bluuebunny/crossref_metadata_2025_split huggingface dataset:
PD-L1 enhances the efficacy of the oncolytic virus VSVΔ51
Authors: Hodgins Jonathan , Park Maria M , Bell John C , Bourgeois-Daigneault Marie-Claude , Ardolino Michele 
Published: January 2023

Abstract
Oncolytic viruses (OVs) are a novel immunotherapy showing great promise in the treatment of cancer. Due to the impaired anti-viral response in cancer cells, OVs such as VSVΔ51 preferentially replicate in cancer cells relative to healthy cells. PD-L1 is a surface protein that binds to the inhibitory checkpoint receptor PD-1 to inhibit anti-cancer immunity in vivo. Previous work has suggested that PD-L1 has the ability to inhibit type I interferon signaling. Given that the type I interferon pathway is responsible for inducing the cellular anti-viral response, we hypothesized that PD-L1 will affect the replication of the OV VSVΔ51 in cancer cells. To this end, a PD-L1 knockout line was generated from the PD-L1-expressing mouse prostate cancer cell line TRAMP-C2 by CRISPR/Cas9 (TRAMP-C2 Cd274−/−). Indeed, WT TRAMP-C2 is more susceptible to VSVΔ51 infection and oncolysis compared to TRAMP-C2 Cd274−/− cells, and TRAMP-C2 Cd274−/− cells exhibit severe defects in viral replication and virion production. Similar results have been observed in a different cell type/line. Mechanistically, TRAMP-C2 Cd274−/− secrete greater amounts of IFN-β compared to WT TRAMP-C2 post-infection (with subsequent enhanced expression of IFN-stimulated anti-viral genes), and have altered signaling in response to IFN-β stimulation and VSVΔ51 infection. Similar results are observed following treatment with the viral mimic, poly(I:C). Importantly, all differences in infection between WT TRAMP-C2 and TRAMP-C2 Cd274−/− are abolished when the activity of IFNAR is blocked. Lastly, preliminary evidence suggests that CD80 surface expression is required for the function of PD-L1. Ultimately, we aim to characterize PD-1-independent functions of PD-L1.
Oncolytic poliovirus immunotherapy for breast cancer
Authors: Frazier Victoria N , Holl Eda , Brown Michael , Boczkowski David , Landa Karenia , Hwang Shelley , Gromeier Matthias , Nair Smita K 
Published: January 2023

Abstract
Oncolytic poliovirus PVSRIPO is a recombinant, non-pathogenic polio:rhinovirus chimera that enters cells via the poliovirus receptor CD155. CD155 expression is virtually universal in solid cancers, including breast cancer. CD155 is also expressed on myeloid cells. PVSRIPO infection of antigen-presenting cells (APC), including dendritic cells (DC) and macrophages, induces type I interferon and APC activation. Intratumor injection of PVSRIPO results in robust T cell infiltration and generates an immune-engaged tumor microenvironment. PVSRIPO is therefore an ideal therapeutic complement to immune checkpoint inhibitors, such as anti-PD1/PDL1.
We tested the hypothesis that blocking PD1/PDL1 in conjunction with PVSRIPO will potentiate durable antitumor immunity in the murine E0771 orthotopic breast cancer immunotherapy model. Intratumor injection of PVSRIPO in 5–7 mm orthotopic tumors induces rapid recruitment of neutrophils followed by infiltration of DC, T cells and B cells. Next, we investigated PVSRIPO with PD1/PDL1 blockade. All treatment groups significantly inhibited tumor growth compared to PBS. There were no significant differences in tumor growth inhibition between PVSRIPO and anti-PD1/PDL1 monotherapies. Combination PVSRIPO+PD1/PDL1 blockade was significantly more effective than the monotherapies at controlling tumor growth.
We also tested neoadjuvant PVSRIPO in E0771-tumor bearing mice. We observed that intratumor PVSRIPO followed by surgery effectively controls tumor growth and prevents tumor regrowth following tumor rechallenge, suggesting induction of a systemic immune response. We are now testing neoadjuvant PVSRIPO with anti-PD1/PDL1 in murine models of cancer.
Human immunity to chikungunya infection
Authors: NAYAK KAUSTUV , Jain Vineet , Kaur Manpreet , Khan Naushad , Rai Ramesh Chandra , Dixit Kritika , Sagar Rohit , Gupta Shipra , Islamuddin Mohammad , Verma Anil , Maheshwari Deepti , Aggarwal Charu , Chawla Yadya , Reddy Elluri Seetharami , Panda Harekrushna , Sharma Pragati , Bhatnagar Priya , Singh Prabhat , Ratageri Vinod H , Chandele Anmol , Ray Pratima , Muralikrishna Kaja 
Published: January 2023

