Biology subjects

Shapiro, J.

Publications and source records attributed to Shapiro, J..

10 recordsLinked to original sources

bioRxiv2026

Post-COVID impairment of memory T cell responses to community-acquired pathogens can be rectified by activating cellular metabolism

Infection rates involving bacterial and viral pathogens have increased precipitously after the COVID-19 pandemic. While it has been speculated that higher infection rates resulted from increased hospitalizations throughout the pandemic or greater use of antibiotics, precisely why rates remain high today has remained unexplained. Mitochondrial dysfunction is known to occur post-COVID and may disrupt immune responses. Within T cells, SARS-CoV-2 infection is linked to low mitochondrial membrane potential, increased mitochondrial apoptosis, and decreased mitochondrial respiration, which together impact cellular activation and function beyond the acute phase of illness. Here, we demonstrate that decreased mitochondrial function in antigen-specific T cells post-COVID may contribute to higher infection susceptibility by metabolically immobilizing T cell memory responses. Using donor-matched peripheral blood samples from 31 COVID-naive individuals who subsequently contracted COVID-19, we tracked how influenza A (IAV), Staphylococcus aureus (SA), and Varicella-zoster virus (VZV) T cell responses were impacted by COVID-19 infection. We found that gene expression linked to T cell activation decreased but mitochondrial redox pathways increased in CD4 memory T cells post-COVID. However, mitochondrial flux and reactive oxygen species production were limited in a plurality of post-COVID memory T cells after stimulation with IAV, SA, and VZV. Furthermore, we found a disordered relationship between memory T cell mobilization of glycolysis, fatty acid metabolism, and oxidative phosphorylation pathways post-COVID which resulted in diminished use of catabolic pathways including glycolysis and fatty acid oxidation in antigen-specific T cells. Modulation of mitochondrial function with metformin and ubiquinol partially rescued the post-COVID decline in T cell catabolism. Collectively, these findings indicate that COVID-19 infection may have lasting effects on inhibiting T cell memory responses to commonly encountered community-acquired pathogens which can be corrected with commonly available medications. This has significant implications for the clinical care of immunologically vulnerable populations in the post-pandemic era.

immunology↗

bioRxiv2024

Germinal center BCR maturation in appendicitis reveals a role for antigen-specific adaptive immune responses during disease

Appendicitis is one of the most common abdominal emergencies globally, yet little is understood about the inflammatory mechanisms or potential drivers of disease. Neutrophil inflammation and increased cytokine expression such as IL-6 and IL-8 are hallmarks of appendicitis inflammation. However, early histological studies identified increased T and B cell infiltration during appendicitis, providing support for adaptive immune activation as well, although this has never been investigated in depth. We hypothesized that antigen-dependent activation of the adaptive immune response contributes to appendicitis pathology, in addition to the known innate-mediated processes. Via a series of transcriptomic approaches and lymphocyte repertoire analysis in human appendiceal tissue, we identified evidence of antigen-dependent B cell activation. Increased somatic hypermutation in the germinal center and plasma cell compartment was comprised of presumed high-affinity IgG and IgA B cells. We propose that the appendiceal microbiome acts as a source of antigen, as significant microbial dysbiosis was observed during appendicitis. This dysbiosis was characterized by outgrowth of pathobionts such as Parvimonas and oral biofilm-formers such as Fretibacterium and Fusobacterium, in line with previous reports. We also identified potential loss of epithelial barrier integrity via spatial transcriptomic analysis of the appendiceal epithelium, supporting the possibility of microbial invasion into the tissue during appendicitis. This study provides insight into the inflammatory mechanisms of a common disease and helps to define the immune and microbial compartment of an often-ignored organ, the appendix.

immunology↗

bioRxiv2023

Deletion of NuRD component Mta2 in nephron progenitor cells causes developmentally programmed FSGS

Low nephron endowment at birth is a risk factor for chronic kidney disease. The prevalence of this condition is increasing due to higher survival rates of preterm infants and children with multi- organ birth defect syndromes that affect the kidney and urinary tract. We created a mouse model of congenital low nephron number due to deletion of Mta2 in nephron progenitor cells. Mta2 is a core component of the Nucleosome Remodeling and Deacetylase (NuRD) chromatin remodeling complex. These mice developed albuminuria at 4 weeks of age followed by focal segmental glomerulosclerosis (FSGS) at 8 weeks, with progressive kidney injury and fibrosis. Our studies reveal that altered mitochondrial metabolism in the post-natal period leads to accumulation of neutral lipids in glomeruli at 4 weeks of age followed by reduced mitochondrial oxygen consumption. We found that NuRD cooperated with Zbtb7a/7b to regulate a large number of metabolic genes required for fatty acid oxidation and oxidative phosphorylation. Analysis of human kidney tissue also supported a role for reduced mitochondrial lipid metabolism and ZBTB7A/7B in FSGS and CKD. We propose that an inability to meet the physiological and metabolic demands of post-natal somatic growth of the kidney promotes the transition to CKD in the setting of glomerular hypertrophy due to low nephron endowment.

