bluuebunny/crossref_metadata_2025_split huggingface dataset:
Immune Regulatory Markers in Clinical Cases of COVID-19
Authors: Madiraju Charitha , Mallarpu Chandra Shekar , Chelluri Srinivasa Ikswaja , Singarapu Maneendra , Krishna Tapaswi , Chelluri Lakshmi Kiran 
Published: August 2023

Abstract
The objective of this research study is to profile anti-viral and pro-inflammatory cytokines, major histocompatibility complex (MHC) class I & II molecules and cell death markers in clinical cases of sepsis. Research study design included three patient cohorts namely, COVID-19 with sepsis (C19wSepsis, N=17), COVID-19 with no sepsis (C19NoSepsis, N=17) and sepsis alone (N=24). Healthy subjects served as controls (N=16). Serum samples derived from patient cohorts and control subjects were analyzed by ELISA for anti-viral and pro-inflammatory cytokines (IFN-gamma and IL-1beta), MHC class I (MHCA) & MHC class II (MHCDRb1) molecules and cell death markers. Data and statistical analyses were performed using GraphPad Prism 7.0. ELISA of serum samples identified a significant increase in serum IFN-gamma, MHCA and MHCDRb1 levels in C19wSepsis cohort compared to C19NoSepsis cohort and control subjects [p &lt; 0.0001]. Although there was a significant increase in IL-1beta levels in serum samples of C19wSepsis compared to control subjects and sepsis alone cohort [p &lt; 0.0005], the levels were comparable between C19wSepsis and C19NoSepsis cohorts [p &gt;= 0.05]. Cell death markers, Caspase-3 and p62/SQSTM1, showed significantly altered levels between the three patient cohorts when compared to controls [p &lt; 0.01]. Representative data from flow cytometry confirm ELISA results. Results from this study identify key immune regulatory markers in clinical cases of COVID-19.
Delayed CD4+ T-cell response in older adults is associated with reduced immunogenicity and reactogenicity after COVID-19 mRNA vaccination
Authors: Jo Norihide , Hidaka Yu , Kikuchi Osamu , Fukahori Masaru , Sawada Takeshi , Aoki Masahiko , Yamamoto Masaki , Nagao Miki , Morita Satoshi , Nakajima Takako E , Muto Manabu , Hamazaki Yoko 
Published: August 2023

Abstract
While the newly developed COVID-19 mRNA vaccines are highly effective, characteristics of the immune response after the vaccination and its association with the adverse effects, especially for an older population, remain elusive. In this study, we recruited a total of 216 SARS-CoV-2-naïve healthy donors of various ages (23–81 years) who received two doses of the BNT162b2 vaccine and assessed age-associated differences in vaccine-induced T-cell responses and adverse effects over 3 months. We observed that older adults (≥65 years) had fewer vaccine-induced Spike-specific CD4+ T cells, including CXCR3+ cTfh and Th1 cells, after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, Spike-specific Th1 cells in older adults expressed higher levels of PD-1, a negative regulator of T-cell activation, which was associated with low Spike-specific CD8+ T-cell response. These data indicated that delayed induction of CD4+ T-cell response in older adults is linked to impaired humoral and cellular immunity and reduced systemic reactogenicity. Therefore, enhancing CD4+ T-cell response following the first dose is key to improving vaccine efficacy in older adults.
This work was supported by the Japan Agency for Medical Research and Development (grant numbers JP21gm5010005, JP20fk0108454, and JP223fa627009; Y.H.), iPS Cell Research Fund (Y.H.), the COVID-19 Private Fund to the Shinya Yamanaka Laboratory, CiRA, Kyoto University (Y.H.), Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (grant number 19K23862; N.J.), Kansai Economic Federation (KANKEIREN; Y.H.), Sumitomo-Mitsui Trust Bank Fund for Covid-19 Research, Kyoto University (Y.H.), and Takeda Science Foundation (Y.H.).
Paradoxically Increased Inflammation in Immunosuppressed Individuals with COVID-19
Authors: Moore-Stanley James Oscar , Knight Sean Blandin , Bakerly Nawar , Kirkham Sara , Williams Thomas , Hussell Tracy 
Published: August 2023

