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

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-gamma and interleukin-1 beta. 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. Modlin and colleagues examined the skin lesions of human leprosy patients using single-cell RNA sequencing coupled to cellular spatial mapping. Their analysis maps the architecture of granulomas in leprosy lesions from patients with leprosy with localized disease (tuberculoid leprosy, reversal reaction) to those with progressive infection (lepromatous leprosy).

Automated summary

The study identified a set of genes involved in antimicrobial responses that are differentially expressed in reversal reactions (RRs) lesions compared to lepromatous leprosy (L-lep) lesions, regulated by interferon-gamma and interleukin-1 beta. By integrating spatial coordinates of key cell types and antimicrobial gene expression, a map depicting the organized architecture of granulomas in RR and T-lep lesions was constructed, showing compositional and functional layers contributing to the antimicrobial response. Modlin and colleagues utilized single-cell RNA sequencing with cellular spatial mapping to examine the architecture of granulomas in leprosy lesions, providing insights from localized disease (tuberculoid leprosy, reversal reaction) to progressive infection (lepromatous leprosy).