Abstract
Chikungunyna virus is expanding globally and continue to cause major public health threat to Indian populations. Vaccine efforts are underway, and it is hoped that these will eventually progress to human evaluation. However, currently we have little understanding of the phenotypes and functions of the human T cells in chikungunya patients, a knowledge that is essential for improving vaccine design/testing and evaluation efforts. Here, we provide a detailed analysis of the CD8 T cell responses in chikungunya patients from India. We found that CD38+ HLADR+ CD8 T cell subset expanded dramatically in chikungunya febrile patients with frequencies averaging about 20% of the total CD8 T cells, and reaching as high as 50% of the CD8 T cells in some patients. The frequencies of these activated CD8 T cells were substantially low and barely above background levels in afebrile patients reporting to the clinic with persistent arthralgia/arthritis that was lasting for more than 30 days. These massively expanding CD8 T cells observed in the acute febrile patients were highly proliferating (KI67 ), robustly expressing markers indicative strong Th1 differentiation (T-bet), cytotoxic functions (Perforin) and inflammatory/synovial tissue homing characteristics (CX3CR1 and CXCR4). Interestingly, antigen-stimulation mediated IFN-g producing functions of these cells was highly compromized, reminiscent of the “cytokine stunned” phenotype. Taken together, these results suggest that these highly differentiated effector CD8 T cell that were massively expanding during acute chikungunya febrile infection might be involved in protection by homing to infected tissues and eliminating infected targets rather than causing inflammation.
The landscape of immune responses and persistent viral reservoirs in systemic and lymphoid tissues in rhesus macaques infected by a newly developed SHIV-CH848
Authors: XU HUANBIN , Ziani Widade , Wang Xiaolei , Veazey Ronald S. 
Published: January 2023

Abstract

Background
The chimeric simian/human immunodeficiency viruses (SHIVs), carrying HIV envelope glycoproteins from transmitted founder (T/F) viruses, are valuable as a challenge viruses in nonhuman primate models for validating HIV-1 vaccines, assessing viral reservoirs and latency, and developing functional “cure” strategies in HIV infection. This study comprehensively investigated immunological changes, viral replication and reservoir size in deep tissues of SHIV-CH848-infected rhesus macaques on antiretroviral therapy (cART).

Material & Method
A total of 10 rhesus macaques (Macaca mulatta, RMs) were intravenously (i.v.)inoculated with SHIV-CH848, containing vpu-env(gp140) sequence from T/F HIV-1 subtype C strain CH848. At 3 months post SHIV infection, 5 animals received cART for 6 months, and remaining 5 animals as untreated controls. Blood, lymph node and rectal biopsies were collected to examine plasma viral load, cell-associated viral RNA/DNA and host immune responses.

Results
SHIV-CH848 inoculation resulted in rapid viral replication, reaching peak viremia at 14dpi. SHIV-CH848 primary infection significantly depleted peripheral and mucosal CD4+ T cells. Also, broadly neutralizing antibodies were also not elicited up to 15 months post infection. Despite gradual recovery of CD4+ T cells after cART, the levels of integrated viral DNA in tissues remained stable throughout 6-months of cART, and rapid viral rebound was observed after ART interruption.

Conclusions
These findings suggest that the new SHIV strain, SHIV-CH848, is able to maintain persistent viral replication in macaques, and establish long-term viral reservoirs/latency in tissues, serving as a valuable model for HIV research.
N6-methyladenosine modification enables viral RNA to escape recognition by RNA sensor RIG-I
Authors: Lu Mijia , Zhang Zijie , Xue Miaoge , Zhao Boxuan Simen , Harder Olivia , Li Anzhong , Liang Xueya , Gao Thomas Z , Feng Zongdi , Niewiesk Stefan , Peeples Mark E. , He Chuan , Li Jianrong 
Published: January 2023

Abstract
Internal N6-methyladenosine (m6A) modification of RNA is one of the most abundant modifications in eukaryotic cells as well as in viruses. However, the biological role(s) of RNA m6A in virus-host interaction remains elusive. Using human metapneumovirus (hMPV), a medically important non-segmented negative-sense RNA virus as a model, we demonstrate that m6A serves as a molecular marker for innate immune discrimination of self from nonself RNAs. We show that hMPV RNAs are m6A methylated and that viral m6A methylation promotes hMPV replication and gene expression. Inactivating these m6A sites with synonymous mutations resulted in m6A deficient recombinant hMPVs that induced significantