bluuebunny/crossref_metadata_2025_split huggingface dataset:
In silico and multi-dimensional functional interrogation of tissue Tregs reveals novel therapeutics for autoimmunity and inflammation
Authors: Valle Jose , Guillen Jovanny , DiMichele Sarah , Pauli Mariela , Tan Corey , Lam Caroline , Dominguez Claudia X , Labastida Rosario , Nganje Charmaine , Peabody Phillip , Yan Hannah , Navas Ashley , Nishimura Koki , Yard Parker , Abraham Ryan , Meury Marcel , Aglietti Robin , Bowers Peter , McKay Austin , Taylor Ian , Eng Nicolas W L , Mitchell Keith , Chen James , Yohn Christopher B , Astarita Jillian , Lyons Jesse , Kleinschek Melanie A , Zarrin Ali A 
Published: August 2023

Abstract
Many inflammatory and autoimmune diseases present with specific organ manifestations. Understanding the immune process at the site of inflammation may offer important insights into novel therapeutic strategies. To this end, we established a biology platform that allows us to develop a deep understanding of human tissue Treg behavior to enable a next generation of therapeutics aimed at activating these regulatory circuits at the location where the disease manifests. We apply single-cell RNA sequencing and computational tools to our proprietary collection of healthy and diseased tissues to generate a high-resolution map of immune-regulatory pathways. Based on these learnings, we established in vitro culturing conditions that induce the expression of these tissue pathways in primary human Treg. Lastly, we have developed a suite of disease relevant phenotypic assays that allows for multi-dimensional functional interrogation of the mapped tissue Treg pathways in our in vitro-conditioned human primary Treg. This combination of complex in silico tools and translational in vitro assays allows us to identify novel regulatory nodes and forms the foundation of our growing pipeline of a new class of tissue Treg-focused therapeutics for immune-mediated diseases.
Galectin-9 mediates gut-associated inflammation and disruption of tight junctions
Authors: Moar Preeti , Kaur Urvinder , Bhagchandani Tannu , Tandon Ravi , Ndhlovu Lishomwa C 
Published: August 2023

Abstract

Background
High levels of Galectin-9 (Gal-9), a β-galactoside-binding mammalian lectin, are associated with systemic inflammation in chronic viral infections like HIV, despite viral suppression by ART. Gut-systemic microbial translocation is a major contributor of persistent inflammation. Whether Gal-9 influences the integrity of the gut during viral infections remains unknown.

Objective
Here we investigated the impact of Gal-9 in the interplay between gut-systemic microbial translocation in the setting of well-treated chronic HIV infection.

Method
We assessed the levels of Gal-9 and sCD14 in the plasma of people with HIV on ART (PWH; n=25) and people without HIV (PWOH; n=15) by ELISA. The integrity of the gut epithelium in the presence and absence of rGal-9 was assessed in the HT-29 cell line by immunofluorescence. TNFa was used as a positive control to disrupt gut integrity. The levels of TNFa were measured by qPCR. Non parametric tests were used in the analysis.

Results
Plasma Gal-9 and sCD14 were elevated in PWH compared to PWOH (all p&lt;0.0001). Further, high Gal-9 levels correlated with high sCD14 in both the PWH (r=0.43, p=0.0317) and PWOH (r=0.79, p=0.0006) groups. Immunofluorescence revealed disruption of the Claudin tight junctions in vitro after 24 hrs of rGal-9 treatment. rGal-9 also induced a 6-fold increase in the expression of TNFα in HT-29 cells.

Conclusion
Our results show that Gal-9 is associated with markers of gut-systemic microbial translocation irrespective of HIV status and given the direct effects of rGal-9 on tight junction barrier function, targeting Gal-9 either by exploiting its secretory pathways or competitive blockade may serve as a novel therapeutic approach to control gut-associated inflammation.
Improved control of SARS-CoV-2 infection with nucleocapsid-specific antibodies
Authors: Penaloza-MacMaster Pablo A , Dangi Tanushree , Sanchez Sarah , Class Jacob , Richner Michelle , Visvabharathy Lavanya , Chung Young Rock , Bentley Kirsten , Stanton Richard , Koralnik Igor Jerome , Richner Justin , Penaloza-MacMaster Pablo 
Published: August 2023

Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein is the main antigen in all approved COVID-19 vaccines and is also the only target for monoclonal antibody (mAb) therapies. Immune responses to other viral antigens are generated after SARS-CoV-2 infection, but their contribution to the antiviral response remains unclear. Here, we interrogated whether nucleocapsid-specific antibodies can improve protection against SARS-CoV-2. We first immunized mice with a nucleocapsid-based vaccine and then transferred sera from these mice into naive mice, followed by challenge with SARS-CoV-2. We show that mice that received nucleocapsid-specific sera or a nucleocapsid-specific mAb exhibited enhanced control of SARS-CoV-2. Nucleocapsid-specific antibodies elicited NK-mediated, antibody-dependent cellular cytotoxicity (ADCC) against infected cells. To our knowledge, these findings provide the first demonstration in the coronavirus literature that antibody responses specific to the nucleocapsid protein can improve viral clearance, providing a rationale for the clinical evaluation of nucleocapsid-based mAb therapies to treat COVID-19.
NIH (DP2DA051912)
Prostaglandin D2 receptor expression in the lung and the effect of PPAR-γ, DP1, and DP2 receptor agonist treatment during respiratory viral infection
Authors: Abysalamah Hazzar marwan , Holloway Kathleen , Shornick Laurie P 
Published: August 2023

Abstract
Prostaglandin D2 (PGD2) may play an anti-inflammatory role in the lung during respiratory viral infection, but little is known about the expression of its receptors (PPAR-γ, DP1, and DP2) in the lung or its mechanism of action. Adult C57BL/6 mice were infected with Sendai virus (500 pfu /g body weight), a natural mouse pathogen that infects airway epithelial cells. Immunostaining of uninfected lungs showed PPAR-γ protein in epithelial cells of larger airways, but not in the alveolar epithelial cells. After viral infection, PPAR-γ protein was no longer detectable in the lungs. Immunofluorescence showed DP1 present in parenchymal cells as well as in some CCSP+ airway epithelial cells, but levels did not appear to change during infection. DP2 expression increased after viral infection and was predominantly in CCSP+ epithelial cells 24 hours post-infection. DP2 also co-localized with MHC Class II+ cells in the parenchyma on days 3 and 7 post-infection. Viral infection of primary tracheal epithelial cells showed PPAR-γ mRNA expression was increased 48 and 72 hours post-infection. There was no change in DP1 or DP2 expression in vitro. To test the effect of each receptor in vivo, mice were infected and treated with PPAR-γ, DP1, and DP2 agonists, or vehicle every 12 hours. Mice treated with the PPAR-γ agonist were protected from body weight loss and had reduced IFN-γ expression on day 7, suggesting that PGD2 may be acting via PPAR-γ to reduce inflammation in the lung.
Supported by grants from Sigma Xi Grant in Aid of Research and Saint Louis University College of Arts and Sciences Brennan Award.
Characterizing effects of HB-EGF on H1N1 infection in mice
Authors: Acosta-Vilanova Heizel Karina , Carter Hannah , Moore Bethany 
Published: August 2023

Abstract
Heparin-Binding EGF-like Growth Factor (HB-EGF) is a ligand for the Epidermal Growth Factor Receptor (EGFR), a tyrosine kinase receptor which promotes cell proliferation and migration. In the epithelium of the lung, HB-EGF is an important factor for wound repair, however little is known about the effects of HB-EGF on viral infection in vivo. Literature suggests that in human alveolar epithelial cell lines, EGFR is an important cofactor in Influenza A infection, and that treatment with HB-EGF decreases both EGFR and viral M1 protein in cells. We use a mouse model to examine this in vivo. In our model, we use a HBEGFff/Lyz2Cre mouse to knock out HB-EGF in myeloid and epithelial cells and infect with a mouse adapted H1N1 influenza virus. We then harvest lungs on day 5 and analyze RNA transcripts by qPCR. We expected to see increased H1N1 polymerase transcript in our KO mice. We saw that increase in our male mice in our initial experiment, but not in females. We plan to repeat this experiment and examine changes in the immunological milieu between our HB-EGFff mice and our controls, and between males and females.
Supported by grant from NIH Postbaccalaureate Research Education Program (PREP) (R25)
Anti-PPIL-5 antibody exacerbates disease of severe influenza in a murine experimental model
Authors: Huang Ching-Tai , Hung Chen-Yiu , Hsiao Sung-Han , Chen Tse-Ching , Chang Chia-Shiang , Huang Yu-Lin , Lin Yung-Chang , Lin Chun-Yen , Dutta Avijit 
Published: August 2023

