Lung organoids as a human system for Mycobacteria infection modeling and drug testing

Mycobacterial infections remain a global public health challenge. Each year, high rates of morbidity and mortality worldwide are a consequence of chronic respiratory infections due to Mycobacteria. According to the World Health Organization (WHO), in 2023, 10.8 million individuals fell ill with Mycobacterium tuberculosis (Mtb), resulting in an estimated 1.25 million deaths. This positions tuberculosis (TB) as the leading cause of death from a single pathogen worldwide after the coronavirus disease (COVID-19) pandemic. On the other hand, the cases of people affected by nontuberculous mycobacteria (NTM) have risen globally, but the precise incidence and prevalence of both pulmonary and extrapulmonary disease remain unknown. In Europe, nontuberculous mycobacterial pulmonary diseases affect between 0.2 and 2.9 per 100 000 individuals, mainly patients with cystic fibrosis (CF) and non-CF bronchiectasis. The diagnosis and treatment of mycobacterial infections are challenging and complex, frequently requiring long-duration treatments with several antibiotics, which in most cases leads to poor patient outcomes. As the role of immune cells has been extensively assessed, in this Review, we summarize the current knowledge about the contribution of epithelial cells in the early steps of Mycobacteria infections. Additionally, we describe how human lung organoid technology provides new tools to better understand host-Mycobacteria interactions in the airways and test new therapeutic targets.