Biology subjects

Gideon, H. P.

Publications and source records attributed to Gideon, H. P..

6 recordsLinked to original sources

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↗

bioRxiv2023

CD4+ T cells are homeostatic regulators during Mtb reinfection

Immunological priming - either in the context of prior infection or vaccination - elicits protective responses against subsequent Mycobacterium tuberculosis (Mtb) infection. However, the changes that occur in the lung cellular milieu post-primary Mtb infection and their contributions to protection upon reinfection remain poorly understood. Here, using clinical and microbiological endpoints in a non-human primate reinfection model, we demonstrate that prior Mtb infection elicits a long-lasting protective response against subsequent Mtb exposure and that the depletion of CD4+ T cells prior to Mtb rechallenge significantly abrogates this protection. Leveraging microbiologic, PET-CT, flow cytometric, and single-cell RNA-seq data from primary infection, reinfection, and reinfection-CD4+ T cell depleted granulomas, we identify differential cellular and microbial features of control. The data collectively demonstrate that the presence of CD4+ T cells in the setting of reinfection results in a reduced inflammatory lung milieu characterized by reprogrammed CD8+ T cell activity, reduced neutrophilia, and blunted type-1 immune signaling among myeloid cells, mitigating Mtb disease severity. These results open avenues for developing vaccines and therapeutics that not only target CD4+ and CD8+ T cells, but also modulate innate immune cells to limit Mtb disease.

immunology↗

bioRxiv2021

Robust IgM responses following vaccination are associated with prevention of Mycobacterium tuberculosis infection in macaques

Development of an effective tuberculosis (TB) vaccine has suffered from an incomplete understanding of the correlates of protection against Mycobacterium tuberculosis (Mtb). However, recent work has shown that compared to standard intradermal Bacille Calmette-Guerin (BCG) vaccination, intravenous (IV) BCG vaccination provides nearly complete protection against TB in rhesus macaques. While studies have focused on cellular immunity in this setting, the antibody response elicited by IV BCG vaccination remains incompletely defined. Using an agnostic antibody profiling approach, here we show that IV BCG drives superior antibody responses in the plasma and the bronchoalveolar lavage fluid (BAL). While IV BCG immunization resulted in the expansion of a robust IgM, IgG, IgA, Fc-receptor binding antibodies, and antibody effector functions in the BAL, IgM titers were among the strongest markers of reduced bacterial burden in the plasma and BAL of BCG immunized animals. Moreover, IgM immunity was also enriched among animals receiving protective vaccination with an attenuated Mtb strain. Finally, a LAM-specific IgM monoclonal antibody reduced Mtb survival in vitro. Collectively, these data highlight the potential importance of IgM responses as a marker and as a functional mediator of protection against TB.

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↗

bioRxiv2019

A computational model tracks whole-lung Mycobacterium tuberculosis infection and predicts factors that inhibit dissemination

Mycobacterium tuberculosis (Mtb), the causative infectious agent of tuberculosis (TB), kills more individuals per year than any other infectious agent. Granulomas, the hallmark of Mtb infection, are complex structures that form in lungs, composed of immune cells surrounding bacteria, infected cells, and a caseous necrotic core. While granulomas serve to physically contain and immunologically restrain bacteria growth, some granulomas are unable to control Mtb growth, leading to bacteria and infected cells leaving the granuloma and disseminating, either resulting in additional granuloma formation (local or non-local) or spread to airways or lymph nodes. Dissemination is associated with development of active TB. It is challenging to experimentally address specific mechanisms driving dissemination from TB lung granulomas. Herein, we develop a novel hybrid multi-scale computational model, MultiGran, that tracks Mtb infection within multiple granulomas in an entire lung. MultiGran follows cells, cytokines, and bacterial populations within each lung granuloma throughout the course of infection and is calibrated to multiple non-human primate (NHP) cellular, granuloma, and whole-lung datasets. We show that MultiGran can recapitulate patterns of in vivo local and non-local dissemination, predict likelihood of dissemination, and predict a crucial role for multifunctional CD8+ T cells and macrophage dynamics for preventing dissemination.\n\nAuthor SummaryTuberculosis (TB) is caused by infection with Mycobacterium tuberculosis (Mtb) and kills 3 people per minute worldwide. Granulomas, spherical structures composed of immune cells surrounding bacteria, are the hallmark of Mtb infection and sometimes fail to contain the bacteria and disseminate, leading to further granuloma growth within the lung environment. To date, the mechanisms that determine granuloma dissemination events have not been characterized. We present a computational multi-scale model of granuloma formation and dissemination within primate lungs. Our computational model is calibrated to multiple experimental datasets across the cellular, granuloma, and whole-lung scales of non-human primates. We match to both individual granuloma and granuloma-population datasets, predict likelihood of dissemination events, and predict a critical role for multifunctional CD8+ T cells and macrophage-bacteria interactions to prevent infection dissemination.

immunology↗

bioRxiv2018

Concurrent infection with Mycobacterium tuberculosis confers robust protection against secondary infection in macaques

Introduction Introduction Main text Methods References For many pathogens, including most targets of effective vaccines, infection elicits an immune response that confers significant protection against reinfection. There has been significant debate as to whether natural M. tuberculosis (Mtb) infection confers protection against reinfection. Here we experimentally assessed the protection conferred by concurrent Mtb infection in macaques, a robust experimental model of human tuberculosis (TB), using a combination of serial imaging and Mtb challenge strains differentiated by DNA identifiers. Strikingly, ongoing Mtb infection provided complete protection against establishment of secondary infection in over half of the macaques and allowed near sterilizing bacterial control for those in which a secondary infection was established. By contrast, boosted B ...

microbiology↗