11 results on '"Kelly V Ruggles"'
Search Results
2. The Sin3B chromatin modifier restricts cell cycle progression to dictate hematopoietic stem cell differentiation
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Alexander Calderon, Tamara Mestvirishvili, Francesco Boccalatte, Kelly V. Ruggles, and Gregory David
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Article - Abstract
/SummaryTo maintain blood homeostasis, millions of terminally differentiated effector cells are produced every day. At the apex of this massive and constant blood production lie hematopoietic stem cells (HSCs), a rare cell type harboring unique self-renewal and multipotent properties. A key feature of HSCs is their ability to temporarily exit the cell cycle in a state termed quiescence. Defective control of cell cycle progression can eventually lead to bone marrow failure or malignant transformation. It is thought that HSCs must re-enter the cell cycle in order to commit to terminal differentiation. However, the molecular mechanisms tying cell cycle re-entry to cell fate commitment in HSCs remain elusive. Here, we identify the chromatin-associated Sin3B protein as a molecular link between cell cycle progression and differentiation in HSCs. We demonstrate that Sin3B is necessary for HSCs’ commitment to differentiation, but dispensable for their self-renewal or survival. Single cell transcriptional profiling of hematopoietic stem and progenitor cells (HSPCs) inactivated for Sin3B reveals aberrant cell cycle gene expression, consistent with the observed aberrant progression through the G1phase of the cell cycle. The defective cell cycle control elicited upon Sin3B inactivation correlates with the engagement of discrete signaling programs, including aberrant expression of cell adhesion molecules and essential components of the interferon signaling cascade in LT-HSCs. Additionally, chromatin accessibility profiling in LT-HSCs reveals the Sin3B-dependent accessibility of genomic elements controlling HSC differentiation, suggesting a functional link between cell cycle progression, and priming of hematopoietic stem cells for differentiation. Together, these results point to controlled progression through the G1phase of the cell cycle as a likely regulator of HSC lineage commitment through the modulation of chromatin features.
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- 2023
3. Clostridia isolated from helminth-colonized humans promote hatching of Trichuris muris
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Shushan Sargsian, Ze Chen, Soo Ching Lee, Amicha Robertson, Julia Sproch, Joseph C. Devlin, Mian Zi Tee, Yi Xian Er, Richard Copin, Adriana Heguy, Alejandro Pironti, Victor J. Torres, Kelly V. Ruggles, Yvonne A.L. Lim, P’ng Loke, and Ken Cadwell
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fluids and secretions ,parasitic diseases - Abstract
Soil transmitted intestinal worms known as helminths colonize over 1.5 billion people worldwide. Although helminth colonization has been associated with altered composition of the gut microbiota, such as increases in Clostridia, individual species have not been isolated and characterized. Here, we isolated and sequenced the genome of 13 Clostridia from the Orang Asli, an indigenous population in Malaysia with high prevalence of helminth infections. Metagenomic analysis of 650 fecal samples from urban and rural Malaysians revealed higher prevalence and abundance of these isolates compared to individuals in the United States, with Peptostreptococcaceae family members displaying a specific association with helminth colonization. Remarkably, Peptostreptococcaceae isolated from the Orang Asli displayed superior capacity to induce hatching of eggs from the murine helminth Trichuris muris. These findings support a model in which helminths select for gut colonization of microbes that in turn support their life cycle by promoting egg hatching.
