bluuebunny/crossref_metadata_2025_split huggingface dataset:
Prior infection exposure alters the immune response at homeostasis and following SARS-CoV-2 vaccination and experimental infection in laboratory mice
Authors: Baxter Victoria Kate , Knight Audrey C , Dillard Jacob A , Anderson Elizabeth J , Pressey Katia D , Hampton Brea K , Taft-Benz Sharon A , Martinez Sabian A , Kamat Kalika D , Cruz Cisneros Marta C , Madden Emily A , Heise Mark T , Ferris Martin T 
Published: August 2023

Abstract
Variable translatability represents a major criticism of the use of mouse models for preclinical research. Lack of exposure to most endogenous murine pathogens results in natural immune responses of specific pathogen free (SPF) lab mice to more closely resemble that of newborns rather than adult humans. Recently, the effects of prior infection exposure (PIE) on immune maturation and responses have been increasingly explored in mice. Here, we employed a PIE model where BALB/c mice underwent sequential subclinical infection with four pathogens at two-week intervals: 1) MHV-68, a gammaherpesvirus, 2) MCMV, a betaherpesvirus, 3) influenza virus, and 4) Heligmosomoides polygyrus, a murine intestinal nematode. Four-to-12 weeks following H. polygyrus infection, mice were sacrificed, spleens were collected for flow cytometric analysis, and lungs were collected for histological evaluation. Compared to SPF mice, PIE spleens demonstrated increased proportions of CD4+ and CD8+ T effector memory cells. In the lungs, PIE induced the formation of bronchus-associated lymphoid tissue and increased infiltration of CD4+ and CD8+ T cells. Following vaccination against SARS-CoV-2 with either a protein subunit-based (S2P) or inactivated (iCoV2) vaccine, iCoV2-, but not S2P-, vaccinated PIE mice demonstrated significantly reduced serum neutralizing antibodies compared to SPF mice. Following infection with SARS-CoV-2-MA10, PIE mice showed a mild reduction in mortality, weight loss, and lung titers, and a significant increase in lung T cell infiltration compared to SPF mice. These data indicate that PIE results in adaptive immune maturation but has a variable effect on SARS-CoV-2-specific vaccine responses and clinical outcomes in mice.
This work was supported by the NIH (K01OD026529, T32AI007151, U19AI100625, U19AI09680), an AAI Careers in Immunology Fellowship Award, an UNC School of Medicine Junior Investigator Development Award, and a NCTraCS and Emerging Challenges in Biomedical Research COVID Pilot Award.
Alteration of metabolite landscape in hypoxia replicates immune cell programs indicative of dysfunctional immunity in severe COVID-19
Authors: Thompson Elizabeth A , Stoddart Laila , Ngecu Wabathi , Cascino Katherine , Karaba Andrew H , Cox Andrea L 
Published: August 2023

Abstract
Our prior work has demonstrated that altered metabolic programs in T cells define dysregulated immunity in acute SARS-CoV-2 infection. Apoptotic T cells were defined by high expression of the mitochondrial membrane protein voltage-dependent anion channel 1 (VDAC1). These cells were markedly increased in elderly patients and correlated with lymphopenia. We devised in vitro systems in healthy T cells to investigate the mechanism driving this unique phenotype. While SARS-CoV-2 did not directly induce this T cell phenotype, factors that enhanced the development of VDAC1+ T cells, including hypoxia, advanced age of healthy T cell donor, and COVID-19 patient-derived plasma. Analysis of patient-derived plasma revealed robust differences in cytokine and metabolomic profiles between people who did or did not exhibit apoptotic T cells. Increased flux through the tryptophan:kynurenin pathway has been suggested as a biomarker of severe COVID-19 and was further enhanced in individuals with apoptotic T cells. Kynurenine directly induced VDAC1+ T cells in a dose dependent manner in vitro. Together, our work indicates metabolic alterations combined with cellular age and hypoxia may induce apoptosis of T cells following SARS-CoV-2 infection. This work highlights mechanisms leading to cellular alterations following infection and highlights key aspects of the host environment that could be targeted therapeutically.
U54CA260492
Elucidating the role played by the NKG2 family of receptors in natural killer cell responses to JC polyomavirus
Authors: Lee Esther , Ahn Jenny , Chen Sarah , Gikundiro Kayitare Eunice , Craemer Melissa , Gressens Simon , Yoder Taylor , Lifton Michelle , Tan C Sabrina , Jost Stephanie 
Published: August 2023

