Biology subjects

Bimber, B. N.

Publications and source records attributed to Bimber, B. N..

9 recordsLinked to original sources

bioRxiv2026

Early-Life Wildfire Smoke Exposure Is Associated with Long-Term Systemic Immune Remodeling and Epigenetic Reprogramming

Wildfire smoke is an escalating global public health threat exposing millions of people, including children, to hazardous air pollution each year. Although wildfire smoke toxicants have been linked to a range of adverse health outcomes, including immune dysregulation, the long-term consequences of real-world pediatric wildfire smoke exposure on health and development remain largely unknown. To investigate the persistent effects of early-life exposure on immune health, here we leveraged a cohort of rhesus macaques that experienced nine consecutive days of hazardous wildfire smoke exposure in infancy during the 2020 Oregon Labor Day wildfires. By integrating ex vivo immune stimulations, multiplex cytokine profiling, single-cell transcriptomics, and genome-wide DNA methylation profiling, we identified persistent immunological consequences across molecular and functional levels. We found that a single severe postnatal exposure, in the first three months of life, was associated with persistent change in the innate immune response, including reduced pro-inflammatory cytokine response to a bacterial endotoxin, with subtle but consistent transcriptional changes in myeloid cells, particularly among males. Wildfire smoke exposure was also associated with changes in proportion of B and T/NK cells, and within the T/NK cell compartment, exposed animals exhibited an expansion of cytotoxic cells. Consistent with this, CD8+ T cells displayed extensive transcriptional remodeling and shifted toward more differentiated effector states, with the greatest differentiation observed in animals exposed at the youngest ages. Genome-wide DNA methylation profiling identified smoke-associated methylation changes consistent with acceleration of epigenetic aging, as well as persistent epigenetic alterations impacting genes involved in oxidative stress responses, innate immunity, T cell differentiation, and hematopoiesis. These findings demonstrate that a single severe wildfire smoke exposure during a critical developmental window is associated with extensive immune and epigenetic remodeling that persist years after exposure, providing new insight into the long-term biological consequences of early-life wildfire smoke exposure.

immunology↗

bioRxiv2026

Lung Resident T Cells Across the Spectrum of TB Infection and Disease

Tuberculosis (TB) remains the leading infectious cause of death worldwide, yet immunological protection against Mycobacterium tuberculosis (Mtb) remain poorly understood. We performed integrated single-cell transcriptomics and functional T-cell cloning on paired bronchoalveolar lavage (BAL) and peripheral blood samples from those exposed to TB, using IGRA and PET-CT to study potentially protective responses across the spectrum of TB infection/disease. Recent Mtb exposure alone was sufficient to remodel the pulmonary T-cell compartment. Longitudinal follow-up demonstrated that all participants who progressed to active TB had baseline PET-CT abnormalities, showing that PET-CT scan can be used to find those at high risk of progression. Furthermore, those who were PET-positive, but did not progress to active TB provide a natural model for protection, and exhibited enrichment of pulmonary cytotoxic CD8-associated T cells, identifying a candidate protective immune program. TAR-seq identified a discrete population of clonally expanded Mtb-responsive T cells and enabled direct linkage of antigen-responsive TCRs to transcriptional state through T cell cloning. Functional T-cell cloning further established a framework connecting antigen specificity, TCR sequence, and pulmonary cell state. Together, these findings provide a comprehensive atlas of human pulmonary T-cell immunity across the spectrum of TB, identify pulmonary immune features associated with durable control of infection, and establish an integrated platform for defining protective T-cell responses to inform next-generation TB vaccine development.

immunology↗

bioRxiv2026

Census and genetic analysis of the United States marmoset population

The common marmoset (Callithrix jacchus), a small monkey native to Brazil, has been used as a biomedical model in the United States (US) since the 1950s, yet the origins, genomic diversity, and population structure of current colonies remain poorly defined. Through the NIH Marmoset Coordinating Center, we registered and sampled most US research marmosets ([~]2,300 living animals) and assembled pedigrees and historical records for >10,000 individuals. We present a resource of >800 whole-genome sequences, largely from US colonies. These data reveal an unexpected population structure that predates the establishment of research colonies. Indeed, this population structure mirrors variation found in marmosets across Brazil. Leveraging sequenced families, we generate the first pedigree-based recombination map and improved estimates of de novo mutation processes for this species. Our insights into genetic diversity, structure, and inbreeding will guide colony management, inform disease modelling and strengthen the marmosets standing as a biomedical model. Further, this work demonstrates how coordinated efforts across colonies can enable a self-sustaining "living laboratory", supporting data sharing and well-powered studies beyond the reach of single institutions.

genetics↗

bioRxiv2026

Distinct phases of immune system programming during ART-suppressed immunodeficiency virus infection

