bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex specific Schistosomiasis induced metabolic modulation of the myeloid lineage
Authors: Fairfax Keke C , Cortes-Selva Diana , Gibbs Lisa , Rajwa Bartek , Amiel Eyal , Cox James E 
Published: January 2023

Abstract
There is a known inverse correlation between chronic helminth infections and metabolic diseases. Despite strong evidence that prior helminth infection exerts a protective effect against the development of metabolic disease, a major gap exists in understanding the mechanism(s) underlying this protection. We recently published that S. mansoni infection induces dramatic transcriptional alterations in hepatic macrophage metabolism, and that this correlates with protection from high fat diet (HFD) induced atherosclerosis and glucose intolerance in male ApoE−/− mice. Since it has previously been shown that during S. mansoni infection the majority of macrophages are monocyte derived, and that schistosome antigens circulate systemically, we sought in the present study to determine the broad effects of S. mansoni exposure on the myeloid lineage using the ApoE−/− HFD model. Surprisingly, we discovered that macrophages derived from the bone marrow of S. mansoni infected male mice have dramatically increased oxygen consumption and mitochondrial mass. This shift is accompanied by increased glucose shuttling into TCA cycle intermediates and decreased cholesterol esters. When we examined the role of biological sex in schistosome induced modulation. We found that S. mansoni infection does not reliably protect ApoE−/− female mice from HFD induced weight gain or glucose intolerance. The sex-dependent effect of infection extends to myeloid precursors, where bone marrow derived macrophages from infected females display the opposite metabolic phenotype as those from infected males. Overall, these data present the first evidence that S. mansoni systemically modulates the myeloid compartment in a sex-dependent manner.
Speckled Protein (SP)140, an immune-specific chromatin reader, contains a CARD and chromatin-interacting domains that dictate subnuclear localization and macrophage identity
Authors: Fraschilla Isabella Rose , Jeffrey Kate L 
Published: January 2023

Abstract
Chromatin regulators that “read” histone post-translational modifications are desirable therapeutic targets in inflammation and cancer. The Speckled Protein (SP) family of chromatin “readers” consists of SP100, SP110, SP140 and SP140L and share high homology with autoimmune regulator (AIRE). SPs possess a caspase activation and recruitment domain (CARD) and multiple chromatin “reader” domains (Plant Homeodomain (PHD), Bromodomain, and SAND). SP140 is preferentially expressed in immune cells and loss-of-function single nucleotide polymorphisms (SNPs) within SP140 significantly associate with immune disorders, such as Crohn’s disease (CD), multiple sclerosis (MS), and chronic lymphocytic leukemia (CLL). We have previously shown that SP140 is a critical orchestrator of macrophage identity and function by occupying and repressing silenced lineage-inappropriate genes. We also demonstrated that PBMCs from patients carrying SP140 SNPs lose SP140 expression and are hypo-responsive to TLR stimulation. How SP140 functions to interact with or maintain heterochromatin for cell identity and function, what SP140 protein domains drive activity, and how disease variants alter SP140 function remain to be determined. Here we show that human SP140 localizes to promyelocytic leukemia (PML) nuclear bodies, sites of transcriptional repression, and we delineate the SP140 protein domains required for this. Furthermore, we determined the impact of SP140 disease-associated SNPs on PML localization and macrophage identity and functional responses. Collectively, our work provides functional characterization of this important chromatin protein and how SP140 disease variants contribute to immunological disease.
Circulating Complement C3-Alpha Chain Levels Predict Survival of Septic Shock Patients
Authors: Cheng Tzu Hsuan , Puskarich Mike , Li Xiang , Fang Zhou , Xu Fou , Chen Yong , Jiang Xian-Cheng , Worat Samrat , Jones Alan E. , Zhang Ming 
Published: January 2023

