Isogenic Human Pluripotent Stem Cell-derived Macrophages to Study Genetic Variants Associated with Tuberculosis
Tuberculosis (TB) remains a major global health concern, with alveolar macrophages (AMs) playing a critical role as the first line of defense against Mycobacterium tuberculosis (Mtb). Early Mtb clearance is strongly linked to robust innate immune responses in AMs, underscoring the need for a reliable human AM platform for TB research. Interestingly, only 5% of Mtb-infected individuals develop active TB, suggesting a significant influence of host genetics. Recent studies identified TYK2 P1104A homozygosity as a key genetic variant associated with TB susceptibility. While previous work links this variant to impaired IL-23-dependent IFN-γ immunity in CD4+ T cells, its effects on AMs remain largely unexplored.
Leveraging human pluripotent stem cell (hPSC)-derived AMs and organoid models, this study will investigate the impact of TYK2 P1104A homozygosity in Mtb infection. Aim 1 focuses on assessing the infection responses of isogenic TYK2 P1104A and TYK2 P1104P hPSC-derived AMs, using CRISPR-edited lines. Aim 2 will explore molecular mechanisms via RNA sequencing of WT, TYK2-/-, and variant AMs under Mtb infection.
This research aims to create a robust hPSC-derived AM platform for studying genetic impacts on TB, offering a valuable tool for the TB research community and advancing understanding of host-pathogen interactions in Mtb infection.