bluuebunny/crossref_metadata_2025_split huggingface dataset:
Butyrate mediates the amelioration of Staphylococcal Enterotoxin B-induced Acute Respiratory Distress Syndrome by downregulating the expression of Histone Deacetylases
Authors: Sultan Muthanna Ali , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: February 2023

Abstract
Despite rigorous global containment and quarantine efforts that have been applied globally to control SARS-CoV-2, the spreading of this contagious disease has accelerated all over the world. In our study, we used staphylococcal enterotoxin B (SEB), which is a superantigen can lead to toxic shock syndrome in C57BL/6 murine model and thus, mimics COVID19. In the current study, we investigated the suppressive effect of sodium butyrate (BUT) on a murine model of SEB-induced Acute Respiratory Distress Syndrome (ARDS). The data shows that supplementation with BUT at a dose of 200 mg/kg orally reduced overall ARDS severity. Plethysmography analysis data indicated that sodium butyrate improves the clinical functions of the lungs. In addition, our flow cytometry data indicated that BUT mediated the suppression of lung mononuclear cells such as CD4+ T cells, CD8+ T cells, VB8+ T cells and NK-T cells while at the same time increasing T regulatory cells. Cytokine storm is one of the most important challenge in COVID19 cases, in our study, we have found that the proinflammatory cytokines such as IL-2, TNFα and IFNγ in broncho-alveolar lavage fluid (BALF) significantly decreased in SEB+BUT compared to SEB+VEH as detected by ELISA. Additionally, histopathological analysis of H & E stained lungs indicated that BUT decreased the level of infiltration of inflammatory cells in the lungs of SEB+BUT compared to SEB+VEH mice. Additionally, we investigated the role of BUT on the expression of histone deacetylases (HDACs). Collectively, our data suggested that BUT ameliorated SEB-induced ARDS by downregulating the expression of class I and Class II HDACs which mediate the increase in T regulatory cells that suppress the inflammatory response in SEB-induced ARDS.
ITK regulates IL-10 production by CD8+ T cells and lung immunopathology during influenza infection
Authors: McGee Michael C , Solouki Sarbina , Limper Candice Bree , Ye Kaixiong , Nidetz Natalie , Islam Rezwanul , Zhang Tianyi , Magazine Nick , Huang Weishan , August Avery 
Published: February 2023

Abstract
Respiratory viral infections are a major cause of human morbidity and mortality. Influenza (flu) infections cause 250,000 deaths and 3–5 million cases of severe illness during the average flu season. Severe flu infections are associated with a combination of strong pro-inflammatory and weak anti-inflammatory immune responses. Production of the immunomodulatory cytokine IL-10 by T cells restricts immunopathology during flu infections, however our knowledge of the signaling pathways regulating IL-10 induction during flu is limited. Using IL-10GFP reporter mouse models, we found that Interleukin-2 inducible T cell kinase (ITK), a critical component in T cell receptor (TCR) signaling, regulates immunopathology and the development of IL-10-producing CD8+ T cells in the airways during influenza A infection. Utilizing alternative coculture, the model antigen ovalbumin (OVA), and transgenic TCR specific for OVA in CD8+ T cells (OTI) adoptive transfer, we determined that ITK regulates flu antigen-specific IL-10+CD8+ T cell differentiation in a CD8+ T cell intrinsic and extrinsic manner. Exogenous IL-2 rescued IL-10 production by Itk−/− CD8+ T cells, in vitro and in vivo, suggesting that ITK may play a role in IL-2-producing T helper cells that promote IL-10 production in CD8+ T cells. The absence of ITK impaired the expression of transcription factors (TFs) IRF4 and Blimp-1, and retroviral transduction enabling the reintroduction of these TFs could partially rescue IL-10 production in Itk−/− CD8+ T cells. Our data suggests that ITK is a critical regulator of IL-10 production by CD8+ T cells and flu-induced pulmonary immunopathology. Modulating ITK signaling may be a strategy for regulating immunopathology due to viral infections.
A role for the transcription factor STAT5 in antagonizing CD8+ T cell exhaustion
Authors: Beltra Jean-Christophe , Manne Sasikanth , Abdel-Hakeem Mohamed S , Nzingha Kito , Zhang Zhen , Huang Hua , Kurachi Makoto , Muroyama Yuki , Huang Yinghui Jane , Su Leon L , Picton Lora , Decaluwe Helene , Huang Alexander C , Berger Shelley L , Garcia Christopher K , Wherry E. John 
Published: February 2023

