bluuebunny/crossref_metadata_2025_split huggingface dataset:
The SARS-CoV-2 encoded ORF8 protein Stimulates Human Monocytes to Produce Pro-Inflammatory Cytokines
Authors: Ruan Gordon J , Wu Xiaosheng , Manske Michelle K , Nowakowski Kevin E , Abeykoon Jithma P , Tang Xingyi , Yu Yue , Witter Taylor L , Taupin Vanessa , Paludo Jonas , Ansell Stephen M , Badley Andrew D , Schellenberg Matthew J , Witzig Thomas E 
Published: January 2023

Abstract
Infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can result in a cytokine storm that is associated with poor outcomes in patients. The activation of a NOD-like receptor pyrin domain containing 3 (NLRP3) inflammasome following SARS-CoV-2 infection has been shown to play a major role in inflammatory immune responses. In this study, we show that open reading frame 8 (ORF8) protein is abundantly secreted as a glycoprotein in vitro. The glycosylated ORF8 stimulates human CD14+/CD16+ monocytes to cause upregulation of proinflammatory cytokine production and cell surface marker expression within 24 hours. The data suggests that stimulation of human monocytes by ORF8 is not receptor mediated. Rather, ORF8 is likely phagocytosed by human monocytes. ORF8 then stimulates the monocytes by independently binding to the NACHT and LRR domains of the NLRP3 protein. Pharmacologic inhibition of NLRP3 significantly diminished the production of pro-inflammatory cytokines from ORF8-stimulated human monocytes. Finally, this study shows that the ORF8 protein is also secreted in patients with newly diagnosed coronavirus disease 2019 (COVID-19). Levels of ORF8 in the blood of patients diagnosed with COVID-19 correlated with disease mortality and trajectory of disease. ORF8 stimulation of monocytes causes pro-inflammatory cytokine production that leads to the development of severe COVID-19.
Exploration of shared antibody motifs in Kawasaki Disease (KD) and COVID-19 related Multisystem Inflammatory Syndrome of Childhood (MIS-C)
Authors: Rahman Zehra , Hicar Mark 
Published: January 2023

Abstract
Amidst the COVID-19 pandemic, there have been several studies elucidating the immune responses of individuals who have been infected with the SARS-CoV-2 virus. Antibodies (Abs) from different individuals that share the same variable gene and are highly similar in their third complementarity determining regions (CDR3) are termed public clonotypes. Eleven such public clonotypes for SARS-CoV-2 related neutralizing Abs have been proposed.
MIS-C was initially confused with KD as both conditions predominantly affect children and can have cardiac manifestations. KD has been previously associated with common cold coronaviruses and a shared immune response has been proposed.
Here we compare previously published neutralizing Abs in SARS-CoV-2 to Abs of pediatric patients with KD, acute COVID-19 and MIS-C in order to identify shared antibody motifs between the two immune responses. Meme analysis of B cell plasmablast derived heavy chain sequences were compared to published Sars-CoV-2 Ab datasets. Shared CDR3 sequence motifs were shown in seven instances in acute COVID-19, two instances in MISC, and none were shown in KD that appeared beyond shared D segment usage. We then compared Abs from MIS-C and KD with published public clonotypes of SARS-COV-2. We identified two of these in the total B cell sequences from MISC and none in the KD total B cell sequences. Data suggests one proposed SARS-CoV-2 public clonotype, that relies on a mid-CDR3 YDSSG motif, is not specific.
This study further supports that KD and MISC are distinct conditions not related by similar antigen driven immune response, which has implications for challenging the current therapeutic approach.
Supported by The Wildermuth Foundation and the Variety Club of Buffalo
Simultaneously targeting hyperinflammation and hyperglycemia following respiratory viral infection
Authors: Wei Xiaoqin , Zhu Bibo , Sun Jie 
Published: January 2023

Abstract
Individuals with hyperglycemia are at great risk of developing exaggerated pulmonary inflammation following infection with respiratory viruses including SARS-CoV-2. Conversely, SARS-CoV-2 infection has been linked to the development of new onset of hyperglycemia and diabetes. Despite global vaccination efforts, SARS-CoV-2 infection continues to be a great public health challenge, and corticosteroids targeting hyper-inflammation remain the mainstay treatment for severe COVID-19. However, steroidal medicine arises the risk of hyperglycemia, limiting its usage. Here, we showed that a second-generation thiazolidines drug MSDC-0602K (MSDC), a mitochondrial pyruvate carrier inhibitor, simultaneously decreased excessive pulmonary inflammation and hyperglycemia in normal and obese hosts during influenza infection, as such, reducing host morbidity and mortality. scRNA-seq analysis revealed that MSDC treatment reduced lung macrophage inflammation, and myeloid-specific ablation of MPC2 led to dampened lung inflammation. Further, MSDC inhibited human lung macrophage inflammatory responses following SARS-CoV-2 infection, and dampened inflammation in lung autopsies of COVID-19 patients. Mechanistically, MSDC treatment destabilized HIF-1a protein, a transcription factor promoting inflammatory responses of lung macrophages, by repressing cellular Acetyl-CoA levels and HIF-1a acetylation. Our results suggest that MSDC has the great potential to treat severe COVID-19 or other respiratory viral infection, particularly in patients with underlying metabolic conditions, by simultaneously repressing hyper-cytokinemia and hyperglycemia.
Supported by NIH AG069264, NIH AI150599
Development of SARS-CoV-2 specific neutralizing recombinant monoclonal antibodies
Authors: Desai Pavitra , Karuppuchamy Thangaraj , Syed Nazia , Unnikrishnan Sarath , Mathivanan Raghul , Priya Nancy , Balasubramanian Rajesh , Bhattiprolu Krishna , Sundarraj Swathi , Sridharan Haripriya 
Published: January 2023

Abstract
Development of effective therapeutic strategies to combat COVID-19 relies on understanding the cellular and molecular mechanisms of infection. Antibodies specific to SARS-CoV-2 aid in accelerating research to characterize viral protein function and immune response to infection. An urgent need for SARS-CoV-2 specific antibodies arose, as several antibodies already available in the market cross-reacted with other members of the coronavirus family.
To address this need for specificity and urgency, we collaborated with a leading pharmaceutical company to develop antibodies specific to SARS-CoV-2. We generated a single chain fragment variable (scFv) library for SARS-CoV-2 using computational expansion of published antibody structures against SARS-CoV-1. This enabled us to make recombinant antibodies in record time of 3 months. These synthetic sequences were grafted onto both human and human-rabbit chimeric Fc enabling use of these antibodies in a multitude of immunoassays. Our antibodies were targeted against the SARS-CoV-2 spike protein; the receptor binding domain in the spike protein plays a vital role in viral entry into host cells and subsequent infection, making it an important target for neutralizing antibodies and antiviral treatments. Some of our antibodies demonstrate neutralizing capabilities, making them a valuable tool to study neutralizing antibody response to infection. These antibodies are specific to SARS-CoV-2 and do not cross-react with other coronaviruses.
The specificity and versatility of our antibodies enables scientists to better understand SARS-CoV-2 and potentially aid in developing therapeutic strategies against COVID-19 which continues to be important as newer variants of the virus emerge.
Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) Infection in a Bat Gastrointestinal Organoid Model
Authors: Hashimi Marziah , Sebrell Thomas , Hedges Jodi , Snyder Deann Teresa , Lyon Katrina , Cherne Michelle D , Robison Amanda , Sidar Barkan , Wilking James , Walk Seth , Schountz Tony , Jutila Mark A , Bimczok Diane 
Published: January 2023