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- 2022
4. SARS-CoV-2 mRNA vaccine elicits a potent adaptive immune response in the absence of IFN-mediated inflammation observed in COVID-19
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Amber Cornelius, Chenzhen Zhang, Mark J. Mulligan, Niels Ødum, Akiko Koide, Jasmine Shwetar, Alberto Herrera, Terkild B. Buus, Marie I. Samanovic, Joseph C. Devlin, Robert J. Ulrich, Ludovic Desvignes, Kelly V. Ruggles, Sergei B. Koralov, Ellie Ivanova, Eleni P. Mimitou, Shohei Koide, Peter Smibert, and Ramin S. Herati
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T cell ,chemical and pharmacologic phenomena ,Inflammation ,biochemical phenomena, metabolism, and nutrition ,Biology ,Acquired immune system ,Article ,Virus ,Vaccination ,medicine.anatomical_structure ,Immune system ,Interferon ,Immunology ,medicine ,bacteria ,Cytotoxic T cell ,medicine.symptom ,medicine.drug - Abstract
Both SARS-CoV-2 infection and vaccination elicit potent immune responses. A number of studies have described immune responses to SARS-CoV-2 infection. However, beyond antibody production, immune responses to COVID-19 vaccines remain largely uncharacterized. Here, we performed multimodal single-cell sequencing on peripheral blood of patients with acute COVID-19 and healthy volunteers before and after receiving the SARS-CoV-2 BNT162b2 mRNA vaccine to compare the immune responses elicited by the virus and by this vaccine. Phenotypic and transcriptional profiling of immune cells, coupled with reconstruction of the B and T cell antigen receptor rearrangement of individual lymphocytes, enabled us to characterize and compare the host responses to the virus and to defined viral antigens. While both infection and vaccination induced robust innate and adaptive immune responses, our analysis revealed significant qualitative differences between the two types of immune challenges. In COVID-19 patients, immune responses were characterized by a highly augmented interferon response which was largely absent in vaccine recipients. Increased interferon signaling likely contributed to the observed dramatic upregulation of cytotoxic genes in the peripheral T cells and innate-like lymphocytes in patients but not in immunized subjects. Analysis of B and T cell receptor repertoires revealed that while the majority of clonal B and T cells in COVID-19 patients were effector cells, in vaccine recipients clonally expanded cells were primarily circulating memory cells. Importantly, the divergence in immune subsets engaged, the transcriptional differences in key immune populations, and the differences in maturation of adaptive immune cells revealed by our analysis have far-ranging implications for immunity to this novel pathogen.
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- 2021
5. A comparative analysis of SARS-CoV-2 antivirals in human airway models characterizes 3CLproinhibitor PF-00835231 as a potential new treatment for COVID-19
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Claire M. Steppan, Annaliesa S. Anderson, Paige Loose, Ana M. Valero-Jimenez, Alberto Herrera, Joseph C. Devlin, Meike Dittmann, Adil Mohamed, Sergei B. Koralov, Rachel A Prescott, Maren de Vries, Austin Schinlever, Ellie Ivanova, Ludovic Desvignes, Kelly V. Ruggles, Rebecca E. O’Connor, and Joseph John Binder
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Protease ,biology ,medicine.drug_class ,business.industry ,medicine.medical_treatment ,Pharmacology ,In vitro ,Viral life cycle ,medicine ,biology.protein ,Vero cell ,Respiratory epithelium ,Potency ,Antiviral drug ,business ,Polymerase - Abstract
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the etiological agent of Coronavirus Disease 2019 (COVID-19). There is a dire need for novel effective antivirals to treat COVID-19, as the only approved direct-acting antiviral to date is remdesivir, targeting the viral polymerase complex. A potential alternate target in the viral life cycle is the main SARS-CoV-2 protease 3CLpro(Mpro). The drug candidate PF-00835231 is the active compound of the first anti-3CLproregimen in clinical trials. Here, we perform a comparative analysis of PF-00835231, the pre-clinical 3CLproinhibitor GC-376, and the polymerase inhibitor remdesivir, in alveolar basal epithelial cells modified to express ACE2 (A549+ACE2cells). We find PF-00835231 with at least similar or higher potency than remdesivir or GC-376. A time-of-drug-addition approach delineates the timing of early SARS-CoV-2 life cycle steps in A549+ACE2cells and validates PF-00835231’s early time of action. In a model of the human polarized airway epithelium, both PF-00835231 and remdesivir potently inhibit SARS-CoV-2 at low micromolar concentrations. Finally, we show that the efflux transporter P-glycoprotein, which was previously suggested to diminish PF-00835231’s efficacy based on experiments in monkey kidney Vero E6 cells, does not negatively impact PF-00835231 efficacy in either A549+ACE2cells or human polarized airway epithelial cultures. Thus, our study providesin vitroevidence for the potential of PF-00835231 as an effective SARS-CoV-2 antiviral and addresses concerns that emerged based on prior studies in non-humanin vitromodels.ImportanceThe arsenal of SARS-CoV-2 specific antiviral drugs is extremely limited. Only one direct-acting antiviral drug is currently approved, the viral polymerase inhibitor remdesivir, and it has limited efficacy. Thus, there is a substantial need to develop additional antiviral compounds with minimal side effects and alternate viral targets. One such alternate target is its main protease, 3CLpro(Mpro), an essential component of the SARS-CoV-2 life cycle processing the viral polyprotein into the components of the viral polymerase complex. In this study, we characterize a novel antiviral drug, PF-00835231, which is the active component of the first-in-class 3CLpro-targeting regimen in clinical trials. Using 3Din vitromodels of the human airway epithelium, we demonstrate the antiviral potential of PF-00835231 for inhibition of SARS-CoV-2.