Abstract
Exhaustion gradually establishes in chronically stimulated CD8s and this process is not reverted by current therapeutic approaches due to establishment of a stable epigenetic program. Recent advances have informed on the developmental process of exhaustion and highlighted TOX as a key lineage-defining TF in the process. Yet, little remains known on molecular pathways capable of antagonizing the TOX-dependent exhaustion program. By depicting transcriptional changes at key developmental steps of exhaustion, we demonstrate an antagonistic role for the TF STAT5 in the development of CD8 T cell exhaustion. STAT5 transcriptional network is heavily silenced upon chronic antigenic stimulation in a TOX-dependent manner which allows initiation of the exhaustion lineage. Increasing STAT5 activity abrogates establishment of the exhaustion lineage leading to the development of effector-like CD8s that acquire a unique transcriptional identity, distinct from exhausted cells, persist throughout chronicity and demonstrate higher protective capacity. Using temporal loss and gain of function approaches, we show that STAT5 triggers loss of progenitor identity by exhausted CD8s (Tex) and subsequent differentiation into the recently identified effector-like intermediate Tex subset. Temporal increase in STAT5 activity also robustly synergizes with PD-L1 blockade by further fostering intermediate Tex cells accumulation. Together, we show that modulating STAT5 activity may counteract the exhaustion process and favor instigation of effector-like characteristic in Tex cells suitable for optimal therapeutic efficacy.
This work is supported by the Parker Institute for Cancer Immunotherapy (PICI). JC-Beltra is a PICI scholar awardee.
An AGS associated mutation causes cellular RNA editing deficiency in mouse brain which lead to IFN pathway activation, mimicking the interferonopathy of patient brains
Authors: Wang Qingde , Guo Xinfeng , Sheng Yi , Wang Tony , Steinman Richard , Billiar Timothy R 
Published: February 2023

Abstract

Objective:
To determine whether and how a gene mutation found in Aicardi-Goutières syndrome (AGS), a severe autoimmune encephalopathy, is sufficient to activate the interferon signaling pathway in the brain.

Background:
Genetic mutations in six coding genes were found associated with AGS patients, however, none of them was demonstrated able to cause IFN pathway activation in the brain tissue, the most critical pathogenetic change of AGS. How an AGS-associated mutation activates the IFN pathway in the brain that leads to brain injury remains to be revealed.

Methods:
A knock-In mouse model was established through CRISPR/Cas9 gene editing approach, in which a single G&gt;T nucleotide replacement was introduced into mouse genome, that encodes the change for p.K948N in mouse ADAR1 at its catalytic domain, equivalent to the p.K999N mutation found in AGS patients. We analyzed the enzyme activity of ADAR1 on the neuron specific mRNA substrates in the KI mice through RNA sequencing, the activities of IFN signaling pathway by measuring expressions of IFN stimulated inflammatory cytokines. Brain injury was observed by pathology studies.

Results:
The genetic mutation was confirmed. RNA transcription and protein translation were tested not affected by the mutation. The cellular RNA process in neurons was altered due to decreased enzyme activity of mutant ADAR1 on certain mRNA substrates. ISG expression were significantly increased at RNA and protein levels. Cell death in the brain was observed in the KI mice.

Conclusion:
A mouse model was successfully established recapitulating the genetic and innate immunologic features of AGS. An ADAR1 gene mutation is sufficient to cause IFN pathway activation in the brain through altering cellular RNA process.
USP13 enhances the function of p62/SQSTM1 by increasing its stability and aggregate formation
Authors: Lee Bin , Kim Young Hun , Lee Woori , Kwak Man Sup , Shin Jeon Soo 
Published: February 2023

