Type I IFN impedes early bacterial control in TB-resistant and -susceptible mice and activates neutrophils to restrict lung macrophage-T cell interactions [RNA-seq]

Only a minority of M. tuberculosis-infected individuals progress to tuberculosis, however the early immune mechanisms determining outcome are unclear. C3HeB/FeJ mice display high, partially type I IFN-dependent, tuberculosis susceptibility, compared to relatively tuberculosis-resistant C57BL/6 mice. Using bulk and scRNA-seq over the first weeks of M. tuberculosis infection, we describe an unexpected, higher early pulmonary type I IFN response in C57BL/6 than C3HeB/FeJ mice, accompanying more pronounced early monocyte-derived macrophage (MDM) accumulation and lesion formation. The C57BL/6 type I IFN response plateaued with formation of extensive CD4+ T cell-MDM interactions in lesions, accompanied by high expression of T cell-attractant chemokines by MDMs. Conversely, delayed immune initiation in C3HeB/FeJ mice preceded rapid domination of lesions by inflammatory neutrophils, depletion of which enhanced CD4+ T cell-MDM interactions. Type I IFNs unexpectedly promoted early bacterial replication and limited lesion CD4+ T cell numbers in both C57BL/6 and C3HeB/FeJ mice, while pronounced later effects on inflammatory neutrophil activation were observed in C3HeB/FeJ, suggestive of context-dependent effects of type I IFNs during M. tuberculosis infection. Overall design: RNA-seq profiling of bronchoalveolar lavage and lung from C57BL/6 and C3HeB/FeJ mice, uninfected and infected with HN878 Mycobacterium tuberculosis strain at day 14 and day 21 of infection. RNA-seq profiling of lung from C3HeB/FeJ mice, uninfected and infected with HN878 Mycobacterium tuberculosis strain at day 26 and treated with either isotype control or anti-IFNAR antibody