bluuebunny/crossref_metadata_2025_split huggingface dataset:
The Lactobacillus rhamnosus R0011 secretome attenuates TNFα-induced pro-inflammatory gene expression in human HT-29 intestinal epithelial cells
Authors: Jeffrey Michael P , MacPherson Chad , Mathieu Olivier , Tompkins Thomas A , Green-Johnson Julia May 
Published: January 2023

Abstract
Probiotic lactic acid bacteria have been associated with a wide array of host-immune modulatory effects including modulation of pro-inflammatory gene expression. However, many questions remain about the exact cellular mechanisms through which these bacteria modulate host cell responses following pro-inflammatory challenge. The aim of this study was to elucidate the effects of the Lactobacillus rhamnosus R0011 secretome on TNFα-induced pro-inflammatory gene expression. Previous analysis has shown that the &lt;10kDa fraction of the Lr R0011 secretome attenuates TNFα-induced IL-8 production from HT-29 intestinal epithelial cells (IECs). Whole-genome wide microarray analysis was used to further interrogate the impact of the &lt;10kDa fraction of the Lr R0011 secretome on TNFα-induced gene expression. Contact with the &lt;10kDa secretome fraction alone induced minimal changes in global gene expression by HT-29 IECs, with no increases in pro-inflammatory gene expression. However, the &lt;10kDa fraction of the Lr R0011 secretome attenuated TNFα-induced expression of the pro-inflammatory mediators CCL10, CXCL1, CXCL10, CXCL11, IL-1β, IL-8, IL-17C, IL-23A, IL-32, and PTGS2, when compared to HT-29 IEC treated with TNFα alone. Co-challenge of HT-29 IECs with the &lt;10kDa fraction of the Lr R0011 secretome and TNFα also resulted in an increase in the expression of dual specificity phosphatase 1 (DUSP1), a key regulator of the MAPK pathway, and of activating transcription factor 3 (ATF3), a negative regulator of innate immunity, relative to HT-29 IECs treated with TNFα alone. This provides insight into mechanisms through which these bacteria may influence innate immune activity at the IEC level through soluble mediators.
The cytosolic DNA- and RNA-sensing pathways play important and non-redundant roles in host defense against vaccinia infection
Authors: Deng Liang , Dai Peihong , Wang Weiyi , Santagostino Sara , Serna-Tamayo Cristian , Meyer Cindy , Wang Yi , Li Tuo , Chen Zhijian J , Colonna Marco , Tuschl Thomas , Merghoub Taha , Shuman Stewart 
Published: January 2023

Abstract
Vaccinia virus is a prototypic poxvirus, and during the life cycle of the virus, viral DNA and RNA can be detected by the nucleic acid-sensing pathways to induce the expression of type I IFN and IFN-stimulating genes, which leads to the establishment of antiviral state. Poxviruses have evolved multiple strategies to evade host immunity. Vaccinia E3, which consists of two distinct Z-DNA-binding and dsRNA-binding domains, is a critical virulence factor. Virus lacks E3L gene (ΔE3L) is non-pathogenic in wild-type mice in an intranasal infection model. We have previously reported that ΔE3L infection of murine primary keratinocytes (KCs) induces Ifnb, Il6, Ccl5 and Ccl4 gene expression and protein secretion via a MAVS/IRF3-dependent mechanism. Here we show that MDA5, a cytosolic dsRNA sensor, is essential for the induction of innate immunity by ΔE3L in KCs, whereas PKR, another cytosolic dsRNA sensor, is not. ΔE3L gains virulence in MDA5, MAVS, or IRF3-deficient mice, but not in STING-or MyD88-deficient mice, in an intranasal infection model. The MDA5-, MAVS-, or IRF3-deficient mice lost 20% of weight but all recovered in response to ΔE3L infection. By contrast, both the MDA5 and STING-mediated sensing pathways contribute to host defense against WT vaccinia virus infection. Lastly, whereas ΔE3L virus fails to replicate in wild-type murine primary fibroblasts, it gains replication capacity in cGAS or STING-deficient murine primary fibroblasts. Taken together, these results indicate that vaccinia viral nucleic acids are detected via the cytosolic DNA- and/or RNA-sensing pathways in a cell-type dependent manner, and both pathways play important and non-redundant roles in host defense against vaccinia infection.
Antiviral activity of cell free hypothiocyanite against various subtypes of Influenza virus
Authors: Gingerich Aaron , Patel Urmi , Hanson Jarod , Rada Balazs , Tripp Ralph A 
Published: January 2023

