The cellular architecture of the antimicrobial response network in human leprosy granulomas

Biology Biology
Genomics Genomics
Immunology Immunology
Infectious Disease Infectious Disease
Microbiology Microbiology
Alex K. Shalek Alex K. Shalek
Marc Wadsworth II Marc Wadsworth II
Travis Hughes Travis Hughes

Ma et al.▾ Ma, F., Hughes, T.K., Teles, R.M.B., Andrade, P.R., de Andrade Silva, B.J., Plazyo, O., Tsoi, L.C., Do, T., Wadsworth II, M.H., Oulee, A., Ochoa, M.T., Sarno, E.N., Iruela-Arispe, M.L., Klechevsky, E., Bryson, B., Shalek, A.K., Bloom, B.R., Gudjonsson, J.E., Pellegrini, M., Modlin, R.L.

Nature Immunology , Volume 22

June, 2021

Abstract

Granulomas are complex cellular structures composed predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated the single-cell phenotypes associated with antimicrobial responses in human leprosy granulomas by applying single-cell and spatial sequencing to leprosy biopsy specimens. We focused on reversal reactions (RRs), a dynamic process whereby some patients with disseminated lepromatous leprosy (L-lep) transition toward self-limiting tuberculoid leprosy (T-lep), mounting effective antimicrobial responses. We identified a set of genes encoding proteins involved in antimicrobial responses that are differentially expressed in RR versus L-lep lesions and regulated by interferon-γ and interleukin-1β. By integrating the spatial coordinates of the key cell types and antimicrobial gene expression in RR and T-lep lesions, we constructed a map revealing the organized architecture of granulomas depicting compositional and functional layers by which macrophages, T cells, keratinocytes and fibroblasts can each contribute to the antimicrobial response.