Abstract
p62/SQSTM1 is a multifunctional protein that serves as a receptor protein for selective autophagy and a scaffold protein. In selective autophagy, p62 functions as a bridge between poly-ubiquitinated proteins and the autophagosome. In addition, p62 acts as a signaling hub for many cellular pathways, including mTORC1, NF-κB, and Keap1-Nrf2. These functions are regulated by post-translational modification of p62. In particular, changes in the binding partner or intracellular function of p62 by phosphorylation or ubiquitination are well studied. However, the opposite process of the p62 ubiquitination, the deubiquitination mechanism is still unclear. It was hypothesized that the unknown pathway of p62 deubiquitination might regulate its stability and functions. In this study, it was found that ubiquitin-specific protease 13 (USP13), one of the USP family, directly bound to p62 and removed ubiquitination at its PB1 domain. The deubiquitinated p62 by USP13 was enhanced the stability and the aggregate formation. Furthermore, increased p62 aggregation by USP13 activated autophagy and inhibited Keap1 from functioning as a negative regulator of Nrf2. Consequently, activated Nrf2 increased its migration to nucleus and acted as a transcription factor, increasing the expression of the antioxidant response gene. Taken together, USP13 enhanced the stability and aggregate formation of p62, which activated autophagy and antioxidant response.
A dysbiotic gut microbiome suppresses antibody-mediated protection against Vibrio cholerae
Authors: Macbeth John , Liu Rui , Alavi Salma , Hsiao Ansel 
Published: February 2023

Abstract
Vibrio cholerae is the etiologic agent of cholera, a severe diarrheal disease that represents a significant burden on global health and productivity. Given the need for more effective prophylactics, more research is needed to ascertain the interplay of protective immune responses and the resident gut microbiome, which in cholera-endemic areas is strongly and repeatedly modulated by malnutrition, cholera, and non-cholera infectious diarrhea. Initially, we conducted fecal transplants from healthy human donors into germ-free mice in order to characterize differential immune response activity. As we observed distinctive responses in our initial sampling, we moved to a more tractable antibiotic-treated mouse model where we assemble representative model communities of either human gut microbes resembling those of healthy individuals or those of individuals recovering from diarrhea or malnutrition. We establish these communities in a murine infection model, and show that the dysbiotic gut microbiome, commonly present in areas where malnutrition and diarrhea are common, suppresses the immune response against Vibrio cholerae through the action of CD4+ cells. Our findings suggest that the composition of the gut microbiome at time of infection may be pivotal for providing robust mucosal immunity, suggesting a target for the improvement of responses to oral cholera vaccines.
Plasmodium falciparum-specific B cell responses in malaria-susceptible children and malaria-immune adults
Authors: Gonzales Stephen Jacob , Reyes Raphael , Batugedara Gayani , Ssewanyana Isaac , Rek John , Lavinder Jason J , Ippolito Gregory C , Bol Sebastiaan , Greenhouse Bryan , Bunnik Evelien 
Published: February 2023

Abstract
Malaria is a vector-borne disease caused by parasites of the Plasmodium genus that infect millions of people annually, with P. falciparum being the most common and deadliest species. Development of immunological protection against clinical malaria requires chronic or repetitive parasite exposure, is mediated by IgG, and is correlated with antibodies against proteins expressed by merozoites, the free form of the parasite that invades erythrocytes. The goal of our study was to better understand the development of this protective antibody response, using merozoite surface protein 1 (MSP1) as a model antigen. MSP1 is highly abundant on the merozoite surface, highly immunogenic, and highly variable between parasite strains. Using B cell tetramers, we isolated MSP1-specific IgM+ and IgG+ memory B cells (MBCs) from immune adults and non-immune children living in Tororo, Uganda, a region of high transmission. In children, MSP1-specific B cells were mainly unswitched (IgM+) classical MBCs (cMBCs; CD21+ CD27+), while adults showed enrichment for class-switched (IgG+) cMBCs. Sequence analysis of the heavy chain variable regions revealed that MSP1-specific MBCs from adults carried higher rates of somatic hypermutation and showed extensive clonal expansion compared to those from children. When expressed as IgG, antibodies from IgM+ MBCs showed low avidity to MSP1, while those from IgG+ MBCs displayed strong reactivity with recombinant MSP1 and whole merozoites and inhibited parasite growth. These results suggest that extensive evolution of B cell responses takes place as a result of life-long P. falciparum exposure, which may be essential for the development of protection against malaria.
A transmissible γδ intraepithelial lymphocyte hyperproliferative phenotype is associated with the intestinal microbiota
Authors: Jia Luo , Alonso Sara , Wu Guojun , Lam Yan , Zhao Liping , Edelblum Karen L 
Published: February 2023