Abstract
The respiratory epithelium is one of the first lines of defense utilized by the body to fend off invading pathogens. One such defense mechanism is a three-component system made up of the thiocyanate ion (SCN−), lactoperoxidase (LPO) and hydrogen peroxide (H2O2) which together create antimicrobial hypothiocyanite ions. Cell derived H2O2 is produced by the NADPH oxidase, dual oxidase enzymes (DUOX1&2). This system is capable of functioning with halides such as iodide as a substitute for thiocyanate. Previously we were able to show that cell derived hypothiocyanite was capable of inactivating influenza virus with a 4–5 log efficiency. We used a cell free method utilizing glucose oxidase as our source of H2O2 to create a high throughput in vitro system to determine that hypothiocyanite inactivates Influenza in a strain independent manner and that thiocyanate is the key substrate in the reaction. We also determined that the more acidic the pH the more efficient the viral inactivation. Additionally, we substituted SCN− with I− and found that different substrates have different levels of antiviral activity. These results support the idea that in vivo this LPO/SCN/H2O2 system plays a vital role in the initial defense against influenza virus and that this system has the potential to change the course of an IAV infection.
Pulmonary monocytes promote the establishment of lung tissue-resident CD8 T cell memory following influenza infection
Authors: Dunbar Paul , Wein Alexander , Kumar Nivedah , Li Zheng-Rong , Cartwright Emily Kathleen , Hayward Sarah L , Kohlmeier Jacob E 
Published: January 2023

Abstract
Lung tissue resident memory CD8 T cells (TRM) are critical for protection against heterologous influenza virus challenge by promoting rapid viral clearance. Unlike other mucosal tissues, we have found that local environmental signals are insufficient for the establishment of lung TRM, and that pulmonary antigen encounter is necessary for TRM to differentiate in the lung. Therefore, we investigated the role of lung antigen presenting cell (APC) subsets in the establishment of lung CD8 TRM following influenza infection. The initial appearance of flu-specific CD8 T cells in the lung with a TRM phenotype begins around day 10 post-infection, which coincides with viral clearance. Correspondingly, while most lung APC subsets contain influenza antigens over the course of infection, monocytes are the most numerous lung APC subset containing influenza antigens at the time of TRM appearance. Furthermore, imaging shows direct interaction between monocytes and T cells in the lung, supporting the idea that monocytes can act as drivers of lung TRM differentiation. In a murine influenza model, CCR2−/− mice, which have a defect in monocyte recruitment to the lung, had significantly fewer flu-specific lung CD8 TRM than WT controls. Notably, this defect was not observed in the flu-specific CD8 memory T cells in the lung vasculature or mediastinal lymph node, indicating this effect is specific for tissue-resident memory cells. In addition, this phenotype is not driven by a lack of CCR2 on T cells, as adoptive transfer of wild-type OT-I T cells into CCR2−/− mice yields the same deficiency of lung TRM. Thus, these data show that antigen presentation by lung CCR2+ monocytes has an important role in the establishment of lung CD8 TRM.
Identification of antigen-specific, lung resident memory B cells after influenza infection
Authors: Allie S Rameeza , Bradley John E , Mudunuru Uma , Randall Troy D. 
Published: January 2023