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- 2020
6. Transcriptional Atlas of Ileal-Anal Pouch Immune Cells from Ulcerative Colitis Patients
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Ashley M. Hine, Jian-Da Lin, Suparna Sarkar, David Hudesman, Ken Cadwell, Shannon Chang, Jordan E. Axelrad, Joseph C. Devlin, Kelly V. Ruggles, and P'ng Loke
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education.field_of_study ,Lamina propria ,business.industry ,Population ,FOXP3 ,Inflammation ,medicine.disease ,Ulcerative colitis ,Inflammatory bowel disease ,Immune system ,medicine.anatomical_structure ,Immunology ,Medicine ,medicine.symptom ,Calprotectin ,business ,education - Abstract
How the human intestinal immune system is distinctly organized to respond to inflammation is still poorly understood. Here, we used single-cell RNA-sequencing to examine lamina propria CD45+ hematopoietic cells from patients with inflammatory bowel disease that have undergone ileal pouch-anal anastomosis, or the colon mucosa of ulcerative colitis patients. We identified a population of IL1B+ antimicrobial macrophages and FOXP3/+BATF+ T cells that are associated and expanded in inflamed tissues, which we further validated in other scRNA-seq datasets from IBD patients. CD8+ T cells were unexpectedly more abundant in the pouch than colon. Cell type specific markers obtained from single-cell RNA-sequencing was used to infer representation from bulk RNA sequencing datasets, which further implicated antimicrobial macrophages expressing IL1B with S100A8/A9 calprotectin as being associated with inflammation, as well as Bacteroides and Escherichia bacterial species. Finally, we find that non-responsiveness to anti-integrin biologic therapies in UC patients is associated with the signature of this antimicrobial macrophage population in a subset of patients. This study identified conserved and distinct features of intestinal inflammation between parts of the small and large intestine undergoing similar inflammation conditions.
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- 2020
7. Microbial contributions to oxalate metabolism in health and disease
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Martin J. Blaser, P'ng Loke, Thomas Battaglia, Aristotelis Tsirigos, Angelina Volkova, Huilin Li, Kelly V. Ruggles, Lama Nazzal, Jiyuan Hu, Allyson L. Byrd, Joseph C. Devlin, and Menghan Liu
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0303 health sciences ,Oxalate metabolism ,030232 urology & nephrology ,Human microbiome ,Endogeny ,Disease ,Biology ,medicine.disease ,Inflammatory bowel disease ,Oxalate ,3. Good health ,Microbiology ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,chemistry ,medicine ,Nephrocalcinosis ,Homeostasis ,030304 developmental biology - Abstract
Over-accumulation of oxalate in humans may lead to nephrolithiasis and nephrocalcinosis. Humans lack endogenous oxalate degradation pathways (ODP), but intestinal microbiota can degrade oxalate and protect against its absorption. However, the particular microbes that actively degrade oxalatein vivoare ill-defined, which restricts our ability to disentangle the underlying taxonomic contributions. Here we leverage large-scale multi-omics data (>3000 samples from >1000 subjects) to show that the human microbiota in health harbors diverse ODP-encoding microbial species, but an oxalate autotroph-Oxalobacter formigenes-dominates this function transcriptionally. Patients with Inflammatory Bowel Disease (IBD) are at significantly increased risk for disrupted oxalate homeostasis and calcium-oxalate nephrolithiasis. Here, by analyzing multi-omics data from the iHMP-IBD study, we demonstrate that the oxalate degradation function conferred by the intestinal microbiota is severely impaired in IBD patients. In parallel, the enteric oxalate levels of IBD patients are significantly elevated and associated with intestinal disease severity, which is consistent with the clinically known nephrolithiasis risk. The specific changes in ODP expression by several important taxa suggest that they play different roles in the IBD-induced nephrolithiasis risk.