Abstract
Dysregulated inflammation is central to the morbidity and mortality associated with COVID-19. Treatment with dexamethasone and IL-6 blockade can be life-saving in patients stratified for moderate - severe disease. Patients with suppressed immunity are often excluded from immune blockade therapy due to the assumption that additional suppression of an impaired immune system will be detrimental to viral clearance. We hypothesised that patients with suppressed immune systems would be slower to clear viral infection, leading to increased damage and therefore, paradoxically, a more intense acute phase response to SARS-CoV-2 infection. This was tested by a sub-group analysis of the Coronavirus Immune Response and Clinical Outcomes (CIRCO) cohort, an observational study of acute COVID-19 in Greater Manchester, UK. Patients were included if they were treated with dexamethasone and had a research blood sample retrieved within 48 hours of admission, and excluded if they were treated with IL-6 blockade or antiviral therapy prior to research sampling. Acute phase serum cytokine levels were compared between eight immunosuppressed and 12 immunocompetent patients positive for SARS-CoV-2. In support of our hypothesis, we found that immunosuppressed individuals had higher levels of the inflammatory cytokines IP-10 (p=0.03) and MCP-1 (p=0.01) compared to immunocompetent patients matched for COVID-19 severity. This suggests that immunosuppressed patients may benefit as much as immunocompetent individuals from systemic treatments to dampen inflammation in COVID-19, and current recommendations of excluding these patients from treatment solely on the basis of immune competence may need to be re-evaluated.
Integrated transcriptomic analysis reveals T and B cell immune signatures influencing resolving outcome in MRSA bacteremia
Authors: Parmar Rajesh , Pickering Harry C , Gjertson David W , Chan Liana C , Yeaman Michael R , Reed Elaine F 
Published: August 2023

Abstract
Staphylococcus aureus bacteremia is a potentially lethal infection particularly when involving methicillin-resistant S. aureus (MRSA). Contrary to MRSA bacteremia that resolves on its own (RB), persistent MRSA bacteremia (PB) happens when the infection persists after receiving antibiotic therapy. Host immune responses in PB vs. RB are poorly understood. Our goal was to identify proteomic, epigenetic, and transcriptomic features associated with PB and RB clinical outcomes. We examined the whole-blood transcriptomes of propensity score matched PB (n = 28) and RB (n = 30) patients. Gene expression (GE) modules were analysed by weighted gene co-expression network analysis (WGCNA) and quantified by module eigengene analysis. Enriched pathways and protein-protein interaction networks were identified. The correlation between host DNA methlytransferase-3A (DNMT3A) genotype and serum IL-10 level was examined in the identified GE modules. Upregulation of T and B cell immune response genes early during MRSA infection discriminate RB from PB patients. T and B cell signalling pathways were significantly increased in RB patients and correlated with lower serum IL-10 levels and the DNMT3A heterozygous A/C genotype. These findings indicate that patients with DNMT3A A/A genotypes have dysregulated adaptive immune responses characterized by impaired T and B cell function that increase the risk of PB outcome. These findings suggest that combining the genotype of the host with transcriptome and proteomic profiles might help determine the outcome of MRSA bacteremia. This knowledge may result in a better understanding of S. aureus pathogenesis and development of new anti-infective therapies and vaccines to improve patient outcomes.
These studies were supported by in-part by the following NIH grants U01-AI124319, R01-AI068804 and R33-AI111661(to MRY) and U01-AI124319 and U19AL128913 (to EFR).
The immunodominant SARS-COV-2 CD8+ T cell repertoire is capable of resisting antigenic drift
Authors: Malone Michael J , Guo Yuwan , Su Laura , Jiang Jenny 
Published: August 2023

Abstract
Immunodominance (ID) is a common phenomenon in infection, vaccination, and cancer where a small set of many possible epitopes are targeted by the immune system. Although favorable in many contexts, ID is inherently susceptible to immune escape. Given that a major concern of COVID-19 has been the possibility of emerging variants escaping immune detection, we sought to investigate the extent of ID in T cells and their ability to target SARS-CoV-2 variants after immune challenge. To do so, we probed T cells from vaccinated and infected donors with a library of DNA-barcoded pMHC-tetramers containing epitopes from conserved, wild-type, and variant spike. After single cell sequencing, we recalled each cell’s T cell receptor (TCR) sequence and its cognate specificity, finding a striking ID to few unmutated epitopes. Interestingly, despite low antigenic diversity, many donors had both clonal and diverse repertoires toward the dominant epitopes. We suspected that integration of these diverse repertoires may allow an individual to reap the metabolic benefits of ID, while simultaneously countering drifting antigens during infections and cancers. We thus transduced the ID repertoires of several donors into cell lines. We will next evaluate their tolerance to mutagenesis by probing them with libraries of DNA-barcoded pMHC-tetramers containing all possible single amino acid point mutations of their original cognate ID epitopes. Such analyses will provide deep insight into the antigen binding properties each TCR, as well as how their cooperation at the individual and population levels could resist immune escape. Application of this approach to other infections and cancers could reveal novel avenues for vaccines and cell-based therapies in cancer.
Supported by grants from NIH (U19 AI128949) and the Chan Zuckerberg Initiative Foundation (CZIF)
High Mobility Group Box 1: A Predictive Biomarker of Aberrant Humoral Responses Implicated in Post-Acute Sequelae of SARS-CoV-2 Infection
Authors: Rubas Noelle C , Peres-David Rafael Aniu , Kunihiro Braden P , Phankitnirundorn Krit , McCraken Trevor , Umeda Lesley , Conching Andie , Maunakea Alika K 
Published: August 2023