Abstract
Respiratory viruses such as SARS-CoV2 cause serious emerging infectious diseases. Even seasonal influenza results in significant morbidity and mortality. Host immunity responds to influenza virus infection to eradicate the pathogen. However, dysregulated responses such as the cytokine storm contribute to severe disease. Mechanistic dissection of immune regulation may offer practical solutions for severe influenza. In our mouse model of severe influenza, a LAG-3 regulatory response evolves with the pro-inflammatory IFN-γ response in influenza virus hemagglutinin (HA)-specific CD4+ T cells. Adoptive transfer of LAG-3(+) IFN-γ(-) HA-specific CD4+ T cells suppressed lung inflammation without compromised virus eradication. Genomic study of LAG-3(+) IFN-γ(−) CD4+ T cells revealed up-regulation of the PPIL-5 [Peptidylprolyl isomerase (Cyclophilin)-like 5] gene. PPIL-5(+) HA-specific CD4+ T cells accumulated in the lung with time after infection. PPIL-5 protein suppressed HA-specific CD4+ T cell activation in vitro in a dose dependent manner. PPIL-5 blockade in vitro with siRNA reversed immune suppression and unleashed activation of HA-specific CD4+ T cells. PPIL-5 blockade in vivo with monoclonal anti-PPIL-5 antibodies attenuated LAG-3 and PD-1 and augmented IFN-γ responses of the lung-infiltrating HA-specific CD4+ T cells, with aggravated disease and intensified mortality of severe influenza. The HA-specific CD4+ T cells took less glucose and produced lactate with anti-PPIL-5 blockade. They adopted anaerobic glycolysis in this reverted inflammatory response. Our results suggest that PPIL-5, similar to LAG-3, is also an immune checkpoint and a possible target to be manipulated for alleviation of severe influenza.
The Research Center for Emerging Viral Infections receives support from The Featured Areas Research Center Program within the framework of the Higher Education Sprout Project by the Ministry of Education (MOE), Taiwan and NSTC 111-2634-F-182-001 from the National Science and Technology Council, Taiwan. This work was supported by Projects MOST 111-2314-B-182-029 (AD) and MOST-105-2321-B-182A-003-MY3 (AD) from the National Science and Technology Council, Taiwan, and by CMRPG3L1671 (CTH), CMRPVVJ0052 (CTH), and CMRPG3J1771 (CYH) from the Medical Research Project Fund, Chang Gung Memorial Hospital, Taiwan.
Hospitalized COVID-19 patients exhibit increased numbers of low density neutrophils expressing the transcription factor ARID3a
Authors: Webb Carol F , Hocker James A , Shankar Malini A , Booth John Leland , Sinko Lauren A , Wu Wenxin , Metcalf Jordan 
Published: August 2023

Abstract
We previously showed that individuals with systemic lupus erythematosus (SLE) and high levels of Type I inflammatory cytokines had increased numbers of low density neutrophils (LDNs) in their peripheral blood compared to healthy donors. Increased numbers of LDNs were associated with increased expression of the transcription factor ARID3a and increased interferon alpha (IFNα) production. Data from other cell types suggest that ARID3a expression occurs upstream of IFNα expression. Therefore, we sought to determine if increases in ARID3a-expressing LDNs might also occur in other severe inflammatory responses, such as infection with SARS-CoV2 where IFNα expression was known to be increased. Subjects admitted to the hospital with a confirmed diagnosis of SARS-CoV2 infection were enrolled in our IRB approved study and peripheral blood mononuclear cells from 24 patients were evaluated via flow cytometry for numbers of LDNs and ARID3a expression at the time of admission and at various time points after hospitalization. Numbers of circulating LDNs were dramatically increased in COVID patient samples at the time of hospitalization, as were percentages of those cells expressing ARID3a protein. IL-6 expression was also high in the LDNs, while IFNα expression was more variable. Over the course of two weeks, IFNα expression appeared to be associated with, or to lag just behind ARID3a expression in most patients, while IL-6 expression levels were not associated with ARID3a or IFNα expression. These data suggest that ARID3a expression is induced in LDNs in association with severe viral infection and may implicate ARID3a as a potential regulator of inflammatory pathways in infection as well as autoimmunity.
Supported in part by grant NIH U19 AI06269
Characterization of CD8+ T cells recognizing a dominant epitope of SARS-CoV-2 spike protein in COVID-19 convalescent, vaccinated, and unexposed individuals
Authors: Zou Ainslee J , Li Jiangyuan , Choy Cecily , Chen Joseph , Hemani Humza , Baptiste Beverly , McKelvey Julia , Melvin Denise , Ruffolo Jeannie , Zukley Linda , Wallace Tonya , Dunn Christopher , Nguyen Cuong , Fan Jinshui , De Supriyo , Chia Chee , Ferrucci Luigi , Egan Josephine , Weng Nan-ping 
Published: August 2023