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- 2020
8. Melanoma-secreted Amyloid Beta Suppresses Neuroinflammation and Promotes Brain Metastasis
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Eva Hernando, Ronald DeMattos, Paul M. Mathews, Beatrix Ueberheide, Kelly V. Ruggles, Indigo V.L. Rose, Grace Levinson, Francisco Galán-Echevarría, Richard Von-Itter, Iman Osman, James Tranos, Shane A. Liddelow, Youssef Zaim-Wadghiri, Lili Blumenberg, Yue-Ming Li, Alfredo Floristán, Kevin Kleffman, Avantika Dhabaria, Diana Argibay, Eleazar de Miera Sainz de Vega, Eitan Wong, Robert J. Schneider, Robert Rogers, and Jenny Chen
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0303 health sciences ,biology ,Amyloid beta ,business.industry ,Melanoma ,Cancer ,medicine.disease ,Phenotype ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,Parenchyma ,Cancer cell ,Cancer research ,medicine ,biology.protein ,business ,030217 neurology & neurosurgery ,Neuroinflammation ,030304 developmental biology ,Brain metastasis - Abstract
SummaryBrain metastasis is a significant cause of morbidity and mortality in multiple cancer types and represents an unmet clinical need. The mechanisms that mediate metastatic cancer growth in the brain parenchyma are largely unknown. Melanoma, which has the highest rate of brain metastasis among common cancer types, is an ideal model to study how cancer cells adapt to the brain parenchyma. We performed unbiased proteomics analysis of melanoma short-term cultures, a novel model for the study of brain metastasis. Intriguingly, we found that proteins implicated in neurodegenerative pathologies are differentially expressed in melanoma cells explanted from brain metastases compared to those derived from extracranial metastases. This raised the exciting hypothesis that molecular pathways implicated in neurodegenerative disorders are critical for metastatic adaptation to the brain.Here, we show that melanoma cells require amyloid beta (Aβ), a polypeptide heavily implicated in Alzheimer’s disease, for growth and survival in the brain parenchyma. Melanoma cells produce and secrete Aβ, which activates surrounding astrocytes to a pro-metastatic, anti-inflammatory phenotype. Furthermore, we show that pharmacological inhibition of Aβ decreases brain metastatic burden.Our results reveal a mechanistic connection between brain metastasis and Alzheimer’s disease – two previously unrelated pathologies, establish Aβ as a promising therapeutic target for brain metastasis, and demonstrate suppression of neuroinflammation as a critical feature of metastatic adaptation to the brain parenchyma.
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- 2019
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9. Distinct features of human myeloid cell cytokine response profiles identify neutrophil activation by cytokines as a prognostic feature during tuberculosis and cancer1
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Victor J. Torres, Joseph C. Devlin, P'ng Loke, Mei San Tang, Kelly V. Ruggles, David Fenyö, Erin E Zwack, and Zhi Li
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0303 health sciences ,Innate immune system ,Myeloid ,Monocyte ,medicine.medical_treatment ,Cell ,Biology ,Cellular Infiltrate ,3. Good health ,03 medical and health sciences ,0302 clinical medicine ,medicine.anatomical_structure ,Cytokine ,Downregulation and upregulation ,Tumor progression ,Immunology ,medicine ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Myeloid cells are a vital component of innate immunity and comprise of monocytes, macrophages, dendritic cells and granulocytes. How myeloid cell lineage affects activation states in response to cytokines remains poorly understood. The cytokine environment and cellular infiltrate during an inflammatory response may contain prognostic features that could predict disease outcome. Here we analyzed the transcriptional responses of human monocytes, macrophages, dendritic cells and neutrophils in response to stimulation by IFN-γ, IFN-β IFN-λ, IL-4, IL-13 and IL-10 cytokines, to better understand the heterogeneity of activation states in inflammatory conditions. This generated a myeloid cell cytokine specific response matrix that can infer representation of myeloid cells and the cytokine environment they encounter during infection and in tumors. Neutrophils were highly responsive to type 1 and type 2 cytokine stimulation but did not respond to IL-10. We identified transcripts specific to IFN-β stimulation, whereas other IFN signature genes were upregulated by both IFN-γ and IFN-β. When we used our matrix to deconvolute blood profiles from tuberculosis patients, the IFN-β specific neutrophil signature was reduced in TB patients with active disease whereas the shared response to IFN-γ and IFN-β in neutrophils was increased. When applied to glioma patients, transcripts of neutrophils exposed to IL-4 or IL-13 and monocyte responses to IFN-γ or IFN-β emerged as opposing predictors of patient survival. Hence, by dissecting how different myeloid cells respond to cytokine activation, we can delineate biological roles for myeloid cells in different cytokine environments during disease processes, especially during infection and tumor progression.