People living with HIV (PLWH) on suppressive antiretroviral therapy (ART) can face non-AIDS complications, partially driven by chronic immune activation. To define immune perturbations during ART-suppressed viral infection, we performed longitudinal single-cell transcriptomic and plasma proteomic analysis of rhesus macaques infected with SIVmac239M and ART-treated for 70 weeks. We identified broad, bi-phasic immune changes. Acute infection involves an interferon-driven signature, correlated with viral replication, that largely resolves with viral control. Cell-associated virus correlated with interferon-stimulated genes in most tissues; however, this was blunted in gut-associated lymph nodes, a feature that may contribute to reservoir persistence. Separate alterations manifest 54-66 weeks-post-infection, after 40 weeks of viral suppression, including broad TGF-{beta} and NF-kB signaling and discrete bursts of inflammatory monocytes, largely restricted to bone marrow. These data highlight the biphasic remodeling of long-term ART-suppressed HIV, identifying specific tissues and cell populations with dysregulation, with implications for the treatment of PLWH.

immunology↗

bioRxiv2026

Antigenic stimulation in conjunction with cytokine is required for mediating IL-17A production in human MAIT cells

Mucosal-associated invariant T (MAIT) cells are donor unrestricted T cells capable of both antigen-specific adaptive responses and cytokine driven innate-like functions. Although human MAIT cells uniformly express ROR{gamma}t and IL23R, they generally produce IFN-{gamma}, and only a small fraction produces IL-17. Recent studies show that combined TCR and cytokine stimulation can elicit functional heterogeneity in blood-derived MAIT cells. Here, we investigate the role of IL-23/IL-23R signaling in mediating the function and transcriptional profiles of lung MAIT cell clones. We demonstrate that BAL-derived lung MAIT cell clones exhibit distinct cytokine profiles and variable IL23R expression. Short-term IL-23 stimulation triggers clone-specific transcriptional programs and IL23R-dependent upregulation of type 17-associated genes. Prolonged conditioning of lung MAIT cell clones with TCR (5-OP-RU) and cytokine (IL-23) stimulation induces stable IL-17A production along with unique transcriptional changes. TCR + IL-23 conditioning alone upregulates clone-specific and shared cytoskeletal/structural gene programs, whereas subsequent PMA/Ionomycin stimulation further induces IL-12 family signaling and metabolic genes. Together, these findings demonstrate that IL23R expression and TCR signaling are required for IL-17A production, highlighting that these conditions may be met in tissue environments where MR1-specific antigens and proinflammatory cytokines coexist.

immunology↗

bioRxiv2025

BCG Vaccination at Birth Shapes the TCR Usage and Functional Profile of MR1T Cells at 9 Weeks of Age

Tuberculosis (TB) is the leading infectious disease killer worldwide and children suffer disproportionately. The ongoing burden of disease, despite widespread vaccination with BCG, highlights the need for novel vaccines. MR1-restricted T (MR1T) cells recognize small molecules, including microbial-derived molecules, presented by the monomorphic MHC class 1- related molecule (MR1). They have both "innate" effector capacity, allowing them to quickly respond to pathogens including Mycobacterium tuberculosis (Mtb), while also having adaptive features (effector memory cell surface phenotype and selective TCR usage). Feasibility of an MR1T cell-based vaccination remains unexplored and critical to this is whether or not MR1T cells possess the capacity for immunological memory. To begin to address this question, peripheral blood mononuclear cells (PBMC) were collected at 9-weeks of age from healthy term- infants in South Africa, who had either received BCG vaccination at birth (n=10) or who had BCG vaccination delayed (n=10). MR1/5-OP-RU tetramer positive cells were sorted using flow cytometry and single-cell RNA and TCR-seq was performed. Ex-vivo MR1T cells from vaccinated infants demonstrated increased expression of type I interferon response genes consistent with a cytokine mediated response to BCG vaccination. Using the TCR clustering algorithm TCRdist3, similar TCRs were grouped together, revealing a cluster significantly enriched in BCG-vaccinated infants. This cluster exhibited elevated expression of pro- inflammatory and cytotoxic genes, consistent with a recall response to prior vaccination and evidence of possible recognition of Mtb. This work provides the first step in addressing if MR1T cells demonstrate immunological memory, however, further work is needed to understand if these clonal expansions persist and possess the capacity for antigenic recall.

immunology↗

bioRxiv2025

Human Neonatal MR1T Cells Have Diverse TCR Usage, are Less Cytotoxic and are Unable to Respond to Many Common Childhood Pathogens.