Abstract
B cells display phenotypic and functional heterogeneity in multiple anatomical locations following vaccination or infection. Influenza-specific memory B cells (Flu+BMEM cells) are found in both lymphoid tissues and lung. It is unclear whether these cells represent circulating or resident memory B cell (BRM) populations. We hypothesized that a portion of the Flu+BMEM cell population in the lung would be non-circulating, BRMs. To determine whether Flu+BMEM cells in the lung are circulating or resident, we parabiotically joined previously-infected, congenically-mismatched mice for 2 weeks and marked those cells currently in circulation by infusing anti-B220 and identified those that have trafficked between the partners by their expression of the CD45 congenic marker. The lungs of these mice had large populations of hemagglutinin and nucleoprotein -specific BMEM cells that did not attain equilibrium within 2 weeks of parabiosis, suggesting that they are non-circulating. The Flu+ BRMs in the lungs consisted of 56% IgM+ and 43.9% isotype-switched BRMs. They were established as early as 15 days after infection and maintained for at least 60 days. The formation of Flu+ BRMs required the germinal center (GC), as blocking CD40L with MR1 antibody, during the primary infection abrogated BRM. However, MR1-treatment of mice with established BRM did not affect BRMs in the lung, even though Flu+ GC B cells could be detected in the LN for up to 90 days. These data suggest that GC-dependent lung-BRMs are established early after infection and maintained independently of GCs. These findings are important in the development of vaccines that elicit BRMs and they will provide mechanistic information into the function of Ag+BMEM cells residing in the mucosa.
Staphylococcus Enterotoxin B mediates Acute Lung Injury through alterations in the composition of microbiome in Gut-Lung Axis
Authors: Sultan Muthanna Ali , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Staphylococcus Enterotoxin B (SEB), produced by Staphylococcus aureus is a super antigen that triggers cytokine storm, and inhalation of SEB leads to toxic shock syndrome, respiratory failure, and often death. Microbiome plays an important role in the development and functions of immune system in different parts of the body Including respiratory and digestive systems. Also, cross talk between mucosal tissue of gut and lung through Gut Lung Axis (GLA) can influence immune and respiratory functions of the lungs. In the current study, we used intranasal exposure of SEB to induce acute lung injury (ALI) in C57BL/6 mice and performed 16S rRNA metagenomics sequencing to investigate nature of alterations in gut and lung microbiome after induction of ALI by SEB when compared to controls. Analysis of microbiome for Caecal flush and lung revealed that SEB inhalation caused a decrease in some species such as Ruminococcus gnavus in the lung and gut while increasing Akkremensia mucinphilia, which is responsible for degrading mucin barrier that separates commensal bacteria and pathogenic bacteria. We also found a decrease in some genus level in SEB group when compared to control group such as Lactobacillus. Collectively, these data suggest that exposure to SEB that triggers ALI, is associated with alterations in the composition of microbiome, which may regulate SEB-meadited pathogenesis in the lungs
Novel role for protein kinase D3 (PKD3) in airway epithelial activation and lung inflammation in response to double stranded RNA
Authors: Veazey Janelle , Chapman Timothy J. , Smyth Timothy , Hillman Sara , Georas Steve 
Published: January 2023

Abstract
Airway epithelial cells (AEC) are among the first to encounter inhaled particles and viruses and initiate subsequent immune responses. We recently reported that protein kinase D (PKD) regulates the barrier function of AEC in vitro after stimulation with the double stranded RNA polyI:C (PMID 21996340). Exposure to polyI:C mimics many features of respiratory viral infection in AEC, including induction of pro-inflammatory cytokines. It remains unknown whether PKD plays a role in AEC cytokine secretion, which we explored both in vitro and in vivo. First, we found that polyI:C-induced IL-8 production in 16HBE cells (a human AEC line) was markedly attenuated by pretreatment with PKD antagonist (CRT0066101 from Tocris (from 13000 ± 3752 to 3676 ± 2224 pg/ml at 5 μM CRT, n=4, p&lt;0.05). Next, we challenged mice with inhaled polyI:C (10 μg, 3 consecutive days) and observed a significant increase in bronchoalveolar lavage (BAL) neutrophils 24 hours post challenge (from 0.4 ± 0.8 to 31.2 ± 9.4%; n=10, p&lt;0.01). Strikingly, BAL neutrophil influx was reduced to near baseline values in mice pre-treated with CRT in a dose-dependent manner (e.g. 3.7 ± 4.7% with 100 μg CRT, n=10, p&lt;0.01). The PKD antagonist also markedly reduced BAL levels of the neutrophil chemoattractant KC (p&lt;0.01). PKD3 is the most abundant isoform in the lung by Western blot and RT-PCR. Finally, we found that polyI:C challenge of PKD3+/− mice (Prkd3Gt(OST191038)Lex/MMUCD from MMRRC) caused roughly 50% less BAL neutrophilia and KC release compared to age- and sex-matched wild type littermates (n=5). We conclude that PKD3 plays a previously unsuspected role in regulating AEC activation in response to double stranded RNA, suggesting a novel role for PKD3 in anti-viral immunity.
VSIG-3/IGSF11 is a ligand of VISTA/PD-1H and inhibits human T cell function
Authors: Wang Jinghua , Wu Guoping , Manick Brian , Hernandez Vida , Renelt Mark , Bi Ming , Li Jun , Kalabokis Vassilios 
Published: January 2023