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- 2019
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10. Altered immunity of laboratory mice in the natural environment is associated with fungal colonization
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Jian-Da Lin, Joseph C. Devlin, Andrea L. Graham, Ying-Han Chen, Ken Cadwell, Alex Cronkite, Frank Yeung, Jacqueline M. Leung, P'ng Loke, Bo Shopsin, Kelly V. Ruggles, Zac W. Stephens, Christina Hansen, June L. Round, Yi Fulmer, Charlotte Drake-Dunn, and Caroline McCauley
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Microorganism ,T cell ,Nod2 Signaling Adaptor Protein ,Autophagy-Related Proteins ,Granulocyte ,Biology ,Microbiology ,Article ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Immune system ,Immunity ,Virology ,medicine ,Fungal colonization ,Animals ,Humans ,Colonization ,Pathogen ,030304 developmental biology ,Aspergillus ,0303 health sciences ,Microbiota ,Altered immunity ,Fungi ,biochemical phenomena, metabolism, and nutrition ,biology.organism_classification ,medicine.anatomical_structure ,Models, Animal ,bacteria ,Parasitology ,Carrier Proteins ,030217 neurology & neurosurgery ,Immune activation - Abstract
Summary Free-living mammals, such as humans and wild mice, display heightened immune activation compared with artificially maintained laboratory mice. These differences are partially attributed to microbial exposure as laboratory mice infected with pathogens exhibit immune profiles more closely resembling that of free-living animals. Here, we examine how colonization by microorganisms within the natural environment contributes to immune system maturation by releasing inbred laboratory mice into an outdoor enclosure. In addition to enhancing differentiation of T cell populations previously associated with pathogen exposure, outdoor release increased circulating granulocytes. However, these “rewilded” mice were not infected by pathogens previously implicated in immune activation. Rather, immune system changes were associated with altered microbiota composition with notable increases in intestinal fungi. Fungi isolated from rewilded mice were sufficient in increasing circulating granulocytes. These findings establish a model to investigate how the natural environment impacts immune development and show that sustained fungal exposure impacts granulocyte numbers.
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- 2019
11. Housing laboratory mice deficient for Nod2 and Atg16l1 in a natural environment uncovers genetic and environmental contributions to immune variation
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Jian-Da Lin, Frank Yeung, P'ng Loke, Christina Hansen, Joseph C. Devlin, Ying-Han Chen, Caroline McCauley, Kelly V. Ruggles, Charlotte Drake-Dunn, Alex Cronkite, Andrea L. Graham, Jacqueline M. Leung, and Ken Cadwell
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Genetics ,0303 health sciences ,biology ,medicine.medical_treatment ,T cell ,Immunology ,biology.organism_classification ,03 medical and health sciences ,0302 clinical medicine ,Variation (linguistics) ,Cytokine ,medicine.anatomical_structure ,Immune system ,Phenotypic analysis ,NOD2 ,medicine ,Immunology and Allergy ,bacteria ,Candida albicans ,ATG16L1 ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
SUMMARYThe relative contributions of genetic and environmental factors to variation in immune responses are still poorly understood. Here, we performed a deep phenotypic analysis of immunological parameters of laboratory mice released into an outdoor enclosure, carrying susceptibility genes (Nod2 and Atg16l1) implicated in the development of inflammatory bowel diseases. Variations of immune cell populations were largely driven by environment, whereas cytokine production in response to stimulation was affected more by genetic mutations. Multi-omic models identified transcriptional signatures associated with differences in T cell populations. Subnetworks associated with responses against Clostridium perfringens, Candida albicans and Bacteroides vulgatus were also coupled with rewilding. Hence, exposing laboratory mice carrying different genetic mutations to a natural environment uncovered important contributors to immune variation.One sentence summaryNatural environment exposure in laboratory mice primarily promotes variation in population frequencies of immune cells, whereas cytokine responses to stimulation are affected more by genetic susceptibility to inflammatory bowel disease.
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- 2019
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