bluuebunny/crossref_metadata_2025_split huggingface dataset:
A Protein Subunit Filovirus Vaccine Facilitates Maternal Immunization in Mice
Authors: Williams Caitlin , Wong Teri Ann S. , Lehrer Axel T. 
Published: February 2023

Abstract
Ebola virus disease (EVD) is highly pathogenic and virulent and has caused large scale outbreaks in Central and West Africa. To date there are no known correlates of protection however, recently the FDA and EMA have approved a vaccine, Ervebo. This vaccine utilizes a replication competent viral vector which may be contraindicated in immunocompromised individuals, pregnant women, and infants. Our lab has developed a recombinant protein subunit vaccine, a platform that is generally considered safe for immunocompromised, pregnant women, and infants. Our vaccine, when properly adjuvanted, demonstrates protection in non-human primates and may also induce maternal immunization. Maternal Immunization is the phenomena of inducing passive immunity via maternal antibody. This occurs via transfer of IgG using the FcRn. This receptor binds the Fc portion of IgG in a pH dependent manner which facilitates transcytosis of IgG across the placental, mammary tissue, as well as gut epithelial layer. In rodents, maternal IgG is transferred across the gut epithelia throughout the nursing period. This project demonstrates in mice the immunogenicity of a protein subunit vaccine comprised of Ebola glycoprotein and adjuvant administered during gestation as well as the transfer of antigen specific maternal antibody to offspring through milk. To investigate maternal immunization we vaccinated female Swiss Webster mice during gestation and measured antigen specific IgG levels in both the mothers and pups as well as in the milk. Antigen specific maternal antibody titers found in pup sera mimic those found in fully immunized adult females weeks after weaning, indicating the potential for maintaining an antigen specific humoral response in neonates.
Intravenous BCG protects SIV+ macaques from tuberculosis.
Authors: Larson Erica C , Rodgers Mark A , Ellis Amy L , Ameel Cassaundra L , Gleim Janelle L , Gubernat Abigail K , Balgeman Alexis , Moriarty Ryan V , Darrah Patricia A , Maiello Pauline , Roederer Mario , Seder Robert A , O’Connor Shelby L , Scanga Charles A 
Published: February 2023

Abstract
Tuberculosis is the most common cause of death due to infection in people living with HIV (PLHIV). BCG, a live attenuated Mycobacterium bovis strain given intradermally to infants, is the only licensed vaccine to prevent TB. However, intradermal BCG offers little protection from pulmonary TB in adults and safety concerns limit its use in PLHIV. Recently, intravenous (IV) BCG has been shown to provide striking protection from TB in rhesus macaques. Given this dramatic success, we tested whether IV BCG could protect macaques with a pre-existing SIV infection using our established model of SIV/Mtb coinfection in Mauritian cynomolgus macaques (MCM). MCM were intrarectally infected with SIVmac239 and 5 months later were vaccinated with BCG at 8 ×107 CFU delivered IV. To prevent disseminated BCG disease in immunocompromised animals, four weeks after IV vaccination animals were treated with an 8-week regimen of isoniazid/rifampin/ethambutol (HRE). Four weeks after HRE cessation, animals were challenged with low-dose Mtb Erdman. SIV+ MCM exhibited no signs of BCG disease before or after HRE treatment. Following BCG vaccination, a rapid and sustained increase in airway T cells was observed in both SIV+ and SIV-naïve animals. Increased antibody titers to Mtb lysate were observed in plasma and airways following IV BCG. PBMC responses to Mtb-specific stimuli by IFNγ ELISpot indicated rapid and early clearance of Mtb in vaccinated animals regardless of SIV infection. All SIV-naïve (n=7) and 7 out of 10 SIV+, vaccinated animals were free of TB and without culturable bacilli in their tissues at 12 weeks post challenge. Flow cytometric analysis of PBMCs and tissues obtained at necropsy are underway to further define immune correlates of protection.
In-vivo engineering of B cells elicits memory retention and allows for secretion of broadly neutralizing antibodies in mice
Authors: Nahmad Alessio David , Lazzarotto Cicera , Zelikson Natalie , Kustin Talia , Tenuta Mary , Huang Deli , Reuveni Inbal , Horovitz-Fried Miriam , Dotan Iris , Rosin-Arbesfeld Rina , Nemazee David , Voss James , Stern Adi , Tsai Shengdar , Barzel Adi 
Published: February 2023