developmental biology↗

bioRxiv2021

Data-driven approaches for genetic characterization of SARS-CoV-2 lineages

The genome of the Severe Acute Respiratory Syndrome coronavirus 2 (SARS-CoV-2), the pathogen that causes coronavirus disease 2019 (COVID-19), has been sequenced at an unprecedented scale, leading to a tremendous amount of viral genome sequencing data. To understand the evolution of this virus in humans, and to assist in tracing infection pathways and designing preventive strategies, we present a set of computational tools that span phylogenomics, population genetics and machine learning approaches. To illustrate the utility of this toolbox, we detail an in depth analysis of the genetic diversity of SARS-CoV-2 in first year of the COVID-19 pandemic, using 329,854 high-quality consensus sequences published in the GISAID database during the pre-vaccination phase. We demonstrate that, compared to standard phylogenetic approaches, haplotype networks can be computed efficiently on much larger datasets, enabling real-time analyses. Furthermore, time series change of Tajimas D provides a powerful metric of population expansion. Unsupervised learning techniques further highlight key steps in variant detection and facilitate the study of the role of this genomic variation in the context of SARS-CoV-2 infection, with Multiscale PHATE methodology identifying fine-scale structure in the SARS-CoV-2 genetic data that underlies the emergence of key lineages. The computational framework presented here is useful for real-time genomic surveillance of SARS-CoV-2 and could be applied to any pathogen that threatens the health of worldwide populations of humans and other organisms.

bioinformatics↗

bioRxiv2021

Glucose-dependent miR-125b is a negative regulator of β-cell function

Impaired pancreatic {beta}-cell function and insulin secretion are hallmarks of type 2 diabetes. MicroRNAs are short non-coding RNAs that silence gene expression, vital for the development and function of {beta}-cells. We have previously shown that {beta}-cell specific deletion of the important energy sensor AMP-activated protein kinase (AMPK) results in increased miR-125b-5p levels. Nevertheless, the function of this miRNA in {beta}-cells is unclear. We hypothesized that miR-125b-5p expression is regulated by glucose and that this miRNA mediates some of the deleterious effects of hyperglycaemia in {beta}-cells. Here we show that islet miR-125b-5p expression is up-regulated by glucose in an AMPK-dependent manner and that short-term miR-125b-5p overexpression impairs glucose stimulated insulin secretion (GSIS) in the mouse insulinoma MIN6 cells and in human islets. An unbiased high-throughput screen in MIN6 cells identified multiple miR-125b-5p targets, including the transporter of lysosomal hydrolases M6pr and the mitochondrial fission regulator Mtfp1. Inactivation of miR-125b-5p in the human {beta}-cell line EndoC{beta}-H1 shortened mitochondria and enhanced GSIS, whilst mice overexpressing miR-125b-5p selectively in {beta}-cells (MIR125B-Tg) were hyperglycaemic and glucose intolerant. MIR125B-Tg {beta}-cells contained enlarged lysosomal structures and showed reduced insulin content and secretion. Collectively, we identify miR-125b as a glucose-controlled regulator of organelle dynamics that modulates insulin secretion. Graphical abstract O_FIG_DISPLAY_L [Figure 1] M_FIG_DISPLAY C_FIG_DISPLAY

molecular biology↗

bioRxiv2021

FGF21 Normalizes Plasma Glucose in Mouse Models of Type 1 Diabetes and Insulin Receptor Dysfunction

Fibroblast growth factor 21 (FGF21) is a member of the fibroblast growth factor (FGF) family of proteins. The biological activity of FGF21 was first shown to induce insulin independent glucose uptake in adipocytes through the GLUT1 transporter. Subsequently, it was shown to have effects on the liver to increase fatty acid oxidation. FGF21 treatment provides beneficial metabolic effects in both animal models and patients with obesity, type 2 diabetes mellitus (T2D) and/or fatty liver disease. In this paper, we revisited the original finding and found that insulin independent glucose uptake in adipocytes is preserved in the presence of an insulin receptor antagonist. Using a 40 kDa PEGylated (PEG) and half-life extended form of FGF21 (FGF21-PEG), we extended these in vitro results to two different mouse models of diabetes. FGF21-PEG normalized plasma glucose in streptozotocin-treated mice, a model of type 1 diabetes (T1D), without restoring pancreatic {beta}-cell function. FGF21-PEG also normalized plasma glucose levels and improved glucose tolerance in mice chronically treated with an insulin competitive insulin receptor antagonist, a model of autoimmune/Type-B insulin resistance. These data extend the pharmacological potential of FGF21 beyond the settings of T2D, fatty liver and obesity.

pharmacology and toxicology↗

bioRxiv2020

Widespread agrochemicals differentially affect zooplankton biomass and community structure