Abstract
Septic shock is a critical clinical condition with a high mortality rate. Previous observations have suggested that circulating complement C3 fragments, released during septic shock, might contribute to the development of complications such as profound hypotension and disseminated intravascular coagulation, resulting in a more severe disease course and a poorer outcome. However, there are conflicting reports regarding the role of C3 in the course of septic shock. Because circulating C3 exists in different sizes through enzymatic processing or spontaneous hydrolysis, these previous studies, which used ELISA-based methods, would not have distinguished among different C3 species. We have used Western blotting, with its associated protein size differentiation feature, to investigate the forms of circulating C3 in two cohorts of septic shock patients: a discovery cohort of 24 patents and a validation cohort of 181 patients. In both cohorts there were significantly lower levels of the C3-alpha chain in non-survivors than in survivors. In addition, the levels of the C3-alpha chain significantly correlated with days of survival. ROC and AUC analyses showed an AUC=0.65 (95% confidence interval [CI]: 0.56–0.75). At a best cutoff value (Youden) of 970.6 mg/ml, the test demonstrated a sensitivity of 68.5% and specificity of 61.5%. At this cutoff point, Kaplan-Meier survival analysis showed that patients with lower levels of C3-alpha chain had significantly lower survival than those with higher levels (p &lt; 0.001). Thus, circulating C3-alpha chain levels in septic shock patients may predict survival rates.
Essential Role of Indoleamine 2, 3-dioxygenase 1 (IDO1) in Metabolic Programming of Innate Immune Responses in Aged Lung during Influenza
Authors: Stout-Delgado Heather W , Harris Rebecca , Lee Stefi , Yang Jianjun , Hong Kyung Sook , Cho Soo Jung 
Published: January 2023

Abstract
Influenza remains a leading cause of morbidity and mortality, with highest incidence of hospitalization and death occurring in persons &gt;65 years of age. The goal of this study was to interrogate biochemical profiles manifested in lung tissue originating from young adult and aged adult mice over the course of infection, with the aim of characterizing metabolic migration in lung during influenza. There was heightened inflammation, cellular infiltration, and alveolitis present in the aged lung that corresponded with increased viral titers, morbidity, and mortality. Focusing on the biochemical and pathway changes illustrated an important role for kynurenine and tryptophan metabolism in modulating lung specific immune responses to influenza. There was a significant decrease in kynurenine production in aged alveolar macrophages by day 7 post influenza infection that was associated with increased inflammatory and diminished regulatory responses. Despite a rapid increase in IDO1 expression in young, there was impaired expression and activity in aged macrophages and lung during the course of infection. Age-associated mitochondrial dysfunction contributed to changes in IDO1 expression and decreased kynurenine production in aged lung and alveolar macrophages and resulted in alternate immunometabolic signaling and heightened pro-inflammatory responses. Treatment with a mitochondrial targeted antioxidant improved IDO1 mediated production of kynurenine as well as ameliorated mortality in aged mice. Taken together, our data provide additional evidence as to why older persons are more susceptible to influenza and suggest a possible therapeutic to improve immunometabolic responses in this population.
Dynamic metabolic reprogramming in innate immune cells: an early response to influenza infection that is essential for effector function
Authors: Smallwood Heather S , Rezinciuc Svetlana , Bahadoran Azadeh , Bezavada Lavanya , DeVincenzo John , Cormier Stephania , McGargill Maureen Ann , Green Douglas R , Thomas Paul Glyndwr 
Published: January 2023

Abstract
Influenza infection (Flu) is a cause of morbidity and mortality that poses increased risk to children and lacks consistent treatment. Modulating immunometabolism has therapeutic potential. Immune metabolism in response to TLR agonists is well characterized compared to Flu. Clinical reports indicate Flu induces hypermetabolism in the lungs and draining lymph nodes. We demonstrated epithelial cells may be a contributing factor as Flu significantly increased glycolysis, glucose uptake, and lactate excretion and reports suggest these conditions diminish immune function. Dendritic cells (DC) and macrophages (MO) are thought to have rigid metabolic profiles that dictate inflammatory phenotypes after TLR stimulation. We found during Flu epithelial cells, DC, and MO have similar metabolism through shared and distinct molecular mechanisms that allow innate cells to retain metabolic plasticity. We found DC and MO significantly increase both glycolysis and respiration in response to Flu while TLR agonists induce glycolysis with respiratory defects. DC from murine lungs during Flu had the same metabolic phenotype. However, when DC metabolism was constrained motility and T cell priming were diminished. We identified a metabolic drug that significantly improved infection outcomes in vivo and reduced Flu in a clinical trial. Its antiviral mechanism is unknown, but we found it cell specifically modulates metabolic regulators and effector function. To investigate this in humans we collected upper airway cells and secretions from children with respiratory viral infections and found glycolysis and respiration were significantly increased. Thus, we find Flu induces hypermetabolism in vitro, in vivo, and in children’s respiratory tract.
IRF1 regulates IFN-λ1 expression in MDA5-mediated suppression of the HBV replication
Authors: Kuo Yali , Ng Jenny , Lu Hsin-Lin , Liao Fang 
Published: January 2023