Abstract
JC polyomavirus (JCPyV) causes progressive multifocal leukoencephalopathy (PML), a potentially fatal complication of severe immune suppression due to monoclonal antibody treatments for cancer, autoimmune diseases and transplantation, or due to uncontrolled HIV infection. There is currently no effective treatment against PML and novel immunotherapies are urgently needed. Natural killer (NK) cells play critical roles in defense against viral infections, yet NK cell responses to JCPyV remain largely unexplored. Here, we first compared NK and T cell responses against JCPyV VP1 peptide pools by intracellular cytokine staining. In about 40% of healthy donors, we detected robust CD107a upregulation and IFNγ production by NK cells, extending beyond T cell responses. Next, using a novel flow cytometry-based killing assay, we showed that co-culture of NK cells and JCPyV-infected SVG-A cells led to a 65% reduction in infection, on average. To identify receptor-ligand interactions modulating NK cell-mediated responses to JCPyV, we performed co-cultures in the presence of select blocking antibodies. We observed enhanced expression of ligands for the activating NKG2D on infected cells and accordingly, NKG2D blockade resulted in decreased NK cell degranulation. In contrast, blockade of inhibitory NKG2A enhanced NK cell response to JCPyV-infected targets. Moreover, we identified JCPyV-derived peptides that elicit dominant NK cell responses and can stabilize HLA-E, the ligand for NKG2A and the activating NKG2C. Altogether, these findings suggest that modulation of NKG2D and NKG2A/C signaling may play key roles in NK cell-mediated control of JCPyV and may be promising immunotherapeutic targets to boost NK cell anti-JCPyV activity.
Supported by grant from NIH (R01 NS116278)
Neuroinvasive EV-D68 infection in cerebral organoids mimics human pathology
Authors: Vazquez Christine , Han Beatrice , Bannerman Carl , Negatu Seble G , Bongiovanni Angelina , Lanoce Emma , Ming Guo-Li , Jurado Kellie Ann 
Published: August 2023

Abstract
Emerging viruses with the capacity to cause neurological disease remain a global health threat. One such virus, Enterovirus-D68 (EV-D68), has recently received attention due to an associative rise in cases of a polio-like paralytic disease called acute flaccid myelitis (AFM) in some children. Although EV-D68 was identified in the 1960s (prototypic strain Fermon), circulating neuroinvasive EV-D68 strains have evolved to infect cells of the central nervous system. AFM remains a rare infection outcome, suggesting that host immune responses may play a role in limiting disease. Studies of such immune responses as well as tools to examine these responses remain limited. To this end, we seek to understand how neuroinvasive and non-neuroinvasive EV-D68 differentially modulate immune responses using both neuronal cultures and cerebral organoids.
We infected neuroblastoma cells (SH-SY5Y cells) with Fermon and neuroinvasive EV-D68 and found that both viruses were able to replicate in these cells, which is different from what is observed during human disease. Thus, to better dissect strain differences and model human disease, we generated cerebral organoids and infected with our EV-D68 strains. We now found that cerebral organoids were more permissive to neuroinvasive EV-D68 infection compared to Fermon. Further, we found that neuroinvasive EV-D68 infection led to a global increase in the interferon-stimulated gene IFIT1 activation, whereas Fermon infection led to modest IFIT1 activation in bystander cells. These data suggest that immune responses can better control Fermon infection compared to neuroinvasive EV-D68, and also highlight the utility of using cerebral organoids to examine neurotropic virus regulation of immune responses.
Supported by grants from the Burroughs Wellcome Fund and the Office of the University of the Provost
Immune-history based correlates of protection for respiratory infections
Authors: Hertz Tomer , Levy Shlomia , Oppenheimer Hanna , Zismanov Shosh , Friedman Lilach M , Nesher Lior 
Published: August 2023

