Biology subjects

Bloom, B. R.

Publications and source records attributed to Bloom, B. R..

4 recordsLinked to original sources

bioRxiv2025

Spatial profiling reveals TREM2+ macrophages as central to Mycobacterium tuberculosis pathogenesis in human pulmonary tuberculosis

Pulmonary tuberculosis (TB) exhibits marked spatial heterogeneity, with alveolar pneumonia and organized granulomas frequently coexisting within the same lung. While granulomas have long dominated conceptual models of TB pathogenesis, the immune programs operating within alveolar TB pneumonia in humans remain incompletely defined. Here, we integrate spatial transcriptomics, single-cell RNA sequencing, high-resolution imaging, and functional assays of human lung biopsies to directly compare alveolar pneumonia with adjacent granulomas from the same individuals. We demonstrate that alveolar TB pneumonia is enriched for TREM2 lipid-laden macrophages characterized by lipid metabolic reprogramming, sparse T-cell infiltration, attenuated antimicrobial gene expression, and abundant Mycobacterium tuberculosis (Mtb) transcripts and antigens. In contrast, neighboring granulomas exhibit organized lymphoid architecture and robust antimicrobial programs. Mechanistically, the mycobacterial virulence lipid phthiocerol dimycocerosate (PDIM) and free mycolic acids induce TREM2 expression and activate TREM2-DAP12 signaling, promoting lipid droplet accumulation, suppressing autophagy, and enhancing intracellular Mtb survival in human macrophages. This immunometabolic state is pharmacologically reversible: 1,25-dihydroxyvitamin D downregulates TREM2, restores autophagy, reduces lipid droplets, and limits bacterial viability. Together, these findings define a spatially localized TREM2 foamy macrophage program within alveolar pneumonia that contrasts sharply with adjacent granulomatous immunity, establishing an niche permissive for bacillary persistence and potentially transmission, as well as identifying a tractable host pathway in human TB pathogenesis.

immunology↗

bioRxiv2020

Single Cell and Spatial Transcriptomics Defines the Cellular Architecture of the Antimicrobial Response Network in Human Leprosy Granulomas

Granulomas are complex cellular structures comprised predominantly of macrophages and lymphocytes that function to contain and kill invading pathogens. Here, we investigated 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 (RR), a dynamic process in which some patients with disseminated lepromatous leprosy (L-lep) transition towards 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 IFN-{gamma} and IL-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 contribute to the antimicrobial response.

immunology↗

bioRxiv2018

Dual RNAseq of human leprosy lesions identifies bacterial determinants linked to host immune response

To understand how the interaction between an intracellular bacterium and the host immune system contributes to outcome at the site of infection, we studied leprosy, a disease that forms a clinical spectrum, in which progressive infection by the intracellular bacterium Mycobacterium leprae is characterized by the production of type | IFNs and antibody production. We performed dual RNAseq on patient lesions, identifying a continuum of distinct bacterial states that are linked to the host immune response. The bacterial burden, represented by the fraction of bacterial transcripts, correlates with a host type | IFN gene signature, known to inhibit antimicrobial responses. Second, the bacterial transcriptional activity, defined by the bacterial mRNA/rRNA ratio, links bacterial heat shock proteins with the BAFF-BCMA host antibody response pathway. Our findings provide a platform for interrogation of host and pathogen transcriptomes at the site of infection, allowing insight into mechanisms of inflammation in human disease.

microbiology↗

bioRxiv2017

A Macrophage Response To Mycobacterium leprae Phenolic Glycolipid Initiates Nerve Damage In Leprosy

Mycobacterium leprae causes leprosy, and is unique among mycobacterial diseases in producing peripheral neuropathy. This debilitating morbidity is attributed to axon demyelination resulting from direct interactions of the M. leprae-specific phenolic glycolipid 1 (PGL-1) with myelinating glia, and their subsequent infection. Here, we use transparent zebrafish larvae to visualize the earliest events of M. leprae-induced nerve damage. We find that demyelination and axonal damage are not directly initiated by M. leprae but by infected macrophages that patrol axons; demyelination occurs in areas of intimate contact. PGL-1 confers this neurotoxic response on macrophages: macrophages infected with M. marinum expressing PGL-1 also damage axons. PGL-1 induces nitric oxide synthase in infected macrophages, and the resultant increase in reactive nitrogen species damages axons by injuring their mitochondria and inducing demyelination. Our findings implicate the response of innate macrophages to M. leprae PGL-1 in initiating nerve damage in leprosy.

microbiology↗