Abstract
MDA5, a member of the RIG-I like receptor family, has been shown to sense HBV DNA and trigger the production of anti-viral molecules to clear the virus. However, the mechanism underlying the suppression of HBV replication mediated by MDA5 signaling remains to be investigated. Our transcriptome analysis using RNA-seq revealed that IFN-λ1, a member of type III interferons, was the most upregulated molecule in Huh7 cells co-transfected with HBV DNA and MDA5 expression plasmid compared to with HBV DNA and RIG-I expression plasmid. Here we aim to investigate the IFN-λ1 expression in MDA5-mediated suppression of HBV replication. Huh7 cells co-transfected with HBV DNA and MDA5 expression plasmid led to increased IFN-λ1 expression associated with decreased HBsAg and HBV RNA. On the other hand, knockdown of MDA5 dramatically impaired IFN-λ1 expression. We next investigated the transcription factors involved in regulating IFN-λ1 expression. IRF1, but not IRF3 and IRF7, was upregulated in Huh7 cells co-transfected with HBV DNA and MDA5 expression plasmid. Knockdown of IRF1 led to reduced IFN-λ1 expression along with reduced inhibitory effect on HBV replication. The promoter region of IFN-λ1 contains ISREs, potential sites for IRF binding. However, ChIP and luciferase reporter assays showed no evidence of direct binding of IRF1 to the ISRE sites of IFN-λ1 promoter. Therefore, it is likely that IRF1 regulates MDA5-mediated IFN-λ1 expression through other mechanism. Mechanism(s) on IRF1 regulating IFN-λ1 expression in MDA5-mediated suppression of HBV replication is currently under investigation.
A novel role for TRIM6 and unanchored ubiquitin in inflammatory disease during virus infection via the PI3K-AKT signaling pathway
Authors: Aguilera-Aguirre Leopoldo , Giraldo Maria I. , Kalveram Birte , Hage Adam , Liang Yuejin , Freiberg Alexander Niclas , Rajsbaum Ricardo 
Published: January 2023

Abstract
The innate immune response is essential to protect the host against virus infections. This response involves activation of signaling pathways leading to inflammatory and antiviral cytokines, which in excess can lead to tissue damage and disease. Therefore, these signaling pathways are regulated by different molecular processes, including the ubiquitin (Ub) system. The TRIM family of E3-Ub ligases has been associated with innate immune signaling. We reported that TRIM6 catalyzes the synthesis of unanchored K48-linked poly-Ub chains, which are not covalently attached to any protein, and promote antiviral type-I Interferon (IFN-I) responses. Here, we generated Trim6−/− mice to study its role in immune responses to two different pathogenic viruses, Influenza virus (IAV) and Ebola virus (EBOV). Surprisingly, Trim6−/− mice have less signs of pathology upon IAV infection even though there are increased IAV titers at early time points post-infection. Next-Generation Sequencing and cytokine multiplex analysis revealed reduced mRNA and protein expression levels of CXCL1, a potent neutrophil chemoattractant. Accordingly, neutrophil infiltration to the lungs was reduced in virus-infected Trim6−/− mice, and blockade of the CXCR1/2 receptors, as well as neutrophil depletion, ameliorated disease caused by both EBOV and IAV in WT but not Trim6−/− mice. Mechanistically, TRIM6 and unanchored Ub form a complex with PI3K-AKT signaling components and their phosphorylation is impaired in Trim6−/− cells leading to reduced CXCL1 expression. Our study uncovers a novel mechanism by which viruses can cause disease and suggest that inhibition of CXCL1 signaling may be used as a therapeutic strategy to highly pathogenic viruses.
Unique MyD88/TRAM signaling post TLR2/6 recognition of conserved viral architectures results in anti-viral immunity and improved clearance of secondary bacterial infection
Authors: Hatton Alexis Alexandria , Shepardson Kelly , Wang Yang , Johns Laura Logan , Goodall Cheri , Douglas Trevor , Rynda-Apple Agnieszka 
Published: January 2023