Abstract
COVID-19, an infectious disease caused by SARS-CoV-2, has given rise to the current global pandemic. Despite the number of infections reaching over 600 million people worldwide, CD8+ T cells against SARS-CoV-2 in COVID-19 convalescent, vaccinated, and unexposed adults have not been fully characterized. Here, we report the frequency, phenotype, and in vitro expansion capacity of circulating CD8+ T cells recognizing 10 epitopes from the SARS-CoV-2 spike (S) protein. Through multi-color flow cytometry using antigen-specific tetramers, we found that the frequencies of circulating CD8+ T cells ranged from undetectable to 1% in HLA-A2+ unexposed, convalescent, and vaccinated individuals. In vitro stimulation showed robust CD8+ T cell expansion (in percentage and magnitude) against the S-YLQ (S-269-277, YLQPRTFLL) epitope compared to other epitopes in convalescent and vaccinated individuals. Lastly, the scTCRseq analysis revealed limited V gene usage for S-YLQ-specific CD8+ T cells. These results identified a dominant S-protein epitope (S-YLQ) of SARS-CoV-2, showing that convalescent and vaccinated individuals have robust specific CD8+ T cell response against this epitope.
Pneumoviruses can impair the central nervous system by different mechanisms
Authors: Kalergis Alexis M , Bohmwald Karen , Andrade Catalina A 
Published: August 2023

Abstract
Pneumoviruses such as the respiratory syncytial virus (hRSV) and the human metapneumovirus (hMPV) are the leading cause of acute lower tract respiratory infection, mainly in infants, elderly and immunocompromised individuals, causing high morbidity and mortality rates. However, these viruses can cause neurological alterations, such as encephalitis and encephalopathy. Viral RNA and pro-inflammatory molecules have been found in patients with neurological signs, supporting the notion of neuroinvasion and/or neuroinflammation caused by hRSV and hMPV. Therefore, this work seeks to evaluate the effects of these viruses on the brain. Accordingly, mice were infected with either hRSV or hMPV or treated with non-infectious controls (mock). Despite detecting viral load in the lungs of hMPV-infected mice, no viral load was detected in their brains, as it was shown for hRSV. However, pro-inflammatory cytokines such as IL-6 and IFN-g were increased only in the sera of hMPV-infected mice. Also, we observed differential patterns in the increase of cytokines in the brain of hRSV or hMPV-infected mice, including IL-6, TNF-a, and IL-4. Moreover, increased blood-brain barrier permeability was observed in mice infected with both viruses. Additionally, after several weeks post-infection, a Marble Burying (MB) test was performed, and we observed an impaired cognitive performance in mice infected with both viruses. All these results suggest that infection with these pneumoviruses can cause long-term behavioral impairment in mice. Our work provides new insight into the effect of hRSV and hMPV on the central nervous system and underscores the need to further understand how respiratory virus can damage brain function in humans.
This work was supported by ANID/FONDECYT grants #11221280; #1190830, ANID scholarship # 21210662, the Millennium Institute on Immunology and Immunotherapy ACE 210015, ICN09_016 / ICN 2021_045; former P09/016-F.
Redox extracellular vesicles induce neurotoxic cytokine production from innate immune cells
Authors: Bondada Subbarao , Zhao Yanming , Alhakeem Sara S , Ho Jenni , Collard James C , Chaiswing Luksana , Butterfield David Alan , St Clair Daret K 
Published: August 2023

Abstract
Therapy induced cognition impairment (TICI) or chemobrain is a well-recognized side effect of cancer therapy, which reduces quality of life for cancer survivors. Most cancer therapies induce reactive oxygen species, which can lead to cancer cell death, but they also promote neuronal cell death both directly and indirectly leading to TICI. High grade gliomas are one of the cancers that respond poorly to therapy and are associated with development of chemobrain. Currently, the mechanisms underlying chemobrain are not well understood. The systemic side effects such as cachexia, fatigue, and cognitive impairment are associated with sustained elevation of inflammatory cytokines and microglial cell activation. We tested the hypothesis that chemotherapy and radiation treatment of glioblastoma (GBM) leads to production of extracellular vesicles (EVs) with oxidized proteins that uniquely stimulate specific immune cells to produce cytokines like TNF-α which was shown to induce therapy induced cognition impairment (TICI) by causing neurotoxicity. Previously we showed that TNF-α has a major role in TICI, as it can cross the blood brain barrier and induce neurotoxicity. We found that chemotherapy or radiation induces production of EVs from cells and tissues that are targets of the drugs. These EVs contain more proteins adducted to 4-hydorxy nonenal (HNE) compared to controls. These EVs contain proteins released from tissues such as brain that are damaged by therapy. The HNE adducted EVs were better than control EVs in inducing macrophages and microglial cells to produce the pro-inflammatory cytokines, TNF-α, and IL-6. Serum IL-6 levels and IL-6 producing cells were significantly increased in vivo when C57BL/6 mice were injected with Redox EVs.
NIH R01 CA21793
Activation of PHACTR2 with oral NIM-1001 treatment enhances regulatory CD4+ T cell function and provides protection from systemic lupus erythematosus
Authors: Leber Andrew J , Hontecillas Raquel , Juni Nuria Tubau , Fitch Sarah N , Bassaganya-Riera Josep 
Published: August 2023