Abstract
The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), the causative agent of COVID-19, is thought to have originated in bats, since multiple viruses with a high level of genetic similarity have been identified in bats. In addition to respiratory symptoms, COVID-19 frequently involves gastrointestinal symptoms such as diarrhea and vomiting, indicating the SARS-CoV-2 can target the gastrointestinal (GI) tract. However, there is no robust in vitro model for assessing the SARS-CoV-2 infection in the bat GI tract. Here, we established gastrointestinal organoid cultures from Jamaican fruit bats (JFB), (Artibeus jamaicensis), which replicated the characteristic morphology of the gastrointestinal epithelium and showed tissue specific gene expression patterns and cell differentiation. To analyze whether JFB intestinal epithelial cells are susceptible to SARS-CoV-2, we performed in vitro infection experiments. While increased SARS-CoV-2 RNA was detected in both cell lysates and supernatants from the infected organoids after 48 h, there was no evidence of active viral replication, and no infectious virus was produced. However, the JFB distal organoids significantly upregulated anti-viral and pro-inflammatory genes in response to SARS-CoV-2. Unexpectedly, SARS-CoV-2 infected JFB organoids had a decreased incidence of apoptotic cell death. Collectively, our data suggest that primary intestinal epithelial cells from JFBs are resistant to SARS-CoV-2 infection and cell damage, likely because they are able to mount a strong antiviral interferon response.
Early post-vaccination gene signatures correlate with the magnitude and function of vaccine-induced HIV envelope-specific plasma antibodies in infant rhesus macaques
Authors: Kandiyil Vidya Vijayan Karuvan , Curtis Alan D , Cross Kaitlyn , Van Rompay Koen K A , Pollara Justin , Fox Christopher , Tomai Mark , Hanke Tomas , Fouda Genevieve , Hudgens Michael , Permar Sallie R , De Paris Kristina 
Published: January 2023

Abstract
Systems vaccinology approaches are important tools in rational vaccine design. Our goal was to determine whether early innate immune responses to the vaccine prime in infant rhesus macaques, immunized with two different HIV envelope (Env) vaccine regimens, were associated with functional antibody responses in the memory phase.
We compared plasma cytokine levels and molecular signatures of a 3M-052-SE adjuvanted HIV Env protein vaccine (n=10) to a regimen combining the adjuvanted HIV Env protein and MVA-HIV Env (n=10) at days (D) 0, 1, and 3 post the vaccine prime. Whole blood transcriptional profiling applying NanoString technology was employed to identify differentially expressed genes (DEG). Innate immune responses were correlated with vaccine-induced adaptive immune responses at weeks 14, 20, 32, and 34.
The vaccine prime induced a rapid, but transient, increase in inflammatory plasma cytokines and changes in mRNA expression that peaked at D1. In the HIV protein group, we identified 31 DEG with increased mRNA levels, whereas a single, downregulated, DEG was identified in the MVA-Env plus Protein group. Day one signatures were positively correlated with week 14 Env-specific IgG responses, and, at week 34, with Env-specific follicular T helper cells and Env-specific antibody-dependent cytotoxicity function, but negatively correlated with Env-specific CD8+ T cell responses. A protein-protein interaction network confirmed that several of the DEG-encoded proteins have predicted interaction partners that are important for B cell activation.
These results support the idea that vaccine-induced HIV-specific antibody and T cell responses can be optimized through the modulation of the vaccine prime.
Supported by National Institutes of Health grants R01 DE028146, P01 AI117915, T32 5108303, the Office of Research Infrastructure Programs/OD P510D011107 (CNPRC), and the Center for AIDS Research award P30AI050410
A Lupus-Associated Variant in IRF7 amplifies IFN-α Production in response to TLR stimulation
Authors: Virolainen Samuel Juhani , Keddari Yasine , Dunn Katelyn , Forney Carmy , Yin Cailing , Donmez Omer , Parameswaran Sreeja , Javier Ellen , Porollo Alexey , Waggoner Stephen , Weirauch Matthew , Kottyan Leah 
Published: January 2023

Abstract
Systemic Lupus Erythematosus (SLE) is an autoimmune disease characterized by chronic immune activation, loss of self-tolerance and organ destruction. More than 90 genetic risk loci are implicated in the etiology of SLE, yet the mechanisms connecting these loci to disease risk are not well understood. We focus on a SLE-associated coding variant (rs1131665) at the IRF7 risk locus that results in an arginine (R, non-risk) to glutamine (Q, risk) amino acid change in the auto inhibitory domain of interferon regulatory factor-7 (IRF7), a key transcriptional regulator of the expression of and response to type I interferon (IFN). The majority of SLE patients exhibit elevated levels of circulating IFN, a feature that correlates with disease activity. We generated cell lines expressing the risk and non-risk variants of IRF7 and isolated plasmacytoid dendritic cells from mice with CRISPR-mediated introduction of a mouse homologue of the risk variant of IRF7. In both experimental systems, the rs1131665 lupus risk variant drives increased toll like receptor-7 (TLR-7) ligand-induced IFN-α expression at both the mRNA and protein levels compared to the non-risk variant of IRF7. Additionally, we performed a covariance analysis that predicts that amino acid residues at the 84, 140, 142 positions interact with the variant position in the three-dimensional structure of IRF7. Mutation of the amino acid at the 84 position from a glutamic acid (E) residue to a threonine (T) residue results in amplified IFN production in response to TLR-7 stimulation. Our findings suggest a genotype-dependent mechanism for lupus risk variants in IRF7 in promoting exaggerated IFN production in SLE.
These experiments would not have been possible with out NIH NIAMS R01 AR073228.
Nutraceutical Apigenin regulates DC function in a RelB-dependent manner during neuroinflammation.
Authors: Jain Pooja , Ginwala Rashida , McTish Emily , Moore Patrick , Revuri Nikil , Raman Chander , Singh Narendra , Nagarkatti Mitzi , Nagarkatti Prakash , Kranz Victoria A , Houle John D , Khan Zafar 
Published: January 2023

Abstract
Apigenin, a natural flavonoid, found in several plants is known to have anti-oxidant and anti-inflammatory properties indicated by its use for centuries as a medicinal approach to treat inflammatory disorders. However, there are significant gaps in knowledge regarding its effect on dendritic cell (DC) function in maintaining an immune balance in immunospecialized locations like the central nervous system (CNS). In order to establish the potential utility of Apigenin as a therapeutic agent against neuroinflammatory diseases, we tested and found that Apigenin treatment ameliorated severity of disease progression and relapse after onset of experimental autoimmune encephalomyelitis (EAE) in C57BL/6 and SJL mouse models of multiple sclerosis. An increased retention of DCs and other myeloid cells in the periphery correlated with decreased immune cell infiltration and reduced demyelination in the CNS in treated mice. Mechanistically, Apigenin treatment reduced RelB expression in presence of LPS in human peripheral blood DCs, which is central to DC maturation, its antigen presentation capabilities and DC-mediated T cell activation. IL-12A and IL-23, downstream pro-inflammatory targets of RelB were reduced upon Apigenin treatment in these cells. Further, RelB causes a metabolic switch in immune cells upon inflammation, which was seen as a decrease in glucose uptake and lactate production (glycolysis), and an increase in mitochondrial activity when LPS-induced DCs were treated with Apigenin. These results indicate a protective role of Apigenin against DC-regulated neurodegenerative effects through a probable RelB mediated pathway thus implicating a potential therapy for neuroinflammatory disease.
Supported by grants from NIH: 1R01NS0971-47
High-potency synthetic STING agonists rewire myeloid stroma in the tumour microenvironment to amplify immune checkpoint blockade efficacy in refractory pancreatic cancer.
Authors: Boda Akash R , Ager Casey R , Rajapakshe Kimal , Lea Spencer T , Curran Michael A 
Published: January 2023

Abstract
Pancreatic ductal adenocarcinoma (PDAC) is clinically unresponsive to immune checkpoint blockade (ICB) immunotherapy. Dense immunosuppressive myeloid stroma (MS) and consequent T cell exclusion from the tumour microenvironment renders PDAC resistant to immune-based therapies. Innate immune activation of the MS via cyclic dinucleotide (CDN) agonists of the STING (Stimulator of Interferon Genes) pathway can trigger T cell infiltration into cold tumours leading to robust anti-tumour immunity. Despite proven therapeutic efficacy in preclinical models, the cellular mechanisms of how CDNs reprogram the suppressive MS to sensitise tumours to ICB is poorly understood.
Using multi-omic profiling of MDSCs and M2 Macrophages of human and murine origin, we show that the synthetic STING agonist, IACS-8803, rewires these populations from immunosuppressive to immune-permissive phenotypes in part through inhibition of c-Myc signaling, energy metabolism modulation, and antagonism of cell cycle. Furthermore, dimensionality reduction analyses of multiparameter flow cytometry data and survival studies in a KPC-derived model of PDAC show a proinflammatory remodeling of the MS and an increased T/NK cell infiltration and function by synthetic CDN STING agonists into the tumour that underlies an amplified therapeutic response to ICB.
We are the first to report that synthetic CDN STING agonists affect MDSC and M2 macrophage repolarization through altering energy metabolism, cell cycle dynamics and c-Myc signalling. This study uncovers molecular and cellular mechanisms by which high-potency STING agonists drive a proinflammatory conversion of the tumour MS to overcome resistance to ICB in an aggressive orthotopic tumour model of PDAC.
Supported by grants from PanCan (206100-90-100300-54-00006617-11111)
Unique and shared molecular features of human B and T lymphocyte memory differentiation
Authors: Singh Amit K , Roy Roshni , Kaileh Mary , Sarantopoulou Dimitra , Hernandez Dena , Arepalli Sampath , Bektas Arsun , Kim Jaekwan , McKelevy Julia , Zukely Linda , Dunn Christopher , Nguyen Cuong , Wallace Tonya , Wood William , Piao Yulan , De Supriyo , Sen Jyoti Misra , Weng Nan-ping , Ferrucci Luigi , Sen Ranjan 
Published: January 2023