Abstract
There is growing evidence that immune-history biases responses to vaccination and natural infections. We hypothesized that immune-history antibody profiles can be used to predict risk of infection from respiratory viruses. To study the predictive power of immune-history, we utilized samples from influenza and SARS-CoV-2 clinical trials, in which symptomatic infections were identified using PCR. We used antigen microarrays to generate baseline antibody profiles to (1) a panel of influenza HA and NA proteins spanning the antigenic evolution of A/H1, A/H3 and B human influenza viruses; and (2) to a panel of SARS-CoV-2 variants of concern spike. While there was extensive heterogeneity in baseline immune history of different individuals, we identified IgG and IgA baseline markers that were correlates of risk using logistic regression models adjusted for baseline covariates. Since IgA and IgG profiles were weakly correlated, we then considered combinations of IgG and IgA markers as correlates of risk. We found that combinations yielded improved correlates of protection.
Most importantly, we identified a subset of individuals with low baseline antibody levels that responded with a significant boost in neutralizing antibody titers after vaccination, but were still at significantly increased susceptibility to infection when compared to those who had pre-existing high levels of binding antibodies. Thus, we identify a highly susceptible population that remains susceptible despite apparent responsiveness to vaccines. Our data demonstrate that baseline binding antibody markers are significantly associated with infection risk and may be utilized to identify individuals most at risk from future exposures.
Supported by grants from NIH (75N93021C00016) and the Israeli Science Foundation (882/17 and 2683/21)
Macrophage scavenger receptor 1, a suppressor of HIV infection, is down-regulated in transgender females
Authors: Chang Theresa Li-Yun , Wang Annie , Herbst Alisa C , Hernandez Cyril , Vaishnav Jeet , Lemenze Alexander , Swaminathan Shobha , Piazza Michelle Dalla , Finkel Diana , Bentsianov Sari , Roche Natalie 
Published: August 2023

Abstract
Transgender people are at greater risk than cisgender people of acquiring HIV and other sexually transmitted infections. Globally, the risk of acquiring HIV infection is nearly 49 times higher in transgender women than in other populations. Although behavioral and psychosocial factors contribute to the higher HIV risk in transgender people, gender-affirming hormone (GAH) (i.e., testosterone for transgender individuals assigned female at birth or estrogen/antiandrogen for transgender individuals assigned male at birth) may alter immune cell functions, resulting in increased HIV transmission. We have profiled gene expression of PBMCs from transgender females and males and have identified four specific genes (MTND1P23, IGSF10, MSR1, and DUXAP9) that were differentially expressed in transgender females. Among these genes, macrophage scavenger receptor 1 was down-regulated 0.5- or 0.4-fold compared to cis females and cis males, respectively. Transient expression of MSR1 suppressed in vitro HIV infection, suggesting that MSR1 protects cells against HIV. The data indicate that down-regulation of MSR1 in transgender women may play a role in their increased HIV risk. Future studies on the mechanisms by which MRS1 inhibits HIV infection may offer new strategies for HIV prevention in transgender women.
NIH R21AI55322
Dendritic cell intrinsic role of Ptpn22 and its pro-autoimmune allele enhance anti-viral immunity
Authors: Orozco Robin C , Shaikh Anam , Nasiri Saeideh , Barnes Jenna , Howard Andrew , Orozco Robin 
Published: August 2023

