Insights into the host response to 'dormant' Mycobacterium tuberculosis utilizing 'Vitamin C-induced dormant Mtb'...

During a latent tuberculosis infection, there exists a dynamic equilibrium between the host and the 'dormant' bacterium wherein they mutually influence each other. An understanding of the host genetic response to 'dormant' tubercle bacilli during infection is necessary for developing targeted strategies against them.

A previously established infection model based on Vitamin C-induced Mtb dormancy was utilized in the present study to identify host responses to 'dormant' Mycobacterium tuberculosis (Mtb) infection by analyzing host transcriptomic data generated from Mtb-infected THP-1 cells. Principal Component Analysis and hierarchical cluster analysis of expression profiles in three cell infection models, namely, 'Active Mtb' (no treatment), 'Vitamin C Mtb' (Vitamin C treatment), and 'Vit C-induced Dormant Mtb' (Vitamin C and isoniazid treatment) infection models at 2-, 24- and 96-hours (h) post-Mtb-infection revealed a discrete clustering of host responses. Co-treatment of infected cells with Vitamin C and isoniazid enabled the capture of host transcriptome response to exclusively 'dormant' (isoniazid-tolerant) bacteria. Pleiotropic modulations in host pathways were observed at 96 h that were either unique to the 'Vit C-induced Dormant Mtb' model or common to the 'Vit C-induced Dormant Mtb' and 'Active Mtb' models of infection. Unique pathways identified in the 'Vit C-induced Dormant Mtb' model included (i) induction of antigen processing and presentation for promotion of host defense machinery, and (ii) decreased expression of genes in 'Fanconi anemia' and 'Homologous Recombination' pathways, indicating an impairment of DNA damage responses. Pathways that were commonly involved in 'Vit C-induced Dormant Mtb' and 'Active Mtb' models included (i) suppression of p53 signaling pathway resulting in a downregulation of pro-apoptotic factors and inhibition of cell apoptosis, (ii) upregulation of p57 leading to cell cycle arrest at the G0/G1 phase and subsequent suppression of DNA replication, and (iii) induction of IDO/TDO-mediated tryptophan catabolism.

Host transcriptome analysis of Mtb-infected cells has revealed that key pathways involved in immune surveillance, DNA repair, and apoptosis are altered, leading to an environment that favors infection. Despite these perturbations, the induction of antigen processing and presentation pathways in the 'Vit C-induced Dormant Mtb' model suggests an attempt by the host to counteract infection. These findings provide valuable insights into how the host cellular environment undergoes extensive modifications during Mtb infection and thereby creates conditions that support bacterial persistence.