Abstract
B7 family members and their receptors play a central role in the regulation of T cell responses through T cell costimulation and coinhibition pathways that constitute very attractive targets for the development of immunotherapeutic drugs. In this study, we report that VSIG-3/IGSF11 is a ligand of B7 family member VISTA/PD-1H and inhibits human T cell functions through a novel VSIG-3/VISTA pathway. Extensive functional ELISA binding screening assay reveals that VSIG-3 does bind the new B7 family member VISTA, but does not interact with other known members of the B7 family. Furthermore, VSIG-3 inhibits human T cell proliferation in the presence of T cell receptor signaling. In addition, VSIG-3 significantly reduces cytokine and chemokine production by human T cells including IFN-γ, IL-2, IL-17, CCL5/Rantes, CCL3/MIP-1alpha, and CXCL11/I-TAC. Anti-VISTA neutralization antibodies attenuate the binding of VSIG-3 and VISTA, as well as VSIG-3 induced T cell inhibition. Thus, we have identified a novel B7 pathway that is able to inhibit human T cell proliferation and cytokine production. This unique VSIG-3/VISTA coinhibitory pathway may provide new strategies for the treatment of human cancers, autoimmune disorders, infection, and transplant rejection and may help to design better vaccines.
Type 1 regulatory T cells (Tr1) homeostasis and function in aging
Authors: Almanan Maha A , Raynor Jana , Chougnet Claire , Salamonis Nathan , Amarachintha Surya , Steinbrecher Kris , Hildeman David A 
Published: January 2023

Abstract
Type 1 regulatory T cells (Tr1) are a unique population of CD4+ Foxp3− cells that express high levels of IL-10, and have been defined based on their expression of CD49b and LAG-3. Despite the critical roles played by Tr1 cells in controlling T cell responses in autoimmunity and infection, the mechanisms underlying the homeostasis of Tr1 cells remain unclear. Here, we investigated the homeostasis, phenotype and function of Tr1 cells with age. We found that Tr1 cells accumulated dramatically with age. Further, Tr1 cells produced more IL-10 per cell compared to Foxp3+ Treg. While aged Tr1 cells expressed significant levels of c-Maf and Egr-2, two of the Tr1 defining transcription factors, they largely lacked expression of CD49b and were heterogeneous in LAG-3 and ICOS expression. Despite this heterogeneity, LAG-3 identified a population of aged Tr1 cells that potently inhibited T-cell proliferation in a partially IL-10-dependent manner in vitro and controlled colitis severity in vivo. Additional flow cytometric analysis revealed that roughly half of the IL-10 producing cells co-produced IFN-γ. Further, single cell mRNA-seq analysis revealed that IL-10+IFN-γ− cells had a TGF-beta signature, while IL-10+IFN-γ+ cells had a STAT4 signature. Strikingly, IL-6 was critical for overall Tr1 cell accumulation, as aged IL-6 KO mice showed a profound reduction in Tr1 cells and their expression of c-Maf. Combined, these data show that IL-6 promotes Tr1 accumulation with age and provide a new insight into a novel feedback loop whereby an inflammatory cytokine drives accrual of an anti-inflammatory cell population.
PD-L1 binds with B7-1 only in cis on the same cell surface
Authors: Chaudhri Apoorvi , Xiao Yanping , Zhu Baogong , Freeman Gordon J. 
Published: January 2023

Abstract
Programmed death ligand 1 (PD-L1)-mediated immune suppression is a major regulator of peripheral tolerance and is often co-opted by tumors to evade immune attack. PD-L1 binds to PD-1 but in addition binds to B7-1 (CD80) to regulate T cell function. The binding interactions of the PD-L1-B7-1 pathway and its functional role need further investigation in order to understand differences between PD-1 and PD-L1 mediated tumor immunotherapy. We examined the molecular orientation for PD-L1 binding to B7-1 using cell to cell binding assays, ELISA, and flow cytometry. Surprisingly, we found that PD-L1 transfected cells did not bind to B7-1 transfected cells, whereas PD-L1 transfected cells bound to PD-1 transfected cells. As expected, B7-1 transfected cells bound to CD28 or cytotoxic T-lymphocyte antigen 4 (CTLA-4) transfected cells. By ELISA and flow cytometry with purified proteins, we found that PD-L1 and B7-1 had a strong binding interaction only when the PD-L1 molecule was accessible and flexible. On decreasing its accessibility, the binding was greatly reduced. We observed the PD-L1-B7-1 interaction competed for the binding of PD-L1 to PD-1. Further, we co-transfected PD-L1 and B7-1 on the same cell surface and confirmed the cis binding using a Nanobit Assay system. These results indicate that the PD-L1-B7-1 interaction can occur in cis when the molecules are on the same cell but not in trans when the molecules are on different cells. This binding orientation emphasizes the functional importance of co-expression of B7-1 and PD-L1 on the same cell. Interaction in cis competes for binding to other receptors and modulates their function. Our findings help in further understanding PD-L1 mediated immune suppression.
A15153G mAb, a novel tool for human TIGIT study
Authors: Li Cheng-Rui , Li Mong-Shang , Yang Xi-Feng 
Published: January 2023