Abstract
The tyrosine phosphatase PTPN22 encodes the enzyme Lyp (PEP in mice) in all immune cells. 5–10% of the North American population expresses the PTPN22 autoimmunity risk allele 1858C&gt;T (rs2476601) causing amino acid substitution R620W (R619W in mice). This mutation alters lymphocyte activation, toll-like receptor signaling, and cytokine production. Ptpn22 knockout (PEP-null) and alternative allele-expressing (PEP-R619W) mice clear persistent virus LCMV-cl13, have enhanced anti-viral T cell function, and a more immunostimulatory dendritic cell (DC) phenotype compared to wildtype (PEP-WT). Adoptive transfer studies suggest a T cell extrinsic mechanism driving enhanced T cell function in PEP-null and -R619W animals. However, the relative contribution of PEP-differing non-T cells during virus infection is not known. We hypothesize that the DC, as the sole PEP-differing cell, is the critical non-T cell driving increased T cell function and enhanced anti-viral immunity. To interrogate this, we employ CD11c Ptpn22 conditional knock out (cKO) mice and bone marrow derived DC (BMDC) cultures from PEP-WT, -null, and -R619W mice. During LCMV-cl13 infection, CD11c Ptpn22 cKO mice have improved disease outcome compared to WT mice. In a T cell: DC co-culture assay, both PEP-null and PEP-R619W DCs lead to more CD4 T cell function over WT DCs. Also, PEP-null and PEP-R619W BMDCs have changed response to virus infection. Taken together, these data suggest Ptpn22 and its allele have DC intrinsic mechanisms that alter anti-viral immunity. Results of this study lead to a more complete understanding of the cellular and molecular mechanisms, particularly in the DC, this common allele alters the immune response during infection.
Supported by grants from the University of Kansas (KU), KU CBID CoBRE Research Award, and KU Center for Genomics.
PI3Kδ shapes Th2 lineage restriction through coordination of IL-2 signaling, Foxo1 inactivation and epigenetic remodeling
Authors: Golec Dominic P , Gazzinelli-Guimaraes Pedro , Chauss Daniel , Hill Tom , Nivelo Luis , Joshi Ilin , Pereira Nicolas , Druey Kirk M , Lack Justin , Afzali Behdad , Villarino Alejandro , Nutman Thomas B , Schwartzberg Pamela L 
Published: August 2023

Abstract
Activated PI3K-delta syndrome (APDS) is a primary immunodeficiency caused by heterozygous activating mutations in PI3Kδ, resulting in recurrent infections as well as allergic diseases. Given that APDS patients show an inability to clear respiratory pathogens (Th1) and development of allergic diseases (Th2), we hypothesized that hyperactivated PI3Kδ (Pik3cdE1020K) may alter CD4 T cell differentiation. Using in vitro polarization of murine naïve CD4 T cells, we observed increased production of IFNγ from Pik3cdE1020K mice under Th1 inducing conditions and marked increases in IL-4 and IL-13 production under Th2 conditions. However, Pik3cdE1020K Th2 cells also expressed high levels of Tbet and aberrantly produced IFNγ. Strikingly, this dysregulation was also observed in vivo; Pik3cdE1020K CD4 cells show pronounced alterations following house dust mite induced airway inflammation, with impaired Th2 and inappropriate polarization to Th1 responses as visualized by scRNAseq. We linked this unstable Th1 and Th2 differentiation in Pik3cdE1020K CD4 T cells in vitro to hyper-responsiveness to IL-2, associated with increased phosphorylation and inactivation of transcription factor Foxo1. CRISPR-mediated targeting of Foxo1 in naïve WT CD4 cells recapitulated the Pik3cdE1020K phenotype. Transcriptomic analysis of Pik3cdE1020K CD4 T cells revealed differential expression of genes involved in histone methylation. Accordingly, Pik3cdE1020K CD4 exhibit altered chromatin modifications, including H3K27 and H3K4 trimethylation. Together these data suggest that balanced regulation of PI3Kδ plays a critical role in enforcing Th1 and Th2 lineage identity.
This research was supported by the Intramural Research Program of NIAID, NIH
BRWD1 establishes germinal center B cell epigenetic states to prevent apoptosis and inflammation
Authors: Wright Nathaniel E , Kennedy Domenick , Veselits Margaret , Ai Junting , Gurbuxani Sandeep , Maienschein-Cline Mark , Mandal Malay , Clark Marcus R 
Published: August 2023