Abstract
Postacute sequelae of SARS-CoV-2 infection (PASC) is the next public health concern of the pervasive COVID-19 pandemic. Molecular pathophysiology of PASC is undetermined, therefore this study evaluated pathways implicated in humoral responses associated with symptom resolution to identify predictive biomarkers of PASC. Individuals recovered from acute infection were recruited into a 6-week study. Initial health questionnaires and proof of previous SARS-CoV-2 infection were collected prior to study enrollment. Body mass indices were calculated with participant height and weight measurements. Blood samples were collected and isolated for plasma and PBMCs to evaluate a panel of immunological biomarkers and cellular profiling, respectively. A singular stool sample was collected for microbial DNA extraction for metagenomic sequencing. Data was integrated with IPA analysis to establish modulated pathways in PASC. Individuals suffering from symptoms of PASC showed evidence of poor immune responses with diminished rates of symptom resolution. Particularly prevalent in obese individuals, PASC associated with attenuated antibody responses and inability to maintain viral inhibition capacities, partially explained by elevated inflammation and inflammatory cellular landscapes. Individuals with worse humoral responses tended to display characteristics of a compromised gut microbiome, suggesting dysregulation of the immunoepigenetic-microbiome axis. Circulating high mobility group box 1 was shown to be a central mediator of this axis, with elevated levels conducive of poor adaptive immunity. Additionally, mediation analysis revealed baseline levels were predictive of viral inhibition at the time of final follow-up.
This study was supported in part by funding provided by Hawaii Community Foundation under award 20HCF-101573. The comments expressed in this report are the sole responsibility of the authors and do not represent the official view of the Hawaii Community Foundation.
Type I interferons and TGF-β cooperate to induce liver fibrosis during HIV-1 infection under antiretroviral therapy
Authors: Ahodantin James , Nio Kouki , Funaki Masaya , Zhai Xuguang , Wilson Eleanor , Kottilil Shyamasundaran , Cheng Liang , Li Guangming , Su Lishan 
Published: August 2023

Abstract
Liver disease has become a major comorbidity health concern in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). To investigate the immune mechanism of liver disease development in ART-treated HIV-infected individuals, we developed humanized mice, NRG mice reconstituted with progenitor cells from human fetal livers, with HIV-1 infection and ART. Animals w/o HIV-1 were treated with TRUVADA (Emtricitabine/ Tenofovir Disoproxil Fumarate) in combination with Raltegravir. Hepatic stellate cells (HepSC) isolated from the liver of healthy donors were used to assess the effect of IFN-I and its potential cooperation with TGF-β in HepSC activation. Finally, identified cellular and molecular mediators of liver disease were analyzed in bloods and liver biopsies from PLWH with ART. We report here that chronic HIV-1 infection with ART induced hepatitis and liver fibrosis in humanized mice, associated with accumulation of M2-like macrophages (M2LMs), elevated TGF-β, and IFN signaling in the liver. Interestingly, IFN-I and TGF-β cooperatively activated HepSCs in vitro. Mechanistically, IFN-I enhanced TGF-β-induced SMAD2/3 activation in HepSCs. Finally, blockade of IFN-I signaling reversed HIV/cART-induced liver diseases in humanized mice. Consistently, we detected elevated markers of liver injury, M2LMs, and of IFN signaling in blood specimens and liver biopsies from PLWH compared with those of healthy individuals. These findings identify the IFN-I/M2LM/HepSC axis in HIV/ART-induced liver diseases and suggest that inhibiting IFN-I signaling or M2LM may provide a novel therapeutic strategy for treating HIV/ART-associated liver diseases in PLWH treated with ART.
This study was supported in part by NIH grants AI127346, AI095097, and DK095962 to Prof. Lishan Su
Immunophenotyping of peripheral blood mononuclear cells in tuberous sclerosis complex
Authors: Balthazard Renaud , Drouin-Engler Rose-Marie , Klement Wendy , Daigneault Audrey , Florès Alina Sreng , Kaufmann Daniel E , Keezer Mark , Larochelle Catherine 
Published: August 2023

