bluuebunny/crossref_metadata_2025_split huggingface dataset:
Plasmablast Ig repertoire dynamics through repeat Plasmodium falciparum challenges reveal signatures of negative selection
Authors: Ferrer Patricia , Frank Andrew , Berry Andrea , Lyke Kirsten , Williamson Kim 
Published: November 2024

Abstract
To understand the development of immunity against malaria, a controlled human malaria challenge (CHMI) model was used to expose malaria-naïve individuals to the same P. falciparum (Pf) strain (NF54) four times over two years. Consistent with the gradual immunity observed naturally, the time to parasite detection increased significantly (delayed patency (DP)) by the 3rd CHMI. Plasmablast Ig repertoire maturation was tracked 7 days after peak parasitemia at each CHMI. Clone copy numbers and CDR3 counts for the major clones (CDR3 &gt;200 or clone copy &gt;20 000) increased significantly after exposure to Pf in all participants with DP and peaked at CHMI-2 in most DP. In contrast, the participants without DP had no significant increase in clone copy number or CDR3 count until CHMI-4. In these major clones, the ratio of replacement to silent mutations (R/S) declined from baseline through the 4 CHMIs and there was a significant decrease in R/S for the 12 Ig heavy chain variable genes associated with anti-Pf immunity in DP only. Phylogenetic analysis indicated that clones with longer tree lengths (more divergence) correlated with increasing negative selection (omega). These patterns suggest that a certain level of B cell activation is needed to reduce parasite replication and DP. However, there is a limit to the maturation of specific clones, possibly because most additional replacement mutations do not improve affinity and are selected against.
Proximal immune-epithelial progenitor interactions drive chronic tissue sequelae post-COVID-19
Authors: Narasimhan Harish , Cheon In Su , Qian Wei , Hu Sheng'en , Parimon Tanyalak , Li Chaofan , Goplen Nick , Wu Yue , Wei Xiaoqin , Son Youngmin , Fink Elizabeth , Santos Gislane , Tang Jinyi , Muehling Lyndsey , Canderan Glenda , Kadl Alexandra , Cannon Abigail 
Published: November 2024

Abstract
The long-term physiological consequences of SARS-CoV-2 – post-acute sequelae of COVID-19 (PASC), are rapidly evolving into a major public health concern. Increasing evidence links PASC to abnormal immune responses and organ recovery post infection but the underlying cellular and molecular etiology remains poorly defined. With insights from 3 independent PASC patient cohorts, we established a clinically relevant mouse model to study post-viral lung disease. Using spatial transcriptomics and imaging, we identified dysregulated proximal interactions between immune cells and epithelial progenitors unique to the fibroproliferation in respiratory PASC but not acute COVID-19 or idiopathic pulmonary fibrosis. Specifically, we found a central role for lung-resident CD8+ T cell-macrophage interactions in maintaining dysplastic epithelial progenitors, thus impairing alveolar regeneration post injury. Mechanistically, CD8+ T cell-derived IFN-γ and TNF stimulated local macrophages to chronically release IL-1β, resulting in the abnormal accumulation of immature epithelial progenitors and lung fibrosis. Notably, therapeutic neutralization of IFN-γ and TNF, or IL-1β after acute infection resulted in markedly improved repair and pulmonary function. In contrast to other approaches requiring early intervention, we highlight therapeutic strategies to rescue fibrotic disease in the aftermath of respiratory viral infections, addressing the current unmet need in the clinical management of PASC.
Longitudinal characterization of CD8+ T cells recognizing a dominant epitope of SARS-CoV-2 spike protein in COVID-19 vaccinated and infected individuals
Authors: Zou Ainslee , Li Jiangyuan , Chen Joseph , Elbahnasawy Mostafa , Choy Cecily , Lu Jian , Reed Quinton , Baptiste Beverly , McKelvey Julia , Melvin Denise , Ruffolo Jeannie , Zukley Linda , Wallace Tonya , Dunn Christopher , Nguyen Cuong , An Yang , Fan Jinshui 
Published: November 2024