Abstract
Germinal centers (GCs) drive adaptive humoral immunity by selecting for B cells with high affinity antibodies and producing memory B cells and plasma cells. We previously defined three GC B cell subpopulations that are undergoing either selection, proliferation, or somatic hypermutation with distinct transcriptional and chromatin accessibility profiles. We hypothesized that the epigenetic reader BRWD1, which regulates chromatin accessibility during B cell lymphopoiesis, also regulates the chromatin accessibility and differentiation of GC B cells. To study the role of BRWD1 in GC B cells, we generated Aicdacre × Brwd1fl/fl mice and performed ATAC-seq to measure chromatin accessibility. Loss of Brwd1 caused an epigenetic collapse whereby differential chromatin accessibility between GC B cell subpopulations was lost. This was accompanied by SPIB and PU.1 binding motifs becoming more accessible among GC B cell subpopulations. Functionally, loss of Brwd1 promoted proliferation, and GC structures were larger and more frequent. However, the rate of somatic hypermutation was unaltered. Interestingly, Brwd1-deficient GCs had massive apoptotic debris by histology, which was consistent with strong inflammatory and apoptosis transcriptional signatures measured by RNA-seq. Finally, Brwd1 deletion caused a decrease in pre-memory B cell differentiation, and resultant plasma cells had decreased immunoglobulin mutations. We conclude that BRWD1 regulates chromatin accessibility to compartmentalize the molecular functions of each GC B cell subpopulation and to prevent apoptosis-induced inflammation.
This research was funded by grants R01 AI143778 and F30 AI174324 from the NIH/NIAID.
IL-12 drives the differentiation of human T follicular regulatory cells
Authors: Locci Michela , Castano Diana , Wang Sidney , Sharpe Hannah , Bustamante Jacinta , Yang Emily , Feng Allan , Le Coz Carole , Romberg Neil D , Utz P J , Henrickson Sarah E , Casanova Jean-Laurent 
Published: August 2023

Abstract
T follicular regulatory (Tfr) cells can counteract the B cell-helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cues initiating the differentiation of T regulatory (Treg) cells into Tfr cells, which is instrumental for the therapeutic manipulation of diseases associated with a Tfr cell imbalance, is still missing. Despite their opposed roles, Tfr and Tfh cell differentiation appears to be controlled by partially overlapping signals, including TCR stimulation and costimulatory molecules. However, it is still unknown if cytokines that have been shown to control the biology of human Tfh cells, including IL-12 and activin A, can influence the differentiation of Tfr cells. To address this question, we evaluated the impact of these two cytokines on the in vitro differentiation of Tfr cells. Herein, we report a role for IL-12 in driving, on activated Treg cells, the induction of molecules that belong to the Tfr cell program, including CXCR5, PD-1, BCL6 and ICOS meanwhile preserving Tfr regulatory function. Conversely, activin A presented a largely negligible effect on the in vitro differentiation of Tfr-like cells and only modestly strengthened the IL-12-driven differentiation of Tfr-like cells. Importantly, patients with inborn errors of immunity in IL12RB1 gene presented with a severe decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides a novel approach for the in vitro generation of human Tfr-like cells.
AI123738
Cellular cholesterol homeostasis supports visceral adipose tissue (VAT) regulatory T cell (Treg) accumulation and promotes metabolic health
Authors: Elkins C , Sivasami Pulavendran , Bae Jennifer , Li Chaoran 
Published: August 2023