Anthropogenic environmental change is causing habitat deterioration at unprecedented rates in freshwater ecosystems. Despite increasing more rapidly than other agents of global change, synthetic chemical pollution -including agrochemicals such as pesticides- has received relatively little attention in freshwater biotic assessments. Determining the effects of multiple agrochemicals on complex community and ecosystem properties remains a major challenge, requiring a cross-field integration of ecology and ecotoxicology. Using a large-scale array of experimental ponds, we investigated the response of zooplankton community properties (biomass, composition, diversity metrics) to the individual and joint presence of three widespread agrochemicals: the herbicide glyphosate, the neonicotinoid insecticide imidacloprid, and fertilisers. We tracked temporal variation in community biomass and structure (i.e., composition, diversity metrics) along single and combined pesticide gradients (each spanning eight levels), under low (mesotrophic) and high (eutrophic) nutrient-enriched conditions, and quantified (i) agrochemical interactions, (ii) response threshold concentrations, and (iii) community resistance and recovery. We found that major zooplankton groups differed in their sensitivity to pesticides: [≥]3 {micro}g/L imidacloprid impaired copepods, rotifers collapsed at glyphosate levels [≥]0.3 mg/L, whereas some cladocerans were highly tolerant to pesticide contamination. Glyphosate was the most influential driver of community properties, with biomass and community structure responding rapidly but recovering unequally over time. Zooplankton biomass showed little resistance when first exposed to glyphosate, but rapidly recovered and even increased with glyphosate concentration; in contrast, richness declined in more contaminated ponds but failed to recover. Our results show that the biomass of tolerant taxa compensated for the loss of sensitive species, conferring greater resistance upon subsequent exposure; a rare example of pollution-induced community tolerance in freshwater metazoans. Overall, zooplankton biomass appears to be more resilient to agrochemical pollution than community structure, yet all community properties measured in this study were affected at glyphosate levels below common water quality guidelines in North America.

ecology↗

bioRxiv2020

Single-cell transcriptomic profile reveals macrophage heterogeneity in medulloblastoma and their treatment-dependent recruitment

The role of macrophages in medulloblastoma, the most common malignant pediatric brain tumor, is unclear. Using single-cell RNA sequencing in a mouse model of sonic hedgehog medulloblastoma and analysis of bulk RNA sequencing of human medulloblastoma, we investigated macrophage heterogeneity. Our findings reveal differential recruitment of macrophages with molecular-targeted versus radiation therapy and identify an immunosuppressive monocyte-derived macrophages following radiation treatment of mouse medulloblastoma, uncovering potential strategies for immunomodulation as adjunctive therapy.

cancer biology↗

bioRxiv2019

β-cell dedifferentiation is associated with epithelial-mesenchymal transition triggered by miR-7-mediated repression of mSwi/Snf complex

{beta}-cell dedifferentiation has been revealed as a pathological mechanism underlying pancreatic dysfunction in diabetes. However, little is known on the genetic and epigenetic changes linked with the dedifferentiation of {beta}-cells. We now report that {beta}-cell dedifferentiation is associated with epithelial to mesenchymal transition (EMT) triggered by miR-7-mediated repression of Smarca4/Brg1 expression, a catalytic subunit of the mSwi/Snf chromatin remodeling complexes essential for {beta}-cell transcription factors ({beta}-TFs) activity. miR-7-mediated repression of Brg1 expression in diabetes causes an overall compaction of chromatin structure preventing {beta}-TFs from accessing and transactivating genes maintaining the functional and epithelial identity of {beta}-cells. Concomitantly, loss of {beta}-cell identity impairs the ability of {beta}-TFs Pdx1, Nkx6-1, Neurod1 to repress non-{beta}-cell genes enriched selectively in mesenchymal cells leading to EMT, change in islet microenvironment, and fibrosis. Remarkably, anti-EMT agents normalized glucose tolerance of diabetic mice, thus revealing mesenchymal reprogramming of {beta}-cells as a novel therapeutic target in diabetes. This study sheds light on the genetic signature of dedifferentiated {beta}-cells and highlights how loss of mSwi/Snf activity in diabetes initiating a step-wise remodeling of epigenetic landscapes of {beta}-cells leading to the induction of an EMT process reminiscent of a response to tissue injury.

genomics↗

bioRxiv2018

Community rescue in experimental phytoplankton communities facing severe herbicide pollution.

Evolutionary rescue occurs when adaptation prevents local extinction in deteriorating environments. Laboratory experiments with microorganisms have shown that the likelihood of evolutionary rescue is greatest in large populations that have previously experienced sublethal doses of stress. To assess this result in natural communities, we conducted a mesocosm experiment with semi-natural phytoplankton communities exposed to glyphosate, a widely used herbicide. We tested whether community biomass and pre-exposure to sublethal stress would facilitate community rescue after severe contamination. Exposure to sublethal stress, but not community biomass, facilitated rescue significantly-even though it led to biodiversity loss. Furthermore, glyphosate had modest effects on community composition, suggesting that community resistance to glyphosate was primarily driven by changes in resistance within taxa, not by community turnover. Our results expand the scope of community evolutionary rescue theory to complex ecosystems and confirm that prior stress exposure is a key predictor of rescue.

ecology↗