bluuebunny/crossref_metadata_2025_split huggingface dataset:
Evolution of inflammation and immunity in a dengue virus 1 human infection model
Authors: Waickman Adam T , Lu Joseph Q , Fang HengSheng , Waldran Mitchell J , Gebo Chad , Van Wesenbeeck Liesbeth , Verpoorten Nathalie , Lenz Oliver , Tambuyzer Lotke , Herrera-Taracena Guillermo , Van Loock Marnix , Endy Timothy P , Thomas Stephen J 
Published: January 2023

Abstract
Dengue virus (DENV) is a significant source of morbidity and mortality throughout the tropics and subtropics. Over 400 million infections are thought to occur every year, resulting in nearly 100 million symptomatic infections and over 20,000 deaths. Early immune response kinetics to DENV infection remain unclear in large part due to the highly variable incubation period exhibited by the virus after introduction into a susceptible host. To fill this knowledge gap, we performed a comprehensive virologic and immunologic analysis of individuals experimentally infected with an under-attenuated DENV-1 strain 45AZ5. This analysis captured both the kinetics and composition of the innate, humoral, and cellular immune response elicited by experimental DENV-1 challenge, as well as the virologic and clinical feature of DENV-1 infection. Revealed in this analysis was an unexpectedly robust DENV-specific IgA antibody response that manifested between the appearance of DENV-specific IgM and IgG in all challenged individuals, as well as the presence of a non-neutralizing/NS1-specific antibody response that was delayed relative to the appearance of DENV-virion specific humoral immunity. RNAseq analysis also revealed several distinct and temporally-restricted gene modules that allowed for the identification and differentiation of the innate and adaptive immune response to DENV-infection. Our analysis provides a detailed description, in time and space, of the evolving matrix of DENV-elicited human inflammation and immunity, and reveals several previously unappreciated immunological aspects of primary DENV-1 infection.
Glycan-specific B-1 cells mediate blockade of endogenous retroviruses emergence through recognition of conserved glycan epitopes
Authors: Yang Yexin , Treger Rebecca , Hernandez-Bird Juan , Iwasaki Akiko 
Published: January 2023

Abstract
Endogenous retroviruses (ERVs), comprising a substantial portion of the vertebrate genome, are remnants of ancient genetic invaders. Although multiple layers of cell-intrinsic control are utilized to prevent retroviral reactivation, ERVs with intact coding potential were found to reactivate in immunodeficient mice. While previous studies have indicated that B cells are indispensable for preventing ERV reactivation, it is not yet clear which B cell population mediates the blockade of ERV emergence to prevent subsequent damage in the host. Here, we employed direct labeling of B cells reactive with emerged ERV particles to characterize the B cell population and clonal repertoire responsible for recognition of ERV, and to study the mechanism by which B cells provide protection against ERV emergence. We found that ERV-reactive B cells are enriched in innate-like B-1 cell compartment that predominantly reside in peritoneal and pleural cavities. We identified ERV-reactive antibodies in unimmunized mice, the level of which further increases upon innate sensor stimulation. B cell receptor repertoire profiling of ERV-reactive B-1 cells revealed increased usage of Igh VH genes that give rise to glycan-specific antibodies, which were further determined to target terminal N-Acetylglucosamine moieties exhibited by endogenous and exogenous viral antigens. We demonstrated that these glycan-specific natural antibodies engage complement pathway to facilitate clearance of reactivated ERV particles. In conclusion, we elucidated the role of glycan-specific B-1 cells and secreted natural antibodies in mediating blockade of ERV emergence through recognition of conserved glycan epitopes.
Supported by grants from Howard Hughes Medical Institute
Importance of microRNAs and gut microbiota in the characterization of a phenotypic drift in lupus-prone MRL/lpr mice.
Authors: Puig Xavier Cabana , Bond Jacob M , Wang Zhuang , Dai Rujuan , Lu Ran , Lin Amy , Oakes Vanessa , Rizzo Amy , Swarwout Brianna , Abdelhamid Leila , Mao Jiangdi , Prakash Meeta , Sangmeister Constanza , Cheung Nathaniel , Cowan Catharine R , Reilly Christopher M , Sun Sha , Ahmed S Ansar , Luo Xin M 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE) is a multi-system autoimmune disease. The cause of SLE is not only genetic; in fact, environmental factors may play a more important role in disease development. The MRL/lpr mouse model lupus-like symptoms due to multiple SLE susceptible loci in the MRL background, and offers an accelerated model compared to the MRL parent strain due to the Faslpr mutation. Recently, our laboratory witnessed a loss of disease phenotype in our in-house colony of MRL/lpr mice. We thus compared mice newly obtained from The Jackson Laboratory (JAX; Stock Number 000485) to our in-house mice. The single-nucleotide polymorphism (SNP) analysis showed no genetic drift, suggesting that environmental factors could be triggering a phenotypic drift. Surprisingly, the newly purchased JAX mice also had attenuation of glomerulonephritis. Even though JAX mice manifested similar attenuation of lupus nephritis, our in-house colony showed differences in organ weights. Furthermore, males showed a significantly higher level of anti-double stranded DNA auto-IgG consistent with germinal center maturation. In addition, in-house males had significantly higher levels of microRNA-21 and microRNA-183 explaining spleen size difference. Moreover, the composition of gut microbiota was different between in-house and new JAX mice at early age, with many groups of bacteria differing at later time points, which might explain some of the phenotypic differences. These results suggest that microRNAs and gut microbiota might be responsible for the phenotypic differences of MRL/lpr mice in JAX and our colonies as they were genetically identical. On the other hand, the attenuation of nephritis in both groups requires further investigation.
Supported by R01AR073240
Dissecting the effect of a novel hypomorphic IL2RB mutation on immune dysregulation.
Authors: Bailey Olivia , Garcia-Perez Josselyn E , Baxter Ryan M , Cabrera-Martinez Berenice , Lui Victor G , Fernandez Isabel Z , Foster Mary J , Gessner Rachel , Gapin Laurent , Pietras Eric M , Kedl Ross , Hsieh Elena 
Published: January 2023

Abstract
Human inborn errors of immunity (IEIs) are a class of genetic disorders caused by monogenic germline mutations that impair the function of the encoded protein. We recently described a novel IEI due to an IL2RB homozygous mutation (p.Pro222_Gln225Del) in two siblings who suffered from multi-organ autoimmunity and CMV susceptibility. This mutation resulted in decreased cell surface protein expression and increased serum IL-2/15 levels, with concomitant increased baseline STAT5 phosphorylation (pSTAT5) but poor pSTAT5 response to IL-2 and IL-15 stimulation. Counterintuitively, this IL-2Rβ hypomorphic mutation led to an expansion of memory CD8+ T and immature CD56bright NK cells, which express the highest levels of IL-2Rβ and require IL-2/15 signaling for survival and differentiation. Yet, their maturation and function appeared impaired, suggesting that both intrinsic (hypomorphic receptor) and extrinsic (serum cytokine milieu) mechanisms were at play. To further interrogate these receptor instrinsic/extrinsic mechanisms we developed a mouse model that harbors the homolog mutation (Il2rbMut/Mut). When mutant bone marrow cells reconstituted a WT host, serum IL-2/15 levels and IL-2Rβ protein surface expression partially normalized, though IL-2/15-induced signaling remained hypofunctional. Additionally, the dysregulated mutant IL-2Rβ-driven CD8+ T cell immunophenotype normalized but the NK phenotype did not. These data highlight the asymmetrical effect that a partial IL-2Rβ defect has on CD8 T and NK cell IL-2/15-dependent signaling and downstream cellular processes. These results imply that strategies to modify serum IL-2/15 levels may serve as a therapeutic approach to treating IL-2/15 signaling defects.
Supported by grants from NIH (T32 AI074491, K23 AR070897)
IgA deficiency destabilizes immunological homeostasis towards intestinal microbiota and increases the risk of systemic immune dysregulation
Authors: Silverman Michael A , Conrey Peyton E , Denu Lidiya , O’Boyle Kaitlin C , Tanes Ceylan , Green Jamal , Bittinger Kyle , Allman David , Lubin Jean-Bernard , Duranova Tereza , Oldridge Derek , Henrickson Sarah 
Published: January 2023

Abstract
Mammals produce large quantities of mucosal and systemic antibodies that maintain the intestinal barrier, shape the intestinal microbiome and promote lifelong mutualism with commensal microbes. Here, we developed an integrated host-commensal approach combining microbial flow cytometry and 16S rRNA gene sequencing to define the population of microbes that induce mucosal and systemic antibodies with CyTOF analysis in pediatric selective Immunoglobulin A (IgA) deficient and household control siblings to determine the impacts of IgA deficiency on host cellular immune phenotype. In healthy controls, mucosal secretory IgA and IgM antibodies coat an overlapping subset of microbes, predominantly Firmicutes and Proteobacteria. Serum IgG antibodies target a similar consortium of fecal microbes, revealing connections between mucosal and systemic antibody networks. Furthermore, we find broad systemic immune dysregulation in a subset of children and mice lacking IgA, including enhanced IgG targeting of fecal microbiota, elevated levels of inflammatory and allergic cytokines and alterations in T cell activation state. Thus, IgA tunes systemic interactions between the host and commensal microbiota. Understanding how IgA affects baseline immune tone has implications for predicting and preventing autoimmune, inflammatory and allergic diseases, as well as providing improved prognostic guidance to patients with IgA deficiency.
Supported by CHOP Microbiome Pilot Grant K08AI135091 Burroughs Wellcome Fund, the American Academy of Allergy, Asthma, and Immunology, the Immune Deficiency Foundation, the Primary Immune Deficiency Treatment Consortium and Chan Zuckerberg Initiative
Profiling the myeloid compartment of PBMC in active tuberculosis reveals substantial changes in CD14+ cells and upregulation of CD16 in pro-inflammatory dendritic cells
Authors: Burel Julie G , Hillman Hannah , Khan Nabeela , Singhania Akul , Dubelko Paige , Casals Ferran Soldevilla , Tippalagama Rashmi , deSilva Aruna D , Scriba Thomas J , Taplitz Randy , Seumois Gregory , Vijayanand Pandurangan , Hedrick Catherine C , Sette Alessandro , Peters Bjoern 
Published: January 2023

Abstract
Tuberculosis (TB) is the second leading infectious killer after COVID-19 worldwide. Gene expression analysis of whole blood and peripheral blood mononuclear cells (PBMC) from TB infected versus uninfected donors suggests that myeloid cells contribute to the immune signature of TB infection. In this study, we carried out the largest cellular and molecular profiling of the circulating myeloid compartment in the context of Mycobacterium tuberculosis (Mtb) infection to date. Using flow cytometry and RNA sequencing, we isolated and interrogated the transcriptomic profile of myeloid cell subsets isolated from PBMC in a cohort of active TB (ATB) patients with paired sampling at diagnosis and mid-treatment, as well as from Mtb sensitized (IGRA+) and unsensitized (IGRA−) healthy individuals. We identified an increased frequency of CD14+ CD16− and CD14+ CD16+ myeloid cells in ATB at diagnosis with upregulated expression of interferon signaling genes that significantly overlapped with previously reported blood TB signatures. In CD14+ CD16+ cells, there was an additional increased expression of MHC-II related genes, which could be traced down to a subset of pro-inflammatory dendritic cells (DCs), namely CD14+ CD163+ DC3. This cell population significantly upregulated CD16 in ATB at diagnosis, thus displaying a CD14+ CD16+ phenotype, similarly to intermediate monocytes. This result also suggests CD16 might play an important role in inflammatory DC function in ATB. Thus, our study demonstrates quantitative and qualitative changes in CD14+ myeloid cells that are contributing to blood TB signatures. Additionally, it reveals phenotypic overlaps between subsets of monocytes and DCs in human blood that may hold disease relevance.
Supported by a grant from NIH (U19 AI118626)
PD-1 inhibition on pulmonary ILC2s promotes TNF-α production and restricts progression of metastatic melanoma tumor growth
Authors: Howard Emily Diane , Hurrell Benjamin P , Helou Doumet Georges , Quach Christine , Painter Jacob D , Shafiei-Jahani Pedram , Fung Marshall , Sharpe Arlene H , Akbari Omid 
Published: January 2023

Abstract
Pulmonary metastatic melanoma is an aggressive form of cancer that is highly resistant to treatment and research efforts targeting this cancer are severely lacking. While pulmonary Group 2 Innate lymphoid cells (ILC2s) represent one of the major tissue-resident innate lymphoid cell populations at steady state and are key drivers of cytokine secretion in their occupational niche, their role in pulmonary cancer progression remains unclear. As the programmed cell death protein-1 (PD-1) plays a major role in cancer immunotherapy and immunoregulatory properties, here we investigated the specific effect of PD-1 inhibition on ILC2s during a pulmonary murine model of melanoma cancer metastasis. We demonstrate that murine models of B16 tumor growth upregulate PD-1 expression on pulmonary ILC2s and that this expression severely promotes tumor growth. Conversely, utilizing targeted murine adoptive transfers we demonstrate that PD-1 inhibition on ILC2s specifically and significantly inhibits tumor growth. Furthermore, the results revealed that PD-1 inhibition upregulated both murine and human ILC2 TNF-α production and secretion, a cytotoxic cytokine that we demonstrate has the ability to directly induce tumor cell death and apoptosis independent of adaptive immunity. Together, the results of these studies may lead to a better understanding of ILC2s and their role in metastatic melanoma, as well as providing a foundation for further elucidation of their anti-tumor mechanisms in cancer progression.
Supported by grants from NIH (R01 ES025786, R01 ES021801, R01 HL144790, R01 HL151493, R01 AI145813 and R01 HL151769)
Innate immune mechanisms underlying sex differences in COVID-19
Authors: Agrawal Anshu , Agrawal Sudhanshu , Salazar Jon , Nguyen James , Rahmatpanah Farah 
Published: January 2023