Abstract
A unique population of regulatory T cells (Tregs), characterized by a clonally expanded TCR repertoire and distinct transcriptional profile, is highly enriched in the visceral adipose tissue (VAT) at steady state but is lost during obesity, which exacerbates VAT inflammation and promotes metabolic disease. Therefore, understanding the factors that control the accumulation of VAT Tregs, which might be dysregulated during obesity, is important for developing novel therapies for obesity-associated metabolic diseases. Here we show that cellular cholesterol homeostasis is particularly important for VAT Treg accumulation and function. First, bulk RNA sequencing analysis of VAT Tregs from mice fed long-term high fat diet (HFD) showed a reduction in gene expression involved in cholesterol homeostasis (CH), corresponding to loss of VAT Tregs in vivo. Second, we found that VAT Tregs showed increased cholesterol-associated gene expression, cholesterol levels, and cholesterol uptake compared to lymphoid Tregs at steady state, suggesting this pathway is particularly important for VAT Tregs. Third, CRISPR-Cas9-mediated ablation of Srebf2, the master regulator of cholesterol homeostasis, followed by adoptive Treg transfer or Treg-specific germline deletion of Srebf2 (Foxp3cre Srebf2-flox) reduced Tregs in the VAT, but not those in other tissues. Deletion of Srebf2 in Tregs also increased VAT inflammatory cytokine expression, inflammatory cell infiltration, and insulin resistance in mice following short-term HFD feeding. These data highlight an importance of cellular CH for VAT Treg accumulation and function and implicate this pathway as a potential therapeutic target for treatment of obesity-associated metabolic diseases.
NIH R01 (5R01DK128061-02)
miR-21 promotes B cell autoreactivity, inflammatory signaling, and metabolism in TLR7-driven systemic autoimmunity
Authors: Bricker Kristen N , Fike Adam J , Luckenbill Sara A , Weber Julia L , Jackson Jasmine S , Olsen Nancy J , Rahman Ziaur 
Published: August 2023

Abstract
MicroRNA-21 (miR-21) is upregulated in SLE patients and promotes disease in multiple autoimmune mouse models; however, mechanisms by which miR-21 promote autoimmunity are unknown. Here we show that TLR7 overexpressing SLE-prone B6.Sle1bYaa mice deficient in miR-21 (Sle1bYaamiR-21−/−) resisted autoimmunity development through reduced germinal center (GC) B cell, T follicular helper cell, and plasma cell responses. Sle1bYaamiR-21−/− mice had reduced serum autoantibody titers and numbers of autoantibody-producing antibody forming cells (AFCs) in the spleen and bone marrow. Downstream of TLR7 signaling, PELI1, a negative regulator of the NF-κB family member c-Rel and a direct target of miR-21, was increased in Sle1bYaamiR-21−/− B cells. Consequently, Sle1bYaamiR-21−/− B cells had reduced c-Rel expression and proinflammatory cytokines IL-6 and IL-1β. Additionally, Sle1bYaamiR-21−/− B cells had reduced oxidative phosphorylation, glycolysis, and mitochondrial membrane potential compared to Sle1bYaa B cells. To define the cell-intrinsic mechanisms, we generated B cell-, T cell- and DC-specific miR-21 conditional knockout (cKO) mice on the Sle1bYaa background. Reduced B cell autoreactivity, inflammatory signaling, and metabolism in Sle1bYaamiR-21−/− mice were recapitulated in B cell-specific miR-21 cKO mice. T cell-specific miR-21 cKO mice had a moderate reduction in cellular responses due to reduced co-stimulatory molecules and glycolysis; however, autoimmune responses remained intact. miR-21 deficiency in DCs had no deficit in cellular or autoimmune responses. Our data substantiate a B cell-intrinsic role for miR-21 in promoting inflammatory signaling and metabolic activity in B cells, leading to autoimmunity.