Abstract
Tuberous sclerosis complex (TSC) is a multisystem disorder caused by loss-of-function mutations in TSC1/2 proteins. This results in constitutive mTOR activation and predisposes to the development of benign tumours, with renal angiomyolipomas (AMLs) and tuber-related drug-resistant epilepsy (DRE) being major causes of morbidity and mortality in adults. Despite the central role of mTOR in leukocyte biology and the beneficial impact of mTOR inhibitors in TSC, the role of the immune system and inflammation in the development of tumours and DRE in people with TSC remains unknown.
Using peripheral blood mononuclear cells (PBMCs) and serum from people with TSC, healthy controls (HC) and non-TSC DRE, we employed flow cytometry and multiplex assays to interrogate the immune profile associated with chronic loss of mTOR inhibition.
We found that higher levels of the astroglial activation marker GFAP are elevated in TSC and show high intergenotype variability. We also observed differences in circulating immune cell populations, cytokines, chemokines and growth factors related to TSC. We found a higher proportion of B cells in parallel with increased total IgG but a reduction in IL-2 and IL-7 and a lower frequency of T cells. TSC with vs without AML showed differences in CD4:CD8 T cells ratio, monocytes and dendritic cells frequencies. Finally, loss of TSC1/2 affected T cell polarization, leading to an increased proportion of Tc17 CD8+ T cells, especially in subjects with DRE.
Overall, our findings indicate TSC is associated with increased blood biomarkers for inflammation, glial activation, and distribution and profile of circulating PBMCs compared to controls.
Characterization of extracellular vesicles in AIDS-associated non-Hodgkin lymphoma
Authors: Hegde Priya , Martínez Laura E , Magpantay Larry , Detels Roger , Hussain Shehnaz , Epeldegui Marta 
Published: August 2023

Abstract
Even with the use of anti-retroviral therapy, HIV+ subjects develop non-Hodgkin lymphoma (NHL) at a higher frequency than uninfected subjects. Extracellular vesicles (EVs) secreted by cells may contain immunomodulatory molecules; for example, tumor cells can secrete EVs containing bioactive PD-L1 that can inhibit anti-tumor responses. We have shown EVs bearing PD-L1, TNF-RII or IL-6Rα can be biomarkers of NHL risk. Here we aim to characterize EVs isolated from EBV+ and EBV− lymphoma cell lines to define their involvement in lymphomagenesis and identify more EV-associated biomarkers for NHL risk (like immune checkpoint molecules CD80, CD86, CD28). EVs were isolated from AIDS-NHL and NHL cell lines using a total exosome isolation kit and analyzed by Western blot. A subset of these were also analyzed by proteomics using Metascape, Reactome, and R. EVs were also isolated from archived serum of HIV+ individuals before NHL onset (n = 51) and matched HIV+ controls (n = 53) from participants of the MACS/WIHS Combined Cohort study, with a total exosome isolation kit and characterized by Western blot. EV-specific markers were detected in EVs isolated from cell lines and serum. EVs isolated from EBV+ cell lines largely expressed LMP1, an EBV CD40 homolog that induces EBV-driven B cell transformation. In EVs isolated from serum, levels of CD80, CD86, or CD28 were comparable between pre-NHL samples and matched controls, though control samples tended to have greater CD80 and CD86 expression. Our findings shed light on the EV marker expression profiles of AIDS-NHL and NHL cell lines and show LMP1 expression in EBV+ cell lines. Additionally, this research provides initial insight into the complex composition of EVs and their role in lymphomagenesis.
Supported by grants from NIH (R01CA228157, P30CA016042-S, R01CA228157S)
Studying NF-κB signaling during neuroinflammation in Alzheimer’s Diseases in vitro using hiPSC-derived brain models
Authors: Songkiatisak Preeyaporn , Aqdas Mohammad , Md Toufiqur Rahman Shah , Oh Kyu-Seon , Sung Myong-Hee 
Published: August 2023