Abstract
Respiratory virus infections can either reduce or increase host susceptibility to subsequent secondary bacterial infections (SBI). Recently, we discovered that the anti-viral immune response initiated by the recognition of exogenous pattern of virus architectures, namely the repeating protein subunit pattern (RPSP), results in improved clearance of S. aureus during SBI in mice. The RPSP is likely conserved in all viruses, suggesting a generalized mode of viral pattern recognition not specific to any single virus. Thus, we identified RPSP as a new PAMP and found it to be recognized by the TLR2/6 heterodimer on the surface of macrophages. We found that this RPSP recognition occurs prior to particle internalization and independent of virus infection. TLRs are known to signal from either the cell surface, through MyD88/Mal, or from the endosome, through TRAM/TRIF, for the induction of inflammatory responses or type I IFNs, respectively. We found that when compared to WT macrophages, tram−/− macrophages exhibited diminished RPSP internalization by confocal microscopy and flow cytometry. However, blocking endosomal acidification by Bafilomycin A1 did not reduce S. aureus killing by RPSP-treated macrophages. This suggests that a non-canonical endosomal signaling pathway may be induced upon RPSP exposure. Indeed, using knockout mice we found that type I IFN, but also MyD88 signaling are critical for improved S. aureus clearance post RPSP. Our results indicate that the recognition of RPSP by TLR2/6 activates a unique intracellular signaling pathway, specifically a combination of the two known pathways, that results in type I IFN-dependent improvement in S. aureus killing by macrophages.
Defining the role of mucosal-associated invariant T (MAIT) cells in B cell help
Authors: Jensen Owen , Trivedi Shubhanshi , Meier Jeremy D. , Leung Daniel T. 
Published: January 2023

Abstract
Pathogen-associated diarrheal diseases account for over 1.6 million deaths annually, yet the number of effective mucosal vaccines remains limited. An exciting potential target for mucosal vaccine adjuvants are mucosal-associated invariant T (MAIT) cells. MAITs are innate-like T cells which are found in the mucosa, blood, and secondary lymphoid organs (SLO), and can respond rapidly to conserved microbial antigens through cytokine secretion and cytotoxic effects. Recent evidence supports a role for MAITs in B cell help. We aim to improve mucosal vaccines by investigating a novel subset of T follicular helper (Tfh)-like MAIT cells and their ability to aid in B cell help and antibody mediated immunity. We describe Tfh-like MAITs from human blood and tonsil samples using linked TCR and phenotype single cell RNAseq, and in vitro culture assays. We further investigate the sufficiency of MAITs aid in antibody mediated immunity in vivo using a MAIT adoptive transfer model into Tcratm1Mom/J (αβ T cell deficient) mice followed by mucosal bacterial challenge. We identify a subset of CXCR5+ MAITs, enriched in human tonsils and murine SLOs that express the Tfh lineage defining transcription factor, BCL6, co-stimulatory markers and cytokines including IL-10 and IL-21 and can aid in B cell help in vitro. Likewise, in vivo we find that MAIT transfer induces pathogen-specific IgA but not IgG responses following mucosal challenge. Overall our study uncovered a novel subset of Tfh-like MAITs and has demonstrated the capacity of MAITs to provide help in antibody responses. Current work aims to uncover the mechanism of MAIT-B cell help which could critically inform efforts to target this population as mucosal adjuvants.
The protective role of B cell anergy in the development of Atherosclerosis
Authors: Waseem Tayab , Keeter W. Coles , Moriarty Alina , Mussbacher Marion , Edemobi Stefan , Getahun Andrew , Cambier John C , Galkina Elena 
Published: January 2023