Abstract
COVID-19 exhibits a sex-bias with males showing signs of more severe disease and hospitalizations compared to females. The mechanisms are not clear but differential immune responses, particularly the initial innate immune response, between sexes may be playing a role. The early innate immune responses to SARS-CoV2 have not been studied because of the gap in timing between the patient getting infected, showing symptoms, and getting the treatment. The primary objective of the present study was to compare the response of DCs and monocytes from males and females to SARS-CoV2 24h after infection. To investigated this, PBMCs from healthy young individuals were stimulated in vitro with the virus. Our results indicate that DCs and monocytes from females displayed increased activation compared to males. In addition, females secreted significantly higher levels of IFN-α and IL-29 early while the secretion of IFN-α was delayed and prolonged in males. Further investigations revealed that the secretion of CXCL-10, a chemokine associated with lung complications, was higher in males than females. The PBMCs from females also displayed increased induction of CTLs. Bulk RNA-seq analysis indicates that IFN related pathways may be upregulated in females at baseline. Altogether, our results suggest that decreased activation of pDCs, mDCs and monocytes, the delayed and prolonged IFN-α secretion along with increased CXCL-10 secretion may be responsible for the severity of COVID-19 in males.
The study is supported by grants R00RG2352 and R01RG3735 to AA from University of California office of the President (UCOP).
Serine Arginine Splicing Factor 7 (SRSF7) is a critical regulator of innate immune activation in macrophages
Authors: Scott Haley M , Wagner Allison R , West Kelsi , Watson Robert , Patrick Kristin L 
Published: January 2023

Abstract
Macrophages are immune cells that receive signals from pathogens and respond by reprogramming gene expression to activate an innate immune response. We currently have a poor understanding of how this response is fine-tuned at a post-transcriptional level. To address this, we turned to recent proteomics studies that identified mRNA processing as a pathway enriched for differentially phosphorylated proteins in macrophages infected with the important human pathogen Mycobacterium tuberculosis (Mtb). We became interested in one of these mRNA processing proteins, a splicing regulatory factor called SRSF7 (formerly known as 9G8), that was differentially phosphorylated at three serine residues during early Mtb infection. Transcriptomics analysis of SRSF7 knockdown RAW 264.7 macrophage-like cells revealed that SRSF7 is required for proper expression of a group of innate immune transcripts including the antiviral genes Mx1 and Ifit3 and the cytosolic DNA sensor Zbp1. Consistent with this phenotype, SRSF7 KD macrophages are permissive to Vesicular Stomatitis Virus (VSV) hyper replication. On the other hand, overexpression of SRSF7 in RAW 264.7 cells leads to elevated ISG abundance in resting cells and enhanced ability to restrict VSV replication. Curiously, it appears that certain ISGs are more reliant on SRSF7 than others, suggesting that SRSF7 acts at the level of the RNA itself. We have started to implicate phosphorylation of SRSF7 in these phenotypes. Together, these studies provide some of the best evidence to date that pathogen sensing cascades can functionalize RNA binding proteins during macrophage activation and highlight a previously unappreciated role for SRSF7 in controlling macrophage antiviral responses.
Supported by grants from 1F31GM143893-01 NIH Predoctoral Fellowship and R35GM133720 from NIH/NIGMS.
Human KIR+ CD8+ T cells target pathogenic T cells in Celiac disease and are active in autoimmune diseases and COVID-19
Authors: Li Jing , Zaslavsky Maxim , Su Yapeng , Guo Jing , Sikora Michael , van Unen Vincent , Christophersen Asbjørn , Chiou Shin-Heng , Chen Liang , Li Jiefu , Ji Xuhuai , Wilhelmy Julie , McSween Alana , Palanski Brad , Mallajosyula Venkata , Bracey Nathan , Dhondalay Gopal , Bhamidipati Kartik , Pai Joy , Kipp Lucas , Dunn Jeffrey , Hauser Stephen , Oksenberg Jorge , Satpathy Ansuman , Robinson William H , Steinmetz Lars , Khosla Chaitan , Utz Paul , Sollid Ludvig , Chien Yueh-Hsiu , Heath James , Fernandez-Becker Nielsen , Nadeau Kari , Saligrama Naresha , Davis Mark 
Published: January 2023

