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Multidrug-resistant tuberculosis (MDR-TB) is a serious threat to global elimination of TB and a difficult challenge in treatment and management of disease. This 4-year project aims to explore how immune checkpoint molecules are modulated in MDR-TB patients depending on clinical disease severity and bacterial strain virulence. Our original findings from TB patients show that antimicrobial macrophage and T cell responses are severely impaired, while myeloid-derived suppressor cells and regulatory T cells expand in the TB lesions. To advance our understanding of immunoregulation in MDR-TB compared to drug-susceptible TB, we will examine stimulatory and inhibitory checkpoint molecules in a well-defined patient cohort in Addis Ababa, Ethiopia. We will model disease progression and quantify disease severity at enrolment and after chemotherapy using a composite clinical TB score and chest X-ray grading. Drug susceptibility testing will determine the level of resistance and genotyping of patient´s strains will signify bacterial virulence. Longitudinal assessment of checkpoint molecules in peripheral blood and induced sputum samples involves deep profiling with RNA-sequencing, multicolor flow cytometry and in vitro suppression assays. We will also exploit in situ imaging of resected lung tissue from MDR-TB patients. This collaborative project offers untapped opportunities for translating new advances on checkpoint molecules in chronic infections into clinical applications for MDR-TB.

Immune enhancing therapies represent an underexplored opportunity to meet the challenges of treatment failure in tuberculosis (TB). My group has generated a platform for epigenetic modulation in chronic TB using histone deacetylase (HDAC) inhibitors that can alter immune cell differentiation and function. We have shown that phenylbutyrate (PBA) can restore Mycobacterium tuberculosis (Mtb)-induced impairment of antimicrobial responses in macrophages and enhance clinical recovery of pulmonary TB. Now, we advance our concept and recently discovered several HDAC inhibitors that can inhibit intracellular Mtb more effectively than PBA. Next, we plan to exploit computer-aided methods including structure- and artificial intelligence-based design of potent HDAC modulators that can control the level of gene inhibition or activation in immune cells more precisely. This work will focus on HDAC inhibition to restore antimicrobial genes, while HDAC activation repress excess activity of immunosuppressive genes. Our panel of de novo HDAC modulators will be explored using a bioassay for high-content imaging and methods for cell-specific transcriptional regulation. The effects of selected compounds on the function of innate and adaptive immune cells and stromal cells will be evaluated in relevant in vitro and in vivo infection models. This project will promote personalized medicine in TB based on endotype-specific therapies for different groups of TB patients including multidrug-resistant TB.