Abstract
Long-term immunity against infections and effective response to vaccination are dependent on remarkable and unique feature of lymphocytes referred as “memory generation”. Despite having multiple mice studies focused on naïve to memory transition of lymphocytes our understanding of human naïve and memory properties is limited. In this study we explored epigenetics (DNA methylation and accessible chromatin), transcriptomics and activation induced gene expression of FACS sorted naïve and memory subsets of B, CD4 T and CD8 T lymphocytes of healthy donors from GESTALT cohort. Shared and specific methylomes between B and T lymphocyte subsets were identified. The relationship between DNA methylation, chromatin accessibility and transcriptome through ATAC-Seq and RNA-Seq data from the same donors is established. Through in-silico analyses and by utilizing data from Roadmap Epigenomics project and ChromHMM, we further identified differentiation-specific connections between DNA methylation, chromatin accessibility, and histone modifications. Transcription factor motif analyses identifies presence of ARNT, OCT and NF-κB motifs around sites hypomethylated in B memory while ETS motifs are in memory-associated hyper-methylated sites. Interestingly, OCT motifs were also significantly enriched in B memory specific accessible chromatin. To understand the extent to which these epigenetic changes effected lymphocytes, we activated naïve and memory subsets of B and CD4+ T lymphocytes in vitro and assayed early and late gene expression changes. These findings will provide the foundation for future studies related to dysregulation of memory cell differentiation in aging and infections.
Supported by Intramural Research Program of the National Institute on Aging.
The SWI/SNF canonical BAF complex and c-Myc cooperate to promote early fate decisions in CD8+ T cells
Authors: Guo Ao , Huang Hongling , Zhu Zhexin , Chen Mark J , Shi Hao , Sharma Piyush , Liedmann Swantje , Haydar Dalia , Yang Mao , Beere Helen , Krenciute Giedre , Roberts Charles W M , Chi Hongbo , Green Douglas R 
Published: January 2023

Abstract
The identification of mechanisms to promote the generation of memory T cells (TMEM) has important implications for vaccination and anti-cancer immunotherapy. Using a CRISPR-based screen for negative regulators of TMEM generation in vivo, we discovered many components of the mammalian canonical SWItch/Sucrose Non-Fermentable (SWI/SNF) complex, also called canonical Brg1/Brg-associated factor (cBAF). cBAF is essential for the differentiation of activated, naïve CD8+ T cells into T effector (TEFF) cells, and loss of cBAF promotes TMEM formation of CD8+ T cells in vivo upon infection with Listeria monocytogenes and influenza A virus (IAV). During the first division of activated CD8+ T cells, we found that cBAF and c-Myc frequently co-assort asymmetrically to the two daughter cells. Daughter cells with high c-Myc are enriched for cBAF expression and display a cell fate trajectory towards TEFF cells, while those with low c-Myc have reduced cBAF, and preferentially differentiate towards TMEM cells. Moreover, the cBAF complex and c-Myc physically interact, and act in concert to establish the chromatin landscape in activated CD8+ T cells. Treatment of naïve CD8+ T cells with an inhibitor of cBAF during the first 48 hours of activation, prior to the generation of chimeric antigen receptor T (CAR-T) cells, markedly improves anti-cancer immunity in a solid tumor model. Our results establish cBAF as a key negative determinant of TMEM cell fate and suggest that manipulation of cBAF early in T cell differentiation can improve adoptive immunotherapy for cancer treatment.
Supported by AI123322