Tuberculosis susceptibility in genetically diverse mice reveals functional diversity of neutrophils

Abstract

AbstractTuberculosis (TB) is a heterogenous disease in humans with individuals exhibiting a wide range of susceptibility. This heterogeneity is not captured by standard laboratory mouse lines. We used a new collection of 19 wild-derived inbred mouse lines collected from diverse geographic sites to identify novel phenotypes duringMycobacterium tuberculosis(Mtb) infection. Wild-derived mice have heterogenous immune responses to infection that result in differential ability to control disease at an early timepoint. Correlation analysis with multiple parameters including sex, weight, and cellular immune responses in the lungs revealed that enhanced control of infection is associated with increased numbers of CD4 T cells, CD8 T cells and B cells. Surprisingly, we observed a negative correlation between IFN-γ production and control of infection. Although in most lines high neutrophils were associated with susceptibility, we identified a mouse line that harbors high neutrophils numbers yet controls infection. Using single-cell RNA sequencing, we identified a novel neutrophil signature associated with failure to control infection.SummaryInfection of a new collection of wild-derived mice withMtbreveals differences in the outcome of infection associated with unique immunological phenotypes.