Neonatal sepsis is a leading cause of childhood mortality. Understanding immune cell development can inform strategies to combat this. MR1-restricted T (MR1T) cells can be defined by their recognition of small molecules derived from microbes, self, and drug and drug-like molecules, presented by the MHC class 1-related molecule (MR1). In healthy adults, the majority of MR1T cells express an invariant -chain; TRAV1-2/TRAJ33/12/20 and are referred to as mucosal-associated invariant T (MAIT) cells. Neonatal MR1T cells isolated from cord blood (CB) demonstrate more diversity in MR1T TCR usage, with the majority of MR1-5-OP-RU-tetramer(+) cells being TRAV1-2(-). To better understand this diversity, we performed single-cell-RNA-seq/TCR-seq (scRNA-seq/scTCR-seq) on MR1-5-OP-RU-tetramer(+) cells from CB (n=5) and adult participants (n=5). CB-derived MR1T cells demonstrate a less cytotoxic/pro-inflammatory phenotype, and a more diverse TCR repertoire. A panel of CB and adult MAIT and TRAV1-2(-) MR1T cell clones were generated, and CB-derived clones were unable to recognize several common riboflavin-producing childhood pathogens (S. aureus, S. pneumoniae, M. tuberculosis). Biochemical and structural investigation of one CB MAIT TCR (CB964 A2; TRAV1-2/TRBV6-2) showed a reduction in binding affinity toward the canonical MR1-antigen, 5-OP-RU, compared to adult MAIT TCRs that correlated with differences in {beta}-chain contribution in the TCR-MR1 interface. Overall, this data shows that CB MAIT and TRAV1-2(-) MR1T cells, express a diverse TCR repertoire, a more restricted childhood pathogen recognition profile and diminished cytotoxic and pro-inflammatory capacity. Understanding this diversity, along with the functional ability of TRAV1-2(-) MR1T cells, could provide insight into increased neonatal susceptibility to infections.

immunology↗

bioRxiv2022

JBrowse 2: A modular genome browser with views of synteny and structural variation

We present JBrowse 2, a general-purpose genome annotation browser offering enhanced visualization of complex structural variation and evolutionary relationships. JBrowse 2 retains the core features of the open-source JavaScript genome browser JBrowse while adding new views for synteny, dotplots, breakpoints, gene fusions, and whole-genome overviews. The software readily allows users to share sessions, open multiple genomes or views, and navigate quickly between these views. It can be embedded in a web page, used as a standalone desktop application, or run from Jupyter notebooks or R sessions. Using a plugin framework, developers can create new data adapters, track types, and visualizations. These improvements are enabled by a ground-up redesign of the JBrowse architecture using modern web technology. We describe application functionality, use cases, performance benchmarks, and implementation notes for web administrators and developers.

bioinformatics↗

bioRxiv2020

In vitro and in vivo characterization of a recombinant rhesus cytomegalovirus containing a complete genome

Cytomegaloviruses (CMVs) are highly adapted to their host species resulting in strict species specificity. Hence, in vivo examination of all aspects of CMV biology employs animal models using host-specific CMVs. Infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a representative model for infection of humans with HCMV due to the close evolutionary relationships of both host and virus. However, the commonly used 68-1 strain of RhCMV has been passaged in fibroblasts for decades resulting in multiple genomic changes due to tissue culture adaptation that cause reduced viremia in RhCMV-naive animals and limited shedding compared to low passage isolates. Using sequence information from primary RhCMV isolates we constructed a full-length (FL) RhCMV by repairing all presumed mutations in the 68-1 bacterial artificial chromosome (BAC). Inoculation of adult, immunocompetent, RhCMV-naive RM with the reconstituted virus resulted in significant replication in the blood similar to primary isolates of RhCMV and furthermore led to extensive viremia in many tissues at day 14 post infection. In contrast, viral dissemination and viremia was greatly reduced upon deletion of genes also lacking in 68-1. Transcriptome analysis of infected tissues further revealed that chemokine-like genes deleted in 68-1 are among the most highly expressed viral transcripts both in vitro and in vivo consistent with an important immunomodulatory function of the respective proteins. We conclude that FL-RhCMV displays in vitro and in vivo characteristics of a wildtype virus while being amenable to genetic modifications through BAC recombineering techniques. Author SummaryHuman cytomegalovirus (HCMV) infections are generally asymptomatic in healthy immunocompetent individuals, but HCMV can cause serious disease after congenital infection and in individuals with immunocompromised immune systems. Since HCMV is highly species specific and cannot productively infect immunocompetent laboratory animals, experimental infection of rhesus macaques (RM) with rhesus CMV (RhCMV) has been established as a closely related animal model for HCMV. By employing the unique ability of CMV to elicit robust and lasting cellular immunity, this model has also been instrumental in developing novel CMV-based vaccines against chronic and recurring infections with pathogens such as the human immunodeficiency virus (HIV) and Mycobacterium tuberculosis (Mtb). However, most of this work was conducted with derivatives of the 68-1 strain of RhCMV which has acquired multiple genomic alterations in tissue culture. To model pathogenesis and immunology of clinical HCMV isolates we generated a full-length (FL) RhCMV clone representative of low passage isolates. Infection of RhCMV-naive RM with FL-RhCMV demonstrated viremia and tissue dissemination that was comparable to that of non-clonal low passage isolates. We further demonstrate that FL-RhCMV is strongly attenuated upon deletion of gene regions absent in 68-1 thus demonstrating the usefulness of FL-RhCMV to study RhCMV pathogenesis.

microbiology↗