Abstract
A potential single-shot HIV therapy may be transplanted engineered B cells allowing strong secretion of broadly neutralizing antibodies (bNAbs). However, extensive, and expensive ex-vivo manipulations performed in specialized facilities hinders clinical potential of this approach. Furthermore, allogeneic B cell therapy necessitates MHC-II compatibility to receive mandatory T-cell help.
To overcome these limitations, we engineer B cells in-vivo. In particular, we demonstrate that a single, systemic dose of dual AAV, one coding for CRISPR/Cas9 and another coding for a bNAb donor cassette, allows for site specific integration in B cells. Following immunizations, we show memory retention and bNAb secretion at high titers. Antibodies secreted by the engineered B cells were found to be of multiple isotypes and IgGs could neutralize autologous and heterologous pseudoviruses. We found engineered B cell subsets in the spleen and blood. We detected homing of in-vivo engineered cells to germinal centers and bone marrow. Biodistribution of the donor AAV over time and as compared to a CRISPR- group, indicated expansion of engineered B cells in lymphatic tissues. We determined minimal CRISPR/Cas9 off-target cleavage, using unbiased, highly sensitive, CHANGE-Seq analysis. Finally, we diminished on-target, non-productive double-strand breaks at undesired tissues by expressing Cas9 from a B cell specific promoter.
Eliciting a specific, neutralizing serological response to hypervariable viruses is a long-standing challenge in medicine. B cell engineering provides an opportunity to express therapeutic antibodies to generate an adaptive and evolving immunity.
Regulation of Inflammatory Bowel Disorder Inflammation by ST8Sia6
Authors: Crotts Sydney B , Friedman David J , Shapiro Michael J , Rajcula Matthew , Shapiro Virginia Smith 
Published: February 2023

Abstract
Inflammatory bowel disorders (IBD), including Crohn’s disease and colitis, have a prevalence between 10–20%. IBD patients experience a reduced quality of life due to symptoms such as diarrhea, abdominal cramps, anal bleeding. The exact etiology of IBD is incompletely understood, but the immune response plays a critical role. Innate immune cells integrate the sum of stimulatory and inhibitory signals to determine overall activation. Solidifying the roles of pertinent proteins and their interactions is critical in mapping the immune response and understanding the implications of clinical treatment of IBD. ST8Sia6 is a sialic acid transferase which adds terminal a2,8 disialic acids to cell surface glycoproteins, and we have found that ST8Sia6 generates ligands for Siglec-2 and Siglec-E on innate immune cells, including colonic macrophages and neutrophils. These siglecs are inhibitory sialic acid-binding membrane receptors expressed on several immune cell subsets. Restraining ST8Sia6 should therefore enhance the immune response by reducing siglec-mediated inhibition. To examine this, our lab has generated a novel ST8Sia6 knockout (KO) mouse. At baseline these mice are healthy, but we have found that ST8Sia6 KO mice challenged with dextran sodium sulfate (DSS)-induced colitis lose weight and succumb to colonic inflammation significantly faster than their wildtype (WT) counterparts, particularly at low doses. ST8Sia6 KO mice exhibit increased histological damage and immune infiltration of the colon and small bowel as compared to WT controls. This data demonstrates a role for ST8Sia6 in regulating the hose immune response to inflammatory bowel disorders.
Loss of IL17 signaling in lupus-prone Ets1 knockout mice leads to worsened autoimmunity combined with increased susceptibility to Staphylococcal skin infections
Authors: Battaglia Michael , Sunshine Alex , Luo Wei , Jin Richard , Garris Matthew , Stith Alifa , Lindemann Matt , Miller Lloyd S , Sinha Satrajit , Wohlfert Elizabeth , Garrett-Sinha Lee Ann 
Published: February 2023