Abstract
COVID-19, caused by SARS-CoV-2 infection, sparked an ongoing global pandemic. While cell-mediated immunity is crucial in mitigating the severity and eradicating viral infections, a comprehensive characterization of CD8+ T cell antigen-specificity, frequency, proliferative capacity, and TCR sequences against SARS-CoV-2 in both COVID-19 vaccinated and recovered adults remains incomplete. In this study, we embark on a longitudinal analysis of circulating CD8+ T cells targeting 10 epitopes from the SARS-CoV-2 spike (S) protein across multiple visits from donors spanning three and a half years. Utilizing multi-color flow cytometry with antigen-specific tetramers, we observed frequencies of circulating CD8+ T cells ranging from undetectable to 1% in HLA-A2+ vaccinated and infected individuals. Notably, we did not observe significant differences in spike-specific CD8+ T cell frequencies between vaccinated and infected donors. However, among vaccinated donors, we noted a decline over time in central memory T cells specific to a dominant S protein epitope, S-YLQ (S-269-277, YLQPRTFLL). Our in vitro stimulation assays revealed robust expansion of CD8+ T cells, both in percentage and magnitude, against the S-YLQ epitope compared to other epitopes in infected and vaccinated individuals. Analysis of longitudinal follow-up data spanning three years is ongoing.
Glucocorticoid-mediated immunosuppression prolongs SARS-CoV-2 replication in the lower airways of rhesus macaques
Authors: Nelson Christine , Kauffman Keith , Sakai Shunsuke , Gomez Felipe , Via Laura , Barber Daniel 
Published: November 2024

Abstract
The mechanisms that regulate the balance between pathogenic inflammation and viral control in the respiratory tract during SARS-CoV-2 are not well-understood. Glucocorticoids have improved clinical outcomes in severe cases of COVID-19, but are not recommended in non-hospitalized patients due to limited efficacy. Here, we used rhesus macaques to examine the effects of glucocorticoids (GC) during acute SARS-CoV-2 infection. Rhesus macaques were pre-treated with intravenous methylprednisolone or saline daily for 5 days and then infected with SARS-CoV-2 delta (B.1.617.2) and animals receiving glucocorticoids were maintained on oral prednisolone. GC treated animals had decreased focal lung inflammation, as detected with 18FDG-PET/CT imaging, but prolonged viral replication in the lower airways and the pulmonary lymph node. A kinetics of single cell RNA sequencing from the airways revealed prolonged type I IFN responses during GC treatment. GC treated animals had a reduced influx of plasmacytoid dendritic cells (pDC) and eosinophils. Most of the IFNb1 produced in the lung after infection was not made by pDCs but by inflammatory myeloid cells. SARS-CoV-2 specific CD8 T cell responses in the airways were also reduced with GC treatment, as were B cells and TFH responses in secondary lymphoid organs. Overall, glucocorticoid treatment during SARS-CoV-2 infection reduced lung inflammation, impaired host immune responses, and delayed viral clearance from the lower respiratory tract.
The Autoimmunity-Associated Minor Allele of PTPN22 Enhances Antiviral Immunity During Coronavirus Infection
Authors: Bevis Alec , Shaikh Anam , Kerr Catherine , Barnes Jenna , Rosa Kate , Cockerham Tammy , Schwarting Nancy , Fehr Anthony , Orozco Robin 
Published: November 2024

Abstract
The deadly consequences of viral infection were clearly demonstrated by the COVID-19 pandemic. Therefore, identifying new therapeutic targets to enhance our antiviral immunity and combat virus infection is essential, such as the immune-regulatory gene PTPN22. 5-15% of North Americans express a PTPN22 alternative allele which is linked with multiple autoimmune diseases. However, there is a significant research gap regarding the role of PTPN22 and its common allele during viral infection. To address this, we used CRISPR/Cas9 generated Ptpn22 knockout (PEP-null) and Ptpn22 minor allele expressing (PEP-619WW) mice and infected them with the common murine model of coronavirus, Mouse Hepatitis Virus (MHV) A59. We hypothesize that PEP-null and PEP-619WW mice have enhanced antiviral immunity during coronavirus infection. Following MHV A59 infection, PEP-null and PEP-619WW mice have reduced weight loss and increased survival over WT mice. Additionally, PEP-null and PEP-619WW mice have enhanced innate immunity, such as increased Natural Killer (NK) cell numbers. Furthermore, we show that PEP-null and PEP-619WW innate immune cells offer enhanced protection during MHV A59 infection, but lymphocytes are necessary for survival. These results demonstrate that PEP-null and PEP-619WW are beneficial during coronavirus infection. This research sets the precedent to interrogate the role of Ptpn22 in other RNA virus infections and as a novel therapeutic target to enhance antiviral immunity.
Navigating the Cellular Labyrinth: Unveiling the Molecular Interplay and Expansion Patterns of Intraepithelial T Lymphocytes
Authors: Ran Ran , Brubaker Douglas , Trapecar Martin , Uslu Merve 
Published: November 2024