Abstract
Intraepithelial lymphocytes (IEL) expressing the γδ T cell receptor provide a first line of defense at the intestinal barrier, yet how the intestinal microbiota influences this sentinel population remains unclear. Since commensal-induced tonic type I interferon (IFN) signaling promotes lamina propria lymphocyte homeostasis, we hypothesized that IFNα/β receptor (IFNAR) signaling may contribute to maintenance of the γδ IEL compartment. Morphometric analysis revealed a 2-fold increase in the number of GFP+ γδ IELs in IFNAR KO mice compared to WT housed in a standard barrier facility (SBF). γδ IEL proliferation was enhanced 50% in SBF IFNAR KO mice relative to SBF WT. This increase in γδ IEL number was not observed in IFNAR KO mice rederived into a cleaner, enhanced barrier facility (EBF) indicating that the γδ IEL hyperproliferative (γδHYP) phenotype occurs independently of IFNAR signaling. The transfer of dirty bedding from SBF IFNAR KO mice to EBF IFNAR KO breeding cages was sufficient to induce the γδHYP phenotype in both the breeders and their offspring, and antibiotic treatment prevented this transmission. SBF WT and IFNAR KO mice were crossed to generate F2 littermates, which all exhibited the γδHYP phenotype regardless of genotype. Evidence of horizontal and vertical transmission of the γδHYP phenotype led us to analyze the fecal microbiota. Greater microbial diversity was observed in mice with the γδHYP phenotype relative to those that did not (Shannon Index, p&lt;0.01). Moreover, 6 amplicon sequence variants (ASV) were strongly associated with the γδHYP phenotype (P=1.075e-05). Thus, we have serendipitously discovered a specific microbiota that is both necessary and sufficient to promote the expansion of the γδ IEL compartment.
Loss of C3aR induces immune infiltration and inflammatory microbiota in a new spontaneous model of colon cancer
Authors: Guglietta Silvia , Weber Lukas , Fosso Bruno , Hardiman Gary , Marzano Marinella , Robinson Mark , Krieg Carsten 
Published: February 2023

Abstract
Several lines of evidence suggest that inflammation plays a pivotal role in the development and progression of colorectal cancer (CRC) and can be unleashed by the loss of innate immunosurveillance. The complement system is a well characterized first line of defense against pathogens and a central component of the immune response. Emerging evidence suggests that complement anaphylatoxin C3a produced upon complement activation and acting via its receptor (C3aR) may play a role in intestinal homeostasis. However, to date, it is unknown whether and how the C3a/C3aR axis can affect CRC. By mining publicly available datasets, we found that CpG island methylation of c3ar1 occurs in CRC patients and is associated with significant downregulation of C3aR. By reverse-translating this finding we were able to shift in APCMin/+ mice the tumorigenesis from the small intestine to the colon therefore generating a novel mouse model, which more closely mirrors the CRC in humans. Transcriptomic analysis on colorectal polyps from our newly developed genetic mouse model revealed a significant increase in innate and adaptive immune signatures in absence of C3aR. Furthermore, loss of C3aR significantly impacted the fecal and tumor-associated microbiota and supported the blooming of pro-inflammatory bacterial species as confirmed by experiments of fecal microbiota transplantation.
Future studies will elucidate whether loss of C3aR can be exploited as a biomarker for sub-groups of CRC and whether the C3a/C3aR axis may be exploited for the generation of more effective therapeutic interventions.
Regulatory network of miRNAs, lncRNAs and target genes associated with immune response in bovine mastitis
Authors: Morenikeji Olanrewaju , Tucker Ashley , Salazar Nicole , Ayoola Adeola , Thomas Bolaji 
Published: February 2023

