL-1β, was associated with NF-κB signaling. Our data suggest that the isoniazid-resistantM. tuberculosisstrain preferentially activates STAT1 in response to cGAS-STING activation and induces a host immune response signature that is characteristic of isoniazid resistance. This study has a potential to provide important new insights into TB pathogenesis and to characterize host gene signatures specifically involved in isoniazid-resistant TB.