Abstract
Intraepithelial T lymphocytes (T-IELs) are essential for protecting the intestinal barrier and facilitating a rapid immune response to local antigens. In this study, αβ T cell receptor sequencing and single-cell RNA sequencing were employed to elucidate the complex dynamics of T cells isolated from the colon epithelium and the lamina propria (LP) in three healthy human. The results reveal a significant enrichment of CD8 and γδT cells in the T-IEL population, in contrast to a predominance of CD4 cells in the LP, underscoring the presence of semi-activated antigen-experienced resident memory populations in both tissues. Differential gene expression analysis highlights an upregulation of activator protein-1 (AP-1) components, Jun and Fos, coupled with a downregulation of NF-κB subunits in both αβ CD4 and CD8 TRM cells within T-IELs, without a corresponding increase in cytokine gene transcription, as compared to LP-T cells. Gene set enrichment analysis and pseudotime analysis of LP-T and IEL-T cells from the same clones suggest the activation of an NF-κB-independent TNF pathway, concurrent with the translocation of αβT cells to the epithelium. Additionally, the LP and IEL repertoires share multiple clones, with some of the most abundant cdr3b sequences in both pools showing remarkable similarity to TCRs known to bind influenza A and CMV antigens. TCR clustering using GLIPH2 reveals common motifs across donors, yet most expanded clones in both locations possess distinct TCRs.
Rosiglitazone, a PPAR-γ agonist inhibits extracellular matrix production in TGFβ1 induced intestinal fibrosis.
Authors: Gaowa Arong 
Published: November 2024

Abstract
Intestinal fibrosis, a common complication of intestinal bowel disease and is defined as an excessive deposition of extracellular matrix protein in the intestinal wall. Rosiglitazone, a PPAR-γ agonist, exerts anti-fibrotic effect in several organ fibrosis; however, its inhibitory effect on intestinal fibrosis is still not completely understood. Here, we investigated the inhibitory effects of rosiglitazone on fibrotic gene expression using TGFβ1 induced intestinal fibrosis model. Intestinal organoids were treated with TGFβ1 alone (2 ng/mL) or TGFβ1 plus rosiglitazone (50 uM) for 24 hours. Markers of fibrogenesis, including collagens and fibronectin were evaluated by measuring mRNA level using RT-PCR, and protein level by immunofluorescence or Western blotting. Signaling pathways involved in fibrosis were characterized by Western blotting analysis of cell lysates using indicated antibodies. We found that rosiglitazone significantly suppressed TGFβ1-induced expression of profibrogenic genes (collagen and fibronectin), epithelial to mesenchymal transition and cytokines production in intestinal fibrosis model. Furthermore, it was found that rosiglitazone inhibited the phosphorylation of Smad2/3 and Erk1/2. Taken together, these findings indicate that rosiglitazone exerts potent anti-fibrotic effect in TGFβ1 induced intestinal fibrosis via Smad- and non-Smad pathway.
A distinct autoimmune signature in Post-treatment Lyme Disease Syndrome (PTLD)
Authors: Chen Xin , Zhou Xin , Wang Haozhen , Ji Xuhuai , Rebman Alison , Soloski Mark , Wagner Christine , Snyder Michael , Robinson William , Aucott John , Davis Mark 
Published: November 2024

Abstract
Post-Treatment Lyme Disease (PTLD) is characterized as a persistent inflammatory condition in a large fraction of patients following antibiotic treatment for Borreliella infection, but what leads to PTLD is not known. Here, we analyzed 56 peripheral blood mononuclear cell (PBMC) samples from 23 individuals at risk for PTLD in a multi-year longitudinal study via single-cell RNA sequencing. We found a significant association between an expanded subset of pro-inflammatory monocytes and Lyme disease, a phenomenon notably more prevalent in PTLD patients compared to individuals who have returned to health (RTH). Furthermore, PTLD patients exhibited a range of autoimmune-related phenotypes, absent in healthy and RTH individuals, including a positive correlation between disease severity and CD8+ KIR+ Tregs, functional impairment of CD4+ FOXP3+ Tregs, and heightened lymphocyte cytotoxicity. Interestingly, these phenotypes are associated with the stimulation by a specific peptidoglycan produced by Borreliella and this may be a key driver of PTLD. These findings hold significant potential for the development of targeted therapeutic strategies for PTLD, potentially transforming patient prognosis.
Essential Role of the Pentose Phosphate Pathway Activation in Macrophages for Granuloma Formation in Sarcoidosis
Authors: Nakamizo Satoshi , Sugiura Yuki , Ishida Yoshihiro , Egawa Gyohei , Kabashima Kenji 
Published: November 2024