Abstract
Previous reports show a small subset of CD8+ T cells expressing Ly49 proteins in mice can suppress autoimmunity in a model of demyelinating disease. Here we find a markedly increased frequency of CD8+ T cells expressing inhibitory Killer cell Immunoglobulin like Receptors (KIR), the human equivalent of the Ly49 family, in the blood and inflamed tissues of various human autoimmune diseases. Increased KIR+ CD8+ T cells in the gut also correlate with disease activity in Celiac disease (CeD) patients. Moreover, KIR+ CD8+ T cells can efficiently eliminate pathogenic gliadin-specific CD4+ T cells from CeD patients’ leukocytes in vitro. Together with gene expression data, this shows that these cells are the likely equivalent of the mouse Ly49+ CD8+ T cells. Furthermore, we observe elevated levels of KIR+ CD8+ T cells, but not CD4+ regulatory T cells, in COVID-19 and influenza-infected patients, and this correlates with disease severity and vasculitis in COVID-19. Single-cell RNA and parallelized TCR sequencing reveals that expanded KIR+ CD8+ T cells from these different diseases and healthy subjects display shared phenotypes and similar T cell receptor sequences. Selective ablation of the murine counterpart in virus-infected mice leads to exacerbated autoimmunity developed after infection. These results characterize a regulatory CD8+ T cell subset in humans which we hypothesize functions to control pathogenic cells in autoimmune and infectious diseases, with important implications for the cellular dynamics and possible therapeutic approaches to suppress unwanted autoimmunity.
Supported by National Institutes of Health U19-AI057229 Howard Hughes Medical Institute Stanford Diabetes Research Center (P30DK116074)
Acid β-glucosidase insufficiency activates the C-X-C Motif Chemokine Ligand 9/CXCR3 axis leading to T cell mediated inflammation in Gaucher disease
Authors: Pandey Manoj K , Magnusen Albert Frank , Trivedi Vyoma Snehal , Hatton Shelby Loraine , Rani Reena , Nyamajenjere Tsitsi Carol , Magnusen Daniel Nii Aryee , McKay Mary Ashley , Woods Christopher , DiPasquale Betsy Ann , Köhl Jörg , Grabowski Gregory Alex 
Published: January 2023

Abstract
Gaucher disease (GD) is caused by GBA1 mutations that lead to decreased activity of lysosomal acid β-glucosidase and abnormal tissue accumulation of its substrate, glucosylceramide (GC). Monocyte lineage cells, e.g., macrophages (Mφs) and dendritic cells (DCs) are prominent disease effectors due to their massive accumulation of GC resulting in “Gaucher cells.” Interaction of Gaucher cells and T lymphocytes trigger massive secretion of IFNγ, TNFα, IL6, IL12p40, IL12p70, IL23, and IL17A/F, that leads to the tissue destruction in GD. The exact mechanisms that trigger excess tissue T cells recruitment in GD are still unclear. CXCR3+ T cells are enriched at inflammatory sites in patients with rheumatoid arthritis and multiple sclerosis. Using D409V/null (Gba19V/−) GD mouse model, this study uncovered the role of CXCR3 receptor and its C-X-C Motif Chemokine Ligand 9 (CXCL9) in induction of excess tissue recruitment of T cells in GD. Intracellular FACS staining of Mφs and DCs from Gba19V/− mice showed elevated amounts of CXCL9. CD4+ T and the CD8+ T cells purified from Gba19V/− mice showed increased amounts of CXCR3. Ex vivo and in vivo chemotaxis experiments, evaluated CXCL9’s recruitment of Gba19V/− T cells. Blockade of T-cell CXCL9 receptor using antibodies to CXCR3 caused marked reduction in their CXCL9-mediated chemotaxis in Gba19V/− mice. These data suggest that Gba1 defects and the resultant deficiency of acid β-glucosidase activate CXCL9-CXCR3 axis for enhanced tissue Tells recruitment of T cells in GD. Collectively, our results indicate a critical role for CXCR3 mediated T cell transmigration to sites of inflammation. Molecular targeting of CXCL9/CXCR3 axis may provide needed anti-inflammatory therapies in human patients with GD.
Supported by Cincinnati Children’s Hospital Medical Center, 3333 Burnet Avenue, Cincinnati, Ohio 45229, USA