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Safe gain-of-function research is necessary to identify new treatments for diseases like for tuberculosis — but the NIH has imposed unfounded stops.

Mycobacterium tuberculosis isolates have a complex phylogenetic structure and vary in clinical phenotypes. Combining high-throughput RNA-seq and global population genomics reveals gene expression as an axis of variation in host interaction. Underscoring this, variants in a regulator of a key virulence pathway are associated with increased transmission and drug resistance.

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The Midwinter Conference of Immunologists was founded in 1961 by a small group of Immunologists, among them Drs. Dan Campbell and Ray Owen. The goal of the Midwinter Conference is to provide a forum w...

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University of Pittsburgh Faculty Position Center for Vaccine Research   The University of Pittsburgh School of Medicine’s Center for Vaccine Resear...

Granulomas are classic manifestations of tuberculosis pathogenesis. They result from an ensemble of immune responses to Mycobacterium tuberculosis infection, but the identities, arrangement, cellular interactions, and regulation of the cells that comprise them have thus far been incompletely understood. To better understand the composition of granulomas, we conducted spatial and single-cell RNA sequencing of granulomas in biopsy specimens from patients with tuberculosis. We found that granulomas consist of concentric transcriptional laminae surrounding areas of central necrosis. We identified distinct populations of granuloma-associated stromal cells, fibroblasts, lymphocytes, mast cells, dendritic cells, neutrophils, and macrophages. Furthermore, gene expression among these cell populations differed by location within granulomas. We used inferential analysis to predict dominant granuloma cell-cell interactions, the activity of major signaling pathways, and transcription factor activities. Using spatial deconvolution, we mapped a conserved pattern of cellular organization dominated by macrophages rich in SPP1/osteopontin expression. Trajectory analysis of macrophage subtypes mapped their differentiation and supported the importance of SPP1 to granuloma macrophage polarization. Using the Mycobacterium marinum-zebrafish model, we found that mycobacterial infection induces spp1 expression in macrophages and that spp1 ablation results in granuloma formation defects and reduced survival in adult animals. Cumulatively, we have identified a dominant macrophage granuloma population as well as its central regulatory gene in human samples and confirmed the importance of spp1 to granuloma biology in vivo.

The Midwinter Conference of Immunologists was founded in 1961 by a small group of Immunologists, among them Drs. Dan Campbell and Ray Owen. The goal of the Midwinter Conference is to provide a forum w...