Abstract
Ets1 is a lineage-specific transcription factor that regulates B and T cell functions in development and disease. Mice that lack Ets1 (Ets1 KO) develop autoimmune disease with high levels of autoantibodies. Naïve CD4+ T cells isolated from Ets1 KO mice differentiate more readily to IL17 producing Th17 cells. To determine if IL17 production contributes to the observed autoimmunity in Ets1 KO mice, we crossed Ets1 KO mice to mice lacking the IL17 receptor A subunit (IL17RA KO) to generate double knock out (DKO) mice. We found that the absence of IL17RA signaling did not ameliorate the autoimmune phenotype of Ets1 KO mice. Instead, DKO animals exhibited worse symptoms with increases in activated B cells, autoantibody titers, T helper 2, and T follicular helper cells. DKO mice showed aspects of immunodeficiency, developing spontaneous skin lesions colonized by Staphylococcus xylosus. When DKO mice were infected with Staphylococcus aureus they were unable to clear the bacteria, indicating a general immunodeficiency to Staph bacteria. Gene expression analysis revealed diminished expression of the Skint gene family in DKO skin. Skint genes play important roles in the maintenance of TCRγδ+ dendritic epidermal T cells (DETC) and in skin wound healing. DKO mice had reduced numbers of DETC in the skin, which may lead to increased susceptibility to Staph infections. We propose that Staph skin infections in DKO mice leads to enhanced immune activation and enhanced autoimmunity. Our studies suggest that therapies targeting IL17RA signaling in autoimmune diseases may result in increased autoimmunity or to increased susceptibility to skin Staph infections.
Utility of immunological and neuronal markers in blood to identify relapse in Multiple Sclerosis patients
Authors: Gawde Saurabh , Axtell Robert C. 
Published: February 2023

Abstract
Multiple sclerosis is a demyelinating disease caused by immune cell infiltration into the Central Nervous System (CNS). Relapsing Remitting Multiple Sclerosis (RRMS) is characterized by episodes of worsening disability (relapses) followed by complete or partial recovery (remissions). Currently, MRI scans are used to conclusively identify relapses, but there is a need for an inexpensive, non-invasive test for monitoring relapses and remission status in MS patients. Serum neurofilament light (NFL) has emerged as a biomarker for relapse in MS. However, a test using NFL alone has poor sensitivity and specificity to identify an MS relapse. Our goal was to identify a panel of biomarkers that could improve the accuracy of distinguishing relapse and remission in MS patients. We used a multiplexed, sensitive assay to measure levels of blood proteins in two cohorts of RRMS patients – a cross-sectional cohort and a longitudinal cohort. In the cross-sectional patient cohort, we found five serum proteins were elevated in relapse, including NFL. Furthermore, we identified 94 serum proteins that were significantly reduced in relapse compared to remission, including IFN responsive chemokines CXCL9 and CXCL11. For the longitudinal cohort, pairwise comparisons found that five plasma proteins were elevated in relapse compared to remission, including NFL. Nine plasma proteins were significantly reduced in relapse compared to remission, including the IFN responsive chemokines CXCL9 and CXCL10. In conclusion, our studies provide evidence that a panel including NFL and IFN responsive chemokines in the blood may serve as biomarkers to distinguish relapse and remission in RRMS patients.
Inflammatory response within the nervous system in Tat induced HIV-associated sensory neuropathy
Authors: Cao Ling , Higley Jane , Healy Ryan , Harrison Benjamin 
Published: February 2023

