Susanna Brighenti

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.