Abstract
BackgroundWith the global emergence of multi-drug resistant strains of Mycobacterium tuberculosis, new strategies to treat tuberculosis are urgently needed such as therapeutics targeting potential human host factors.ResultsHere we performed a statistical meta-analysis of human gene expression in response to both latent and active pulmonary tuberculosis infections from nine published datasets. We found 1655 genes that were significantly differentially expressed during active tuberculosis infection. In contrast, no gene was significant for latent tuberculosis. Pathway enrichment analysis identified 90 significant canonical human pathways, including several pathways more commonly related to non-infectious diseases such as the LRRK2 pathway in Parkinson’s disease, and PD-1/PD-L1 signaling pathway important for new immuno-oncology therapies. The analysis of human genome-wide association studies datasets revealed tuberculosis-associated genetic variants proximal to several genes in major histocompatibility complex for antigen presentation. We propose several new targets and drug-repurposing opportunities including intravenous immunoglobulin, ion-channel blockers and cancer immuno-therapeutics for development as combination therapeutics with anti-mycobacterial agents.ConclusionsOur meta-analysis provides novel insights into host genes and pathways important for tuberculosis and brings forth potential drug repurposing opportunities for host-directed therapies.
Highlights
With the global emergence of multi-drug resistant strains of Mycobacterium tuberculosis, new strategies to treat tuberculosis are urgently needed such as therapeutics targeting potential human host factors
Gene expression omnibus (GEO) datasets were filtered based on the following criteria: 1) the gene expression profile was exclusively derived from human cells of tuberculosis patients and probed using a humanbased genome array platform; 2) there was at least one control group and patient group in the dataset, with the control group consisting of only healthy subjects, and the patient group consisting of patients only infected by Mycobacterium tuberculosis (Mtb) without other diseases such as HIV; 3) each patient and control group had at least three samples
Statistical meta-analysis for differentially expressed genes during pulmonary TB (PTB) We employed an iterative process of database querying, filtering and computational analyses for all datasets (Fig. 1)
Summary
With the global emergence of multi-drug resistant strains of Mycobacterium tuberculosis, new strategies to treat tuberculosis are urgently needed such as therapeutics targeting potential human host factors. The causative agent of tuberculosis (TB), the bacterium Mycobacterium tuberculosis (Mtb), infects about one third of the world’s population. The prolonged duration of Mtb infection as well as the alarming emergence of multi-drug resistant strains makes the development of new and effective antitubercular therapeutics a global health priority [2, 3]. Despite a high efficacy at the onset of administration, the confounded intervention and prolonged treatment period present challenges for patient compliance and potentially foster the emergence of multidrug-resistance of Mtb. it is imperative to develop more effective therapeutic approaches such as host-directed therapies. Targeting the host has its advantages in potentially being less susceptible to the drug resistance problem, with greater opportunities for repositioning known drugs to new indications
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