Abstract
Phosphatase and actin regulator 2 (PHACTR2) is an RPEL domain containing protein recently shown to be differentially expressed in regulatory CD4+ T cells (Tregs). Within rheumatic conditions, specifically systemic lupus erythematous, Tregs possess lesser suppressive capacity, are more likely to lose CD25 and FOXP3 expression and to experience low IL-2 environments. Using a combined loss-of-function and therapeutic approach, we sought to characterize the role of PHACTR2 in Treg biology and rheumatic disease. In a study of in vitro differentiation of naïve CD4+ T cells, Phactr2−/− cells differentiated into CD25hi FOXP3+ Tregs at a lesser proportion than WT cells. Using a bm12 adoptive transfer model of alloactivation, Phactr2−/− mice exhibit greater inflammation, demonstrated through increased spleen weight, greater incidence of ascites, and increased Th1 cells in the spleen post-transfer. Activation of PHACTR2 in an MRL/lpr model of lupus, by daily oral treatment with NIM-1001, protected against proteinuria and provided a three-fold increase in splenic Tregs. Similarly, in the NZB/W F1 model, oral treatment with NIM-1001 significantly reduced histological severity of disease in the kidney, increased splenic Tregs and decreased bone marrow plasma cells. NIM-1001 down-regulated multiple plasma chemokines and cytokines including CXCL1 and CCL4 in a dose-dependent manner. This data suggests that the PHACTR2 pathway merits development as a promising therapeutic mechanism for lupus and other diseases exhibiting impairments in Treg regulatory function.
Liver cells transduced with AAV.MOG increase the frequency of MOG-specific T regulatory cells capable of reducing EAE by adoptive transfer
Authors: Senior Kevin G , Min Daniel , Keeler Geoffrey D , Gaddie Cristina D , Chan Christopher , Wilson Olivia , Baker Maya , Hoffman Brad E 
Published: August 2023

Abstract
Multiple Sclerosis is a demyelinating autoimmune disease brought on by self-reactive, myelin-specific T effector cells. Immunosuppressants are the most utilized tool to combat disease progression; however, they bring unwanted side effects. We have previously published on a novel gene immunotherapy that uses an adeno-associated virus (AAV) containing the full sequence of the myelin oligodendrocyte glycoprotein (MOG) that restores tolerance through liver-directed gene therapy, resulting in the generation of antigen-specific T regulatory cells (Tregs) that can ameliorate Experimental Autoimmune Encephalomyelitis (EAE). While the data is promising, the mechanism of this therapy remains enigmatic. To begin defining the mechanism initially, we cultured MOG-specific CD4+ T cells from 2D2 mice with liver cells from B6 mice that received either AAV.MOG or a saline control. We found a significant increase in the frequency of CD4+CD25+FoxP3+ Tregs when 2D2 T cells were cultured with liver cells from AAV.MOG-vectored mice in a 1:2 ratio compared to the control. Next, we injected 2D2 mice with AAV.MOG and isolated CD4+CD25+ T cells 2 weeks later. To evaluate their suppressive ability they, or control cells, were adoptively transferred to recipient naïve B6 mice. After 24 hours, active EAE was induced. By day 15, disease severity in mice that received AAV.MOG donor 2D2 T cells was significantly reduced compared to the controls (CD4+CD25+T cells from wildtype B6 mice given either AAV.MOG or AAV.AQP4) Overall, these results demonstrated that livers transduced with AAV.MOG can induce 2D2 Tregs in vitro and that CD4+CD25+ T cells from vectored 2D2 mice reduce EAE severity.
Supported by a grant from the NIH (R01AI128074) and the Children’s Miracle Network