Abstract
HIV sensory neuropathy (HIV-SN) affects 30–50% of patients infected with HIV. The role of Tat in HIV-SN has not been studied extensively. Previously, using the doxycycline (DOX) inducible HIV-1 Tat transgenic (iTat) mice, we showed that Tat expression induced neuropathy-like behaviors. Here, we further investigated the role of inflammatory responses within dorsal root ganglia (DRG) and lumbar spinal cord in the development of peripheral neuropathy. To induce Tat expression, DOX was given to iTat mice daily (i.p.) for 14 days. Lumbar spinal cord and DRG tissues were collected at days 0 (no injection), 3, 7, 14, 21, 28 and 35 following the initial injection of DOX. Vehicle control mice received pH-matched phosphate-buffered saline injections. qRT-PCR was performed with DRG tissues. Tat expression induced either transient or progressive upregulation of RNA levels of CCL2, CCL3, CCL4, CCL5, CXCL10, and IL-1beta. Lumbar spinal cord tissues underwent NanoString RNA analysis using a panel of 200+ inflammation-related genes. The patterns of the changes of these genes over time were clustered via the Short Time-series Expression Miner program. Out of the 4 patterns identified, the most significant one was a cluster of genes that were downregulated over time upon Tat induction. Gene ontology term enrichment analysis of this gene cluster via the PantherGo tool further identified a set of genes (IL-6, MAPK2K4, IL-10, HRAS1, BCL2L1, RHOA, JUN, and CREB1) that prevent/inhibit neuronal cell death/apoptosis. In all, both upregulation of selected pro-inflammatory cytokines within DRG, and down regulation of inflammation-related, neuronal survival genes within the spinal cord, could contribute to Tat-mediated peripheral neuropathy.
Obesity effects serum levels of SARS-CoV-2-specific antibodies in COVID-19 patients
Authors: Blomberg Bonnie , Reidy Lisa , Romero Maria , Diaz Alain , Cray Carolyn , Kahl Kristin , Frasca Daniela 
Published: February 2023

Abstract
SARS-CoV-2 (Severe Acute Respiratory Syndrome Corona Virus-2), cause of COVID-19 (Coronavirus Disease of 2019), represents a significant risk to people living with pre-existing conditions including increased inflammatory responses and consequent dysfunctional immunity.
In these studies we evaluated the effects of obesity, a condition associated with chronic systemic inflammation, on the secretion of SARS-CoV-2-specific IgG antibodies in the blood of COVID-19 patients. Results showed that SARS-CoV-2 IgG antibodies are negatively associated with Body Mass Index (BMI) in COVID-19 obese patients, as expected based on the known effects of obesity on humoral immunity, as we have previously published for the response to the influenza vaccine. Antibodies in COVID-19 obese patients are also negatively associated with serum levels of pro-inflammatory and metabolic markers of inflammaging and pulmonary inflammation, such as SAA (serum amyloid A protein), CRP (C-reactive protein) and ferritin, but positively associated with NEFA (nonesterified fatty acids). These results altogether help to identify an inflammatory signature with strong predictive value for immune dysfunction that could be targeted to improve humoral immunity in individuals with obesity as well as with other chronic inflammatory conditions.
HIV infection drives immune activation of angiogenic T cells
Authors: Li Tong , Zhu Ziang , Chen Jinya , Kumar Jai , Kumar Princy , Catalfamo Marta 
Published: February 2023