Abstract
Sarcoidosis is a disease of unknown cause that forms granulomas in various organs, has no specific treatment established. Here, we investigated the mechanism of granuloma formation by applying single-cell RNA sequencing to skin biopsy specimens from human patients with sarcoidosis. In cutaneous sarcoidosis granuloma lesions, there was an increase in macrophages expressing angiotensin-converting enzyme (ACE) and lysozyme, which are known to be elevated in the serum of sarcoidosis patients. These macrophages were hypermetabolic, especially in the pentose phosphate pathway (PPP). Immunostaining of organs from patients with sarcoidosis revealed elevated expression of PPP-related enzymes in granuloma lesions beyond the skin, including those in the lung, lymph nodes, and heart. When human peripheral blood monocytes were cultured with interferon gamma and CD40L, along with concanavalin A (a C-type lectin), there was an elevation in PPP-related enzymes in macrophages, and granulomas with giant cells were formed. Inhibitors of the PPP pathway inhibited granuloma formation. Similarly, PPP inhibitors also suppressed granuloma formation in a mouse model. Until this study, the details and metabolic pathways of granuloma constituent cells were completely unknown. However, our findings have elucidated that macrophages with elevated PPP-related enzymes contribute to granuloma formation and that targeting PPP-related enzymes could be a therapeutic approach in granulomatous diseases.
IL10 signal of lung interstitial macrophages prevents progressive lung fibrosis by suppressing commensal dysbiosis
Authors: Kim Seung Hyeon , White Zachary , Gainulina Anastasiia , Kang Soeun , Kim Jiseon , Dominguez Joseph , Cabrera Ivan , Gunzer Matthias , Hay Nissim , Jung Steffen , Chevrier Nicholas , Sano Teruyuki , Kim Ki-Wook 
Published: November 2024

Abstract
Our understanding of lung microbial ecology underscores the impact of diseases on microbe-host interactions, influencing lung disease pathogenesis. However, the intricate mechanisms governing host immune responses and the lung microbiome remain incompletely elucidated. IL-10, an anti-inflammatory cytokine, crucially modulates immune responses, yet the significance of the IL-10/IL-10 receptor (IL-10R) axis in maintaining lung homeostasis is unknown. We found that IL-10R signaling in lung interstitial macrophages (IMs) preserves balanced lung microbiota, contributing to homeostasis. The lack of IL-10 surprisingly triggered spontaneous lung inflammation, progressing to pulmonary fibrosis without external factors. IL-10R deficiency in CX3CR1-expressing MHC IIhi IMs led to inflammatory phenotypes similar to IL-10-deficient mice. 16S bacterial rRNA sequencing identified dominant colonization of Proteobacteria (e.g., D. acidovorans) and Actinobacteria (e.g., R. erythropolis) in IL-10R-deficient CX3CR1-expressing MHC IIhi IMs mice lungs. Lung inflammation occurred in germ-free (GF) IL10-/- mice after commensal colonization, while GF IL10+/+ mice remained unaffected. Using human fecal microbiota transplantation, we observed that human gut commensals induce lung inflammation in GF IL-10-/- mice. These results highlight the roles of IL-10R-expressing MHC IIhi IMs in lung homeostasis, regulating the interaction between host immune responses and commensal microbiota.
Murine chorioamnionitis alters the neonatal and infant immune response to respiratory syncytial virus.
Authors: Knobbe Jessica , Bermick Jennifer 
Published: November 2024

Abstract
Chorioamnionitis is infection and/or inflammation of the fetal membranes and placenta during pregnancy and is a risk factor for neonatal bronchopulmonary dysplasia (BPD) and childhood asthma and wheezing. BPD and childhood asthma are associated with more severe infection with respiratory syncytial virus (RSV). Despite this, it is unknown whether chorioamnionitis alters the neonatal or infant immune response to RSV. To investigate this, we used a murine model of chorioamnionitis and infected pups with RSV on postnatal days 3-5 (neonate) or postnatal days 14-16 (infant). 5-days post-infection, mRNA was isolated from lungs and analyzed via qPCR for expression of MUC5AC, GOB5, IL1B, IL5, IL6, IL13, IL17A, IFNB, IFNG, RSV-N, RSV-F, RSV-G, and GAPDH. We hypothesized that murine chorioamnionitis-exposed neonatal and infant offspring would display increased severity of RSV infection with increased lung mRNA expression of pro-inflammatory cytokines and a higher viral burden. Our neonatal results displayed significantly lower relative mRNA expression of IL1B in chorioamnionitis-exposed pups (p=0.0035, Mann-Whitney test). Our infancy results displayed increased expression of RSV-N (p=0.0288), MUC5AC (p=0.0594), and GOB5 (p=0.0510), and decreased expression of IFNB (p=0.0101) in chorioamnionitis-exposed pups. In conclusion, murine chorioamnionitis alters both the neonatal and infant immune response to RSV.
B7H3 (CD276) regulation of myeloid cell differentiation in pulmonary fibrosis
Authors: LIU TIANJU 
Published: November 2024

