The histopathological hallmark of tuberculosis (TB) diseases is the formation of granulomas at the site of infection. Granulomas are highly diverse in their histopathologic appearance and their ability to restrict the infection. Even in the same infected host, while some granulomas successfully restrict the infection, others permit pathogen growth and cause organ damage and disease transmission. However, we know little about granuloma cellular structures, due to scarcity of clinical samples and lack of adequate technologies. Conventional immunohistology is unable to resolve the complex cellular interactions and lesion heterogeneity.
To untangle the complexity of TB granulomas, we have established a long-term research program focusing on understanding of cellular response to Mycobacterium tuberculosis in individual granulomas in human tissues using single-cell spatial biology techniques. By employing a high-plex imaging system, we spatially mapped the immune landscape of lung tissue sections from TB patients. Computational analyses identified multiple spatial microenvironments and granuloma types, which were present across all patients. The proportion and spatial organization of major leukocyte populations in each microenvironment and lesion type were highly heterogeneous. Our granuloma level analysis identified that different lesion types were associated with distinct effector T cell populations, highlighting diverse immunological niches that are present in the lung tissues of TB patients.
Our findings reveal that each granuloma type represents a distinct form of cellular response in the lungs of TB patients. These results highlight the complexity in the architecture of TB granulomas and suggest that resolving the lesion heterogeneity may assist in the understanding of TB pathogenesis and development of new diagnostics and therapies.