Abstract
T cell immunoglobulin and ITIM domain receptor (TIGIT) is a recently identified member of the PVR (poliovirus receptor) family of immunoglobulin-like domain containing proteins that is expressed on subsets of T cells and NK cells. With mouse model studies, TIGIT has been established as a new co-inhibitory, or “checkpoint” molecule in immune regulation. It is thus considered as a potential therapeutic target for cancer and for autoimmune/inflammatory disorders. However, due to limited availability of antibody reagents to human TIGIT, the biological function of this molecule in human cells, as well as its detailed mechanisms, has not been fully elucidated. We have developed a novel monoclonal antibody, clone A15153G, specific to human TIGIT. As expected, this antibody reacts with a subset of human peripheral blood T cells and most CD56+ NK cells. When A15153G antibody was applied in culture, it strongly suppressed anti-CD3 induced human T cell proliferation, suggesting that A15153G is an agonistic antibody. By multi-color flow cytometric analysis using this antibody, we found that the expression patterns of human TIGIT on the surface of CD4+ and CD8+ T cells are different. In the CD4+ T cells, TIGIT is mainly expressed in memory-like population; in contrast, significant percentage of “naïve” CD8+ T cells also expressed high levels of TIGIT in addition to memory population. Moreover, CD8+ T cells generally express higher levels TIGIT than CD4+ T cells. Studies of cytokine production profiles of TIGIT expressing cells are ongoing.
Associations between inflammation and senescent/exhaustion markers, CD57, KLRG1, and PD-1 differ in elderly and young
Authors: Shive Carey , Banks Richard , Popkin Daniel , Bonomo Robert , Canaday David H , Anthony Donald 
Published: January 2023

Abstract

Background
Inflammatory indices such as IL-6 and soluble CD14 are elevated in the elderly, and aging is also associated with immune senescence and exhaustion. Soluble indices of inflammation and immune senescence have independently been associated with mortality and morbidity in the elderly. Whether these pathways are mechanistically linked is not clear.

Methods
This pilot study examined the relationship of plasma levels of IL-6, IP10, and sCD14 to T cell expression of immune checkpoint markers PD-1, CD57, and KLRG1 inelderly (≥70 years old; n=10) and young (≤40 years old;n=10) participants.

Results
Elderly participants had elevated plasma levels of IL-6 (p= &lt;0.0001), sCD14 (p=0.0009), and IP10 (p= 0.012) compared to young participants. Surface expression of PD-1 (p= 0.002), CD57 (p= 0.0005), and KLRG1 (p= 0.04) was elevated on memory CD4 T cell in elderly participants. Co-expression of immune checkpoint markers PD-1, CD57, and KLRG1 on CD4 T cells inversely correlated with plasma levels of IL-6 in the elderly; whereas coexpression of checkpoint markers on CD8 T cells positively correlated with plasma levels of IP10 in young participants. Plasma levels of sCD14 positively associated with PD-1 expression on CD4 TEM cells in elderly but inversely correlated with PD-1 expression onCD8 CM and TEM cells in young participants.

Conclusion
The relationship between soluble indices of inflammation and immune check pointmarker expression varies between elderly and young and between CD4 and CD8 T cells. Further studies are warranted to understand the complex interactions of inflammation and immune senescence and how they contribute tomortality and morbidity in the elderly.
Natural nano particle MIR2911 suppresses tumor growth by targeting TGFβ pathway.
Authors: Zhou Zhen , Wang Lintao , Zen Ke 
Published: January 2023

Abstract
Malignant tumor is one of the major diseases threatening the health of human beings. In many human cancers, transforming growth factor beta (TGFβ) expression is increased. Further researches also indicate that, in the development of tumors, TGFβ promotes the formation and development of tumors through a variety of mechanisms. Our research group previously found that traditional Chinese medicine honeysuckle encodes a special miRNA, MIR2911, with high expression level and stability. MIR2911 can be absorbed through GI tract and inhibit many influenza virus subtypes replication. Our study found that MIR2911 is more stable than many other miRNAs. With up to 85% of the GC content, we hypothesized that several MIR2911 moleculars could combine with each other and form natural nanoparticles, which can easily enter into tumor cells. Bioinformatics analysis also showed that MIR2911 can target TGFβ and inhibit its expression. This project intends to use the natural nanoparticles formed by MIR2911 as a tumor therapeutic drug, by inhibiting the TGF pathway, to achieve the purpose of the treatment of tumor.