Human Airway Macrophage Immunity in Tuberculosis: Defining Early Determinants of Infection

About This Grant

ABSTRACT Clinical tuberculosis outcomes are shaped by host immune responses to Mycobacterium tuberculosis (Mtb), yet the specific innate immune phenotypes that drive Mtb control remain unclear. Human airway macrophages, the first pulmonary cells to encounter inhaled Mtb, differ in their innate ability to prevent infection. Large cohort studies have linked Type I Interferon (IFN) pathways to TB progression, but their role in airway macrophage mediated Mtb control is not well defined. Our preliminary data identify eight airway macrophage clusters from human bronchoalveolar lavage (BAL), with the IFN, interstitial, and chemokine clusters exhibiting the highest number of differentially expressed genes after Mycobacterium infection. Notably, a higher proportion of cells in the IFN cluster correlates with improved Mtb control. We hypothesize that early airway macrophage IFN cluster response is key in determining initial Mtb infection outcomes. In our Aim 1 will define the function of the airway macrophage IFN cluster in early Mtb infection. In Aim 2 will establish a TB close-contact cohort to examine the association between airway macrophage clusters and IGRA positivity following Mtb exposure. To achieve this, we are partnering with the Hennepin County Public Health Tuberculosis Clinic to recruit healthy volunteers and TB close contacts for BAL collection. Using scRNA-seq and ATAC-seq, we will characterize the transcriptomic and epigenetic landscape of airway macrophages. These experiments offer a powerful integrated approach to identify the cellular bases of Mtb infection and leverage these to identify why some people progress to establishment of Mtb infection, and some do not.