Abstract
In people living with HIV (PLWH), immune activation and systemic inflammation are associated with cardiovascular risk independently of the traditional risk factors or duration of antiretroviral treatment and CD4 counts. Endothelial inflammation and injury play a critical role in the pathogenesis of cardiovascular risk/disease. Recent reports had shown that T cells can promote vascular repair by secretion of proangiogenic factors. Because of these functional properties these T cells are called angiogenic T cells (Tang) and are defined by expression of CXCR4 and CD31. Accordantly, we found that in vitro, TCR stimulated CD8 Tang from healthy volunteers induced secretion of proangiogenic cytokines including angiopoietin-2, fibroblast growth factor, and vascular endothelial growth factor (VEGF) by HUVECs. Because HIV chronic infection drives T cell immune activation, we hypothesized that HIV infection alters Tang’s proangiogenic function. To address this question, we studied the phenotype and function of Tang in PBMCs from PLWH and healthy volunteers. We found that PLWH had a significant decrease in the proportion of both CD4 and CD8 Tang when compared to healthy controls, and this difference was more striking in the CD8 Tang. CD8 Tang from PLWH had an activated phenotype and showed an increased expression of granzymes (A and B) when compared to healthy controls. In PLWH, the frequency of GZA+GZB+CD8 Tang was positively associated with 10yr cardiovascular risk score. In addition, upon TCR stimulation, CD8 Tang from PLWH showed a diminished ability to secrete VEGF. These results suggest that in the context of HIV infection, CD8 Tang possesses a pro-inflammatory potential and reduced proangiogenic function to promote endothelial repair.
Patient-reported comorbidity affects symptom duration in non-hospitalized patients with mild to moderate COVID-19 in a clinical study
Authors: Haran John P , Zheng Yan , Alonzo-Palma Norma , Wingertzahn Mark 
Published: February 2023

Abstract

Background:
Most COVID-19 cases in the US are managed via outpatient care, yet the outpatient natural history of COVID-19 is not well understood. We assessed outpatient natural history of COVID-19 as part of a clinical food study evaluating KB109 safety and its effects on select health measures when combined with supportive self-care (SSC) vs SSC alone. KB109 is a novel synthetic glycan developed to support immune system homeostasis through gut microbiome modulation. The SSC-alone arm permitted COVID-19 natural history exploration, the focus of this abstract.

Methods:
Adult patients were randomized 1:1 to SSC alone or SSC+KB109. Randomization was stratified by site, age subgroup, and comorbidity status. Signs/symptoms of COVID-19 and other end points were evaluated over a 35-d study period. Patients self-assessed 8 COVID-19–related cardinal symptoms; 5 additional symptoms were collected (13 overall symptoms).

Results:
Overall, 350 patients were randomized (SSC alone, n=176). Interim results are presented; full analysis expected in March 2021. In the SSC-alone interim results (n=89), 36.0% of patients self-reported ≥1 comorbidity. Median time to resolution of the 8 cardinal symptoms was 12d in patients with no comorbidities vs 27d in patients with ≥1 comorbidity (HR=1.708 [0.875, 3.332]). Median time to resolution of the 13 overall symptoms was 14d in patients with no comorbidities vs 27d in patients reporting ≥1 comorbidity (HR=1.800 [0.953, 3.400]). The most common comorbidities were hypertension (19.1%) and chronic lung disease (9.0%).

Conclusions:
This is the first clinical study to show ≥1 comorbidity is associated with a protracted time to resolution of symptoms in non-hospitalized patients with mild to moderate COVID-19.
Stearoyl-CoA desaturase mediated monounsaturated fatty acid availability supports humoral immunity
Authors: Zhou Xian , Zhu Xingxing , Li Chaofan , Shapiro Virginia , Hitosugi Taro , Sun Jie , Copland John A. , Zeng Hu 
Published: February 2023

Abstract
Immune cells can metabolize glucose, amino acids, and fatty acids (FAs) to generate energy. The role of different FA species, and their impacts on humoral immunity remains poorly understood. Here we report that proliferating B cells require monounsaturated FAs (MUFA) to maintain mitochondrial metabolism and mTOR activity, and to prevent excessive autophagy and endoplasmic reticulum (ER) stress. Immune challenges increase systemic MUFA availability in vivo. Furthermore, B cell extrinsic Stearoyl-CoA desaturase (SCD) activity generates MUFA to support early B cell development and germinal center (GC) formation in vivo during immunization and influenza infection. Thus, SCD-mediated MUFA production is critical for humoral immunity.
Type I interferon enhanced double negative 2 B cell differentiation and lupus autoantibody production
Authors: Lu Changming , Liu Shanrun , Gao Min , Hsu Hui-Chen , Mountz John D 
Published: February 2023