Abstract
Neuroinflammation is a key pathological driver of various neurological diseases, including Alzheimer’s disease (AD). NF-κB signaling pathway is widely recognized as a hallmark of inflammation and cellular senescence in which aged microglia may undergo cellular senescence partly influenced by NF-κB. Our previous data indicated that ex vivo microglia comprised of two distinct subpopulations distinguished by morphology and motility. Most microglia cells formed a tight cell cluster, termed “clustered microglia”. The rest was a subpopulation of microglia with smaller cell size and high motility, termed “free-roaming microglia”. In microglia from aged animals, the composition of clustered versus free-roaming subsets was shifted toward a higher prevalence of free-roaming microglia where c-Rel is expressed and the canonical NF-κB signaling is more sustained. To study NF-κB signaling in the context of neuroinflammation, we are developing 3D models, using hiPSC neurons derived from healthy donors of various age groups and co-culturing them with primary microglia from knock-in mice in which their endogenous c-Rel was labeled with a fluorescent protein. Moreover, individuals with APOE-e4 genotype have an increased risk of developing AD. To develop 3D brain models for AD, we will use co-culture of microglia and neurons derived from hiPSCs of APOE-e4 carriers. Live cell imaging and biomarker assessment of microglia and neurons activated by Amyloid β (1–42) will uncover important molecular mechanisms associated with age-dependent interactions between neurons from healthy versus AD-risk individuals, and resident macrophages of the young and aged brains.
An uncommon presentation of primary sclerosing cholangitis leading to the diagnosis of B cell lymphoma and common variable immunodeficiency
Authors: Cox Katie , Miller Holly , Wadera Sheetal , Goode Erin 
Published: August 2023

Abstract
Common Variable Immunodeficiency (CVID) is a disorder of B cells, with hypogammaglobulinemia and an impaired immune response leading to increased risk of infection, autoimmune complications, and risk of malignancy.
A 17-year-old, previously healthy male presented with three months of pruritus, jaundice and transaminitis. Imaging and biopsy showed liver heterogeneity without evidence of cholestasis or ductal dilation. Over time, imaging was consistent with primary sclerosing cholangitis (PSC). The patient eventually required liver transplant after several complications, despite stent therapy.
Explant liver pathology revealed diffuse large B cell and follicular lymphoma, grade 3A with mature monoclonal B cells follicular in origin, negative for MYC rearrangement and MUM1. PCR detected IgH and IgK B cell clonality. He received chemotherapy without complication, for primary hepatic non-Hodgkin’s lymphoma.
Continued flatulence and diarrhea prompted endoscopy, revealing eosinophilic esophagitis. Due to his variable pathology, he was evaluated for a primary immunodeficiency. His labs demonstrated globally diminished immunoglobulins, a low Hib titer and one pathogenic mutation in TNFRSF13B (c.542C&gt;A; p.Ala181Glu), a transmembrane activator and calcium-modulating cyclophilin ligand interactor (TACI). Thus, the patient was diagnosed with CVID.
This case highlights a unique presentation of CVID from demonstration of PSC and primary hepatic diffuse large B cell lymphoma. Consideration of immunodeficiencies early on in challenging cases of autoimmune and unique oncologic diagnoses may lead to earlier treatment of underlying conditions and prevention of future complications.
Structural insights into human monoclonal antibodies with pan-coronavirus reactivity
Authors: Barnes Christopher O , Abernathy Morgan 
Published: August 2023

Abstract
Human monoclonal antibodies from convalescent individuals that target the SARS-CoV-2 spike protein have been deployed as therapeutics against SARS-CoV-2. However, the emergence of SARS-CoV-2 variants have diminished the efficacy of almost all antiviral monoclonal antibodies. Moreover, most SARS-CoV-2 specific antibodies are inactive against divergent sarbecoviruses and the larger Orthocoronavirinae subfamily. Thus, continued development of immunotherapies resilient to SARS-CoV-2 viral evolution, and capable of recognizing zoonotic coronaviruses with spillover potential is necessary. Using coldspot-guided antibody discovery, a screening approach that focuses on portions of the virus spike glycoprotein that are both functionally relevant and averse to change, we identified human neutralizing antibodies to highly conserved viral epitopes. We identified and structurally-characterized neutralizing antibodies to the fusion peptide, to the stem helix near the heptad repeat 2 region and to subdomain 1 of the spike glycoprotein, that are broadly cross-reactive and protective in vivo. Collectively, our data adds to the growing body of evidence suggesting the potential use of broadly neutralizing antibodies for prophylaxis or therapy against emerging SARS-CoV-2 VOC and future zoonotic spillover events.
C.O.B. is supported by the Howard Hughes Medical Institute Hanna Gray Fellowship and is a Chan Zuckerberg Biohub investigator.