Abstract
Although Mycobacterium tuberculosis (MTB) has existed for thousands of years, its immune escape mechanism remains obscure. Increasing evidence signifies that microRNAs (miRNAs) play pivotal roles in the progression of tuberculosis (TB). RNA sequencing was used to sequence miRNAs in human acute monocytic leukemia cells (THP-1) infected by the virulent MTB-1458 strain and the avirulent vaccine strain Mycobacterium bovis Bacillus Calmette-Guérin (BCG). Sets of differentially expressed miRNAs (DE-miRNAs) between MTB-1458/BCG-infected groups and uninfected groups were identified, among which 18 were differentially expressed only in the MTB-1458-infected THP-1 group. Then, 13 transcription factors (TFs) and 81 target genes of these 18 DE-miRNAs were matched. Gene Ontology classification as well as Kyoto Encyclopedia of Genes and Genomes pathway enrichment analysis showed that the candidate targets were predominantly involved in apoptotic-associated and interferon-γ-mediated signaling pathways. A TF-miRNA-mRNA interaction network was constructed to analyze the relationships among these 18 DE-miRNAs and their targets and TFs, as well as display the hub miRNAs, TFs, and target genes. Considering the degrees from network analysis and the reported functions, this study focused on the BHLHE40-miR-378d-BHLHE40 regulation axis and confirmed that BHLHE40 was a target of miR-378d. This cross-talk among DE-miRNAs, mRNAs, and TFs might be an important feature in TB, and the findings merited further study and provided new insights into immune defense and evasion underlying host-pathogen interactions.
Highlights
Considering the degrees from network analysis and reported functions, this study found that (i) MYB-miR-3184-5p-BMF/IRF1/PML had the highest degree of all transcription factors (TFs), miRNA, and mRNAs in the network. (ii) Three miRNA interactions, (IRF1-miR-3184-5p-IRF1, CEBPB-miR-3184-5p-CEBPB, and BHLHE40-miR-107/miR-378d-BHLHE40), presented the same targets and TFs, respectively, and the whole connection formed like a loop. (iii) Some targets, such as ARL8B, and TFs, such as MYB, IRF1, and CEBPB, participated in the TB
Strain H37Rv-infected macrophages, 36 genes related to immune response regulation, chemokine secretion, and leucocyte chemotaxis were upregulated, and 30 genes associated with amino acid biosynthetic and energy metabolism, connective tissue development, and extracellular matrix organization were downregulated, compared to avirulent straininfected macrophage [14]
Virulent M. bovis and Bacillus Calmette-Guérin (BCG) can lead to different immune responses associated with TB pathogenesis [2]
Summary
Tuberculosis (TB) is a zoonotic communicable disease caused by Mycobacterium tuberculosis complex (MTBC) and is still one of the deadliest diseases worldwide. The WHO has developed its TB termination strategy in 2014, but there is still a lack of efficient detection and treatment methods. This is attributed to the complex pathogenic mechanism of Mycobacterium tuberculosis (MTB). Mycobacterium bovis (M. bovis) Bacillus Calmette-Guérin (BCG) is the only existing TB vaccine that can induce different immune responses compared to the virulent strain [2].
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