Abstract
Anergy is critical for silencing autoreactive B cells and preventing autoimmune diseases. Very little is known about the induction and maintenance of anergic B cells within atherosclerosis. To assess the role of B cell anergy in atherosclerosis, we decided to use the Ars/A1 transgenic model, where anergic B cells express receptors that bind to self-antigen and hapten p-azophenylarsonate (Ars). To further differentiate the role of anergy versus BCR signaling we used MD4 mice, which respond normally to antigen, but have a transgenic BCR specific for hen egg lysosome. Ars/A1, MD4, and BL/6 littermate controls were injected with AAV-PCSK9 to increase circulating cholesterol levels and fed a western diet (WD) for 16 weeks. While there were no significant differences in weight or total plasma cholesterol levels, Ars/A1 mice had a significant decrease in plaque burden compared to littermate controls. Interestingly we observed an increase in B-regulatory cells in Ars/A1 mice compared to BL/6 and MD4 mice. With recent reports suggesting that anergic B cells dampen the overall immune response our data suggests that anergy and not B cell signaling is the important mechanism of controlling the inflammatory environment in atherosclerosis.
Regulatory T cells suppression of antigen-specific CD8+ T cells in vivo is contact-dependent
Authors: Mansoori Mohammad Nizam , Shevach Ethan Menahem 
Published: January 2023

Abstract
T Regulatory cells (Tregs) plays an important role in regulating immune mediated responses against self and foreign antigens by various known and unknown mechanisms. Recent studies have shown that antigen-specific iTreg suppress CD4+ effectors T cells in vitro and in vivo by depleting peptide-MHC-II complexes from the DC surface. These, results raise questions as to how Treg suppress CD8+ T effectors, particularly in vivo. To explore Treg mediated suppression of CD8+ T cells, we generated CD4+ iTregs from OT-II mice specific for Ova323–339 in association with I-Ab and determined their capacity to suppress CD8+ T cells from OT-I mice specific for Ova257–264 in association with H-2Kb. CD4+ OT-II iTreg suppressed the in vitro proliferation of OT-I T cells in the presence of Dendritic Cells (DCs) pulsed with both Ova323–339 and Ova257–264 or with DCs singly pulsed with each peptide. Surprisingly, the expansion of OT-I CD8+ T cells in vivo was not suppressed by OT-II iTreg when the two peptides were presented on separately pulsed DCs but was suppressed when both peptides were presented on the same DCs. These results strongly suggest that suppression of the expansion of CD8+ T cells in vivo requires close contact between Treg and responder CD8+ T cell on the surface of the same DC and raise the possibility that Treg may remove a large molecular complex from the DC surface by a process of trogocytosis.
Mechanistic mathematical representation of CD8+ T cell mediated drug-induced liver injury (DILI) Part 2: translation from experimental antigen, ovalbumin (OVA), to drug, amodiaquine (AQ) response
Authors: Kenz Zackary , Battista Christina , Shoda Lisl 
Published: January 2023

AbstractIdiosyncratic DILI (iDILI) is poorly understood and costly to patients and drug developers. Some iDILI events appear immune-mediated. This work builds on the DILIsym representation of T cell cytotoxicity against OVA-expressing hepatocytes1, to translate the OVA representation to AQ-induced hepatotoxicity.AQ-related changes include a physiologically-based pharmacokinetic (PBPK) model for mouse AQ exposure, AQ metabolism to reactive metabolites (RMs), RM-mediated ER stress leading to inflammation, fewer endogenous AQ responsive T cells of reduced affinity and avidity for AQ antigen.Simulations show no CD8+ T cell mediated ALT elevations in simulated wild-type mice treated with AQ, consistent with data2 and provide a mechanistic basis for the result. With low levels of AQ antigen, low T cell numbers and lower affinity and avidity interactions were insufficient for a cytotoxic T lymphocyte (CTL) response. With high levels of AQ antigen, T cell expansion and differentiation occurred but regulatory pathways, i.e., T cell exhaustion, inhibited an effective CTL response. In PD1−/− mice treated with anti-CTLA4, CD8+ T cell mediated AQ DILI was apparent (ALT &gt;100 U/L)3,4. In DILIsym, blocking coinhibitory activity on proliferation and differentiation was permissive for AQ DILI (ALT &gt;100 U/L) and could be further exacerbated by blocking differentiation to an exhausted phenotype (ALT &gt;200 U/L).The results provide proof-of-concept for translation of OVA hepatotoxicity to AQ DILI and set the stage for exploration of human AQ DILI5.