Abstract
Systemic Lupus Erythematosus (SLE) is characterized by high level of type I interferon (IFN) and abnormal expansion of effector B cells including IgD−CD27−double negative (DN), CD21−T-bet+DN2 B cells, and antibody secreting cells (ASCs). It remains unclear as to the role of type I and type II interferon (IFN) to promote DN2 B cell differentiation. The in vivo effects of type I IFN signaling in promoting DN B cells were accessed using the BXD2 mouse model of lupus which exhibit a low Th1 response, compared to normal B6 mice. Compared to normal B6 mouse, there was a significantly elevated percent of DN B cells in the BXD2 mice, but this was reduced in BXD2 mice that are deficient in IFNAR1 (BXD2-Ifnar1−/−). Compared to wild-type BXD2 mice, there was a lower level of IgG autoantibodies specific to DNA, histone and Smith (Sm) in BXD2-Ifnar1−/− mice. BXD2-Ifnar1−/− B cells presented impaired differentiation into the DN and the DN2 populations under an in vitro stimulation condition in the presence of IFNb and a TLR7 agonist. To determine if type I IFN stimulation can direct differentiation of healthy B cells to these effector B cells without the influence of type II IFN, B cells purified from healthy individuals were stimulated under a DN stimulation condition (anti-Ig+IL-21+BAFF+TLR7) in the presence and absence of IFNb. We found that IFNb significantly increased the percentage and of DN and DN2 B cells, but decreased the percentage of CD27+CD38+ plasmablasts/plasma. Under the same condition, IFNb increased the secretion of autoantibodies specific to DNA, histone and Sm. Our results suggest that type I IFN signaling stimulates DN2 B cell differentiation and can promote the abnormal expansion of these B cells in vivo independent of type II IFN.
Epigenetic regulation of IgA class-switching by miR-146a through selective downregulation of Smad2, Smad3 and Smad4
Authors: Casali Paolo , Moroney Justin B , Daw Cassidy , Morales Grecia , Chupp Daniel P , Zan Hong 
Published: February 2023

Abstract
IgA is the predominant antibody isotype at mucosal surfaces. It plays a critical role in mucosal homeostasis and provides a first line of defense in immune protection. Class switch DNA recombination (CSR) to IgA is initiated by TGF-β, which induces Smad2, Smad3, Smad4 and Runx3 binding to the Iα promoter. This promotes germline Iα-Cα transcription, thereby increasing accessibility to the Igα locus. Epigenetic modifications, such as microRNAs, have been shown to modulate the antibody response, although the role of microRNAs in B cell differentiaton processes, such as guiding CSR to specific Ig isotypes, remains unexplored. miR146a has been shown to regulate T cell, dendritic cell and macrophage functions in innate and adaptive immune responses. Here we show that miR146a, which targets Smad2, Smad3 and Smad4 3′UTRs and is the most abundant miRNA in resting B cells, is significantly downregulated in B cells undergoing CSR to IgA. Deletion of miR146a, as in miR146a−/− B cells, frees Smad2, Smad3 and Smad4 from transcriptional repression, thereby increasing recruitment of these transcription factors to the Iα promoter. This results in increased germline Iα-Cα transcription and CSR to IgA without alterations to Aicda and Prdm1 expression. Accordingly, miR146a−/− mice displayed an elevated gut, systemic IgA responses and kidney IgA deposition, a hallmark of hyper IgA nephropathy. This was recapitulated in μMT/miR146a−/− mixed bone marrow chimera mice, further demonstrating the B cell-intrinsic role of miR146a in the modulation of CSR to IgA. Thus, by silencing Smad2, Smad3 and Smad4 transcription, miR-146a plays an important B cell intrinsic role in the modulation of the IgA response.