Biology subjects

Mattila, J. T.

Publications and source records attributed to Mattila, J. T..

5 recordsLinked to original sources

bioRxiv2026

A tissue time machine to forward-predict single-timepoint data applied to tuberculosis granulomas

Recent advances have improved understanding of infection; however many detailed datasets are based on single timepoints post-infection and cannot generate longitudinal insights needed to predict infection outcomes. For example, pulmonary infection with Mycobacterium tuberculosis (Mtb) initiates a complex system of immune and bacterial interactions that leads to granuloma formation, yet single snapshots in time need elaboration long-term. We develop a new approach, the tissue time machine, applied to predict outcomes of non-human primate granulomas from initiation to endpoint using single timepoint tissue datasets including high-dimensional spatial features. This involves identifying granuloma digital partners, simulations most closely resembling real granulomas from a virtual library of over 50,000. By analyzing digital partners, we predict infection outcomes of 22/28 granulomas, and that Mtb-specific, IFN-{gamma}-producing T cell recruitment rates influence uncertainty for the 6/28. This method is applicable to any system that allows for mechanistic predictions over time using heterogeneous, incomplete, and high-dimensional datasets.

systems biology↗

bioRxiv2024

Systematic deconstruction of myeloid cell signaling in tuberculosis granulomas reveals IFN-γ, TGF-β, and time are associated with conserved myeloid diversity

Myeloid cells are key constituents of tuberculosis (TB) granulomas. They are the major target of pathogen infection and play central roles in pathogen control, antigen presentation, adaptive immune cell recruitment, and tissue homeostasis. However, the role of myeloid cells in TB has been studied largely through ex vivo experimental approaches that do not capture the dynamic phenotypic and functional states of these cells in the disease environment. To address this gap, we used a combination of bulk and single-cell RNA sequencing (scRNA-seq), computational modeling, and imaging to define the molecular diversity of myeloid cells in granulomas from Mycobacterium tuberculosis-infected nonhuman primates. We observed an increase in myeloid cell diversity in granulomas compared to non-granulomatous lung tissue. This increased transcriptional diversity is defined by a continuum of macrophage differentiation-, metabolism-, and cytokine-regulated transcriptional programs. In vitro experimental modeling of monocyte-to-macrophage differentiation in defined cytokine environments implicates differentiation time, IFN-{gamma}, and TGF-{beta} signaling as candidate drivers of macrophage diversity. We next examined the conservation of these populations across additional experimental models of Mtb infection and found myeloid cell subsets enriched across the TB disease spectrum. To further contextualize these responses, we constructed an atlas of myeloid cells across diverse human lung pathologies, finding myeloid cell subpopulations that were similar between TB and other lung pathologies as well as subpopulations that distinguish between diseases. Collectively, this study identifies points of integration between myeloid cell biology in TB granulomas and other lung diseases that can be used for defining the signals that instruct myeloid cell behavior in TB and other diseases, as well as advance myeloid cell-targeted therapies.

immunology↗

bioRxiv2022

Type I IFN signaling mediates NET release to promote Mycobacterium tuberculosis replication and granuloma caseation

Neutrophils are the most abundant cell type in airways of tuberculosis patients. Recent investigations reported induction of neutrophil extracellular traps (NETs) during Mycobacterium tuberculosis (Mtb) infection, however, the molecular regulation and impact of NETosis on Mtb pathogenesis is unknown. We find that in response to Mtb infection in neutrophils, PAD4 citrullinates histones to decondense chromatin that gets packaged into vesicles for release as NETs in a manner that can maintain neutrophil viability and promote Mtb replication. Type I interferon, which has been associated with NETosis in numerous contexts but without a known mechanism, promotes formation of chromatin-containing vesicles and NET release. Analysis of nonhuman primate granulomas supports a model where neutrophils are exposed to type I interferon from macrophages as they migrate into the granuloma, where they release NETs that contribute to necrosis and caseation. Our data reveals NETosis as a promising target to inhibit Mtb replication and granuloma caseation.

microbiology↗

bioRxiv2022

T cell transcription factor expression evolves as adaptive immunity matures in granulomas from Mycobacterium tuberculosis-infected cynomolgus macaques

Mycobacterium tuberculosis (Mtb), the causative agent of tuberculosis (TB), is a global health concern, yearly resulting in 10 million new cases of active TB. Immunologic investigation of lung granulomas is essential for understanding host control of bacterial replication. We identified and compared the pathological, cellular, and functional differences in granulomas at 4, 12, and 20 weeks post-infection in Chinese cynomolgus macaques. Original granulomas differed in transcription factor expression within adaptive lymphocytes with those at 12 weeks showing higher frequencies of CD8+T-bet+ T cells, while increases in CD4+T-bet+ T cells were observed at 20 weeks post-infection. The appearance of T-bet+ adaptive T cells at 12 and 20 weeks was coincident with a reduction in bacterial burden, suggesting their critical role in Mtb control. This study highlights the evolution of T cell responses within lung granulomas, suggesting that vaccines promoting the development and migration of T-bet+ T cells would enhance mycobacterial control.

immunology↗

bioRxiv2020

Single-cell profiling of tuberculosis lung granulomas reveals functional lymphocyte signatures of bacterial control

Mycobacterium tuberculosis lung infection results in a complex multicellular structure, the granuloma. In some granulomas, immune activity promotes bacterial clearance; in others, bacteria persist and grow. We identified correlates of bacterial control in cynomolgus macaque lung granulomas by co-registering longitudinal PET-CT imaging, single-cell RNA-sequencing, and measures of bacterial clearance. We find that bacterial persistence occurs in granulomas enriched for mast, endothelial, fibroblast and plasma cells, signaling amongst themselves via Type II immunity and wound healing pathways. In contrast, these interactions are largely absent in granulomas that drive bacterial control, which are often those that form later in the course of infection; these restrictive lesions are characterized by cellular ecosystems enriched for Type1-Type17, stem-like, and cytotoxic T cells engaged in pro-inflammatory signaling networks that involve diverse myeloid and non-immune cell populations. There is also a temporal aspect to bacterial control, in that granulomas that arise later in infection (in the context of an established immune response) share the functional characteristics of restrictive granulomas and are more capable of killing Mtb. Taken together, our results define the complex multicellular ecosystems underlying (lack of) granuloma resolution and highlight host immune targets that can be leveraged to develop new vaccine and therapeutic strategies for TB. One-Sentence SummaryBacterial control in TB lung granulomas correlates with distinct cellular immune microenvironments and time of formation after infection.

immunology↗