Abstract
Myeloid-derived suppressor cells (MDSCs) are induced in cancer and fibrosis, while absent in healthy tissues. The expansions of MDSC are correlated with disease severity and lung function deterioration in the latter. B7H3 induced in lung fibrosis causes the recruitment of MDSCs. However, the mechanism underlying the biogenesis of MDSCs is unclear. To study if B7H3-induced expansion of MDSCs is due to inhibition of the differentiation of myeloid progenitors, the role of B7H3 in the regulation of BM-derived myeloid cells was studied. The results showed that B7H3 deficiency in BM LysM+ myeloid cells significantly increased differentiation to mature myeloid cells. In contrast, treatment with B7H3 inhibited such differentiation. In mice, LysM+ cells-specific B7H3 deficiency induced mature myeloid cell differentiation, but significantly decreased immature MDSCs, which was associated with less immunosuppressive capability. Lack of B7H3 caused a significant reduction of MDSC marker genes characteristic. Furthermore, the delayed B7H3 antibody treatment or by ablating of its secretion from collagen-expressing cells reduced BM-derived MDSCs and PD1-expressing progenitors but increased mature myeloid cell number, which was accompanied by attenuated lung fibrosis. These findings suggested that activated fibroblasts in lung fibrosis may be a key source of soluble B7H3 essential for the signal to BM skewing myeloid lineage fate and induced biogenesis of MDSC
Effects of Exercise Therapy on Circadian Rhythm Regulation of Neutrophils
Authors: Huang Xingping , Hu Jiannan , Huang Xingping , Liu Shuchang , Guo Xiaorong , Wu Grace , Jayakumar Preethi , Yao Yonghong , Deng Meihong , Huang Hai , Jiang Yi 
Published: November 2024

Abstract
Background: Physical inactivity is recognized as a risk factor for numerous common illnesses, while exercise has been shown to be beneficial. Neutrophils are the first line of cell-mediated defense, with characterized by circadian rhythms. The liver is metabolically active organ that is strongly influenced by circadian regulation. The effects of exercise-induced circadian changes may modify the neutrophils phenotype and function.
Methods: Male mice undergoing a four-week treadmill regimen for 1h at ZT3(3h after lights on). Bone marrow, blood and liver tissue were analyzed at different time points. Circadian genes and neutrophil subpopulations were assessed.
Results: The circulating neutrophil numbers were fluctuated according to a circadian pattern with a peak at ZT3 and a nadir at ZT15. Rhythmicity analysis revealed that the circadian amplitude was increased, but the period and phase were unaltered. Mice subjected to exercise had fewer immature and higher mature neutrophils in bone marrow at ZT3. The expression of clock-related genes in liver, including Arntl and Clock, increased at ZT3, while others, like Per1 were decreased. The number of aged neutrophil follows diurnal patterns with a peak at ZT3, and exhibited a greater percentage and number of neutrophils with an aging phenotype in blood at Exercise group.
Summary: Exercise modulates circadian-dependent neutrophils quiescence, promotes maturation of myeloid neutrophils and driven circulating neutrophil aging phenotype.
Forebrain organoids reveal neuronal capacity to elicit protective antiviral responses.
Authors: Negatu Seble , Vazquez Christine , Bannerman Carl , Ming Guo-li , Jurado Kellie 
Published: November 2024

Abstract
Mosquito-borne arboviruses with potential to cause neurotropic disease are a global health threat. These neurotropic viruses are the most common cause of infectious encephalitis (inflammation of the brain), yet our knowledge of antiviral immune regulation at this site remains limited. Neurons are the highly targeted by these viruses and thus must be important mediators of viral replication and spread. Our studies sought to use La Crosse Virus, an emerging arbovirus, to define intrinsic neuronal orchestration of antiviral responses between infected cells and neighboring uninfected bystanders. We observed widespread infection and viral growth in both murine cortical neurons and cerebral organoids. Transcriptomics approaches revealed infection of cortical neurons induced expression of interferon-stimulated genes (ISGs) in both infected and bystander neurons. In forebrain organoids, we found that uninfected bystander neurons have high ISG expression as compared with neighboring infected neurons. Intriguingly, this bystander activation was capable of restricting viral spread. This finding demonstrates that intraneuronal communication mediates protective antiviral response in the CNS. Future directions aim to define the mediators of communication and the protective antiviral signatures using spatial transcriptomics of infected organoid sections.