Abstract
Bovine mastitis is mainly caused by Escherichia coli and Streptococcus uberis. It is associated with complex multifactorial phenotypes, requiring an integrative approach to elucidate the molecular networks underlying variable disease outcome. The association of lncRNAs, miRNAs and their target as key players in immunity regulation has not been studied in bovine mastitis. We hypothesize that non-coding genes could mediate immune response in bovine mastitis and have potential as disease markers or drug targets. Through bioinformatic analyses, we investigated the networks of lncRNAs, miRNAs and mRNAs, and identified key regulatory elements driving immune response in bovine mastitis. Our analyses reveal 16 highly significant immune response genes including MYD88, IL-10, IL-4, ICAM1, CXCL8, IL-18 and CSF2. Notably, of the 2904 miRNAs reported, six - bta-miR-24-3p, bta-miR-149-5p, bta-miR-223, bta-miR-185, bta-miR-328, and bta-miR-874, were predicted to bind multiple regions of target genes. Likewise, eight out of 22 lncRNAs including NONBTAT001181.2, XR_003030515.1 and XR_003030515.1 bind 13 mRNA targets. Of interest, some of these are conserved in 15 different species, including Homo sapiens. Our functional analyses show that these lncRNAs and miRNAs may regulate pathogenesis of bovine mastitis through lipopolysaccharide-mediated signaling pathway, regulation of chemokine (C-X-C motif) ligand 2 production, regulation of IL-23 production, positive regulation of chemokine production and pattern recognition receptor activity. This interactome lays a foundation for molecular interconnectivity of regulatory elements in bovine mastitis, deserving further elucidation for potential vaccine and therapeutics.
A highly diverse set of novel immunoglobulin-like transcript (NILT) genes in zebrafish indicates a wide range of functions
Authors: Yoder Jeffrey A , Wcisel Dustin J , McConnell Sean , Hernandez Kyle M. , Andrade Jorge , de Jong Jill L. O. , Litman Gary W , Dornburg Alex 
Published: February 2023

Abstract
Multiple novel immunoglobulin-like transcripts (NILTs) have been identified from salmon, trout and carp. NILTs typically encode activating or inhibitory transmembrane receptors with extracellular immunoglobulin (Ig) domains. Although predicted to provide some level of immune recognition in ray-finned fish, we currently lack a definitive framework of NILT diversity, thereby challenging our ability to understand the evolutionary origin and specific function of these genes. In order to better understand the diversity of NILT genes and their possible roles in immune function, we identified 5 NILT loci in the Atlantic salmon (Salmo salar) genome, defined 86 NILT Ig domains within a 3 Mbp region of zebrafish (Danio rerio) chromosome 1, and described 41 NILT Ig domains as part of an alternate haplotype for this same genomic region. We then identified transcripts that define 43 different NILT genes and reflect an unprecedented range of sequence diversity and combinatorial diversity of Ig domains for a single family of non-recombining receptors. Zebrafish NILTs include a single putative activating receptor but extensive inhibitory and secreted forms as well as membrane-bound forms with no known signaling motifs. Whole genome sequences from different genetic backgrounds reveal at least three alternative haplotypes of the zebrafish NILT gene cluster that display gene content variation. This observation indicates that different individual fish can encode different combinations of NILTs which could impact their immune function. Furthermore, these results reveal a higher level of genetic complexity and sequence diversity for NILTs than previously described, suggesting that this gene family likely plays multiple roles in host immunity.
Macrophages Harbor Transcriptionally Active Defective HIV Provirus Which Contribute to Immune Activation
Authors: Kuniholm Jeffrey , Armstrong Elise , Coote Carolyn , Henderson Andrew 
Published: February 2023

Abstract
People living with HIV suffer from a variety of co-morbidities including neurological deficits and cardiovascular disease even while on antiretroviral therapy (ART). Chronic inflammation has been implicated in these co-morbidities and has long been described in HIV patients. Characterization of the HIV DNA (provirus) reservoir in CD4 T cells from HIV patients on ART has revealed that more than 90% are defective and unable to complete the viral life cycle. Macrophages are susceptible to HIV infection and are positioned at the nexus of pathogen detection, inflammation, and priming of adaptive immune responses. We hypothesized that HIV-infected macrophages harbor defective HIV proviruses which remain transcriptionally competent and affect adaptive immune responses. To test this, we examined the status of HIV proviruses in primary human monocyte-derive macrophages (MDMs) and their expression of HIV transcripts. MDMs were infected with HIV in vitro and using an intact provirus detection assay we observed that roughly half of HIV proviruses were defective. Reverse transcription droplet-digital PCR (RT-ddPCR) detected a distribution of HIV transcripts, many of which lack the full 5′ LTR sequence consistent with transcription starting from an intragenic site. When CD8 T cells were co-cultured with autologous HIV-infected MDMs, they increased their expression of CD107a, a degranulation marker, indicating that infected macrophages could trigger CD8+ activation. Together, these results support that alternative transcriptional mechanisms, which persist in the absence of a fully functional LTR, are active during HIV infection in macrophages, contributing to macrophage dysfunction and persistent HIV-associated diseases.