ABSTRACT: Humans are highly genetically diverse, and most are resistant to Mycobacterium tuberculosis. However, lung tissue from genetically resistant humans is not readily available to identify potential mechanisms of resistance. To address this, we model M. tuberculosis infection in Diversity Outbred mice. Like humans, Diversity Outbred mice also exhibit genetically determined susceptibility to M. tuberculosis infection: Progressors who succumb within 60 days of a low dose aerosol infection due to acute necrotizing granulomas, and Controllers who maintain asymptomatic infection for at least 60 days, and then develop chronic pulmonary TB with occasional necrosis and cavitation, over months to greater than 1 year. Here, we identified specific regions of granuloma-associated lymphoid tissue (GrALT) and B-cell gene expression pathways as key features of asymptomatic lung infection using cytokine, antibody, granuloma image, and gene expression datasets. Cytokines and anti-M. tuberculosis cell wall antibodies discriminated acute vs chronic pulmonary TB but not asymptomatic lung infection. To find unique features of asymptomatic lung infection, we trained a weakly supervised, deep-learning neural network on lung histology images. The neural network accurately produced an interpretable imaging biomarker: perivascular and bronchiolar lymphocytic cuffs, a type of GrALT. We expected CD4 T cell genes would be highly expressed in asymptomatic lung infection. However, the significantly different, highly expressed genes in lungs of asymptomatically infected Diversity Outbred mice corresponded to B-cell activation, proliferation, and antigen-receptor signaling, including Fcrl1, Cd79, Pax5, Cr2, and Ms4a1. Overall, our results suggest that genetically controlled B-cell responses are important for establishing asymptomatic M. tuberculosis lung infection.
