Tuberculosis (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 different Mycobacterium tuberculosis strains and the host. In this project, we investigated the host immune response to different M. tuberculosis strains, 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-1beta in the infected cells was stronger in all virulent M. tuberculosis strains. 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-KB and STAT1. The differentially expressed ISGs in response to the isoniazid-resistant M. tuberculosis strain were associated with STAT1 signaling, while the expression of many cytokines, such IL-1beta, was associated with NF-KB signaling. Our data suggest that the isoniazid-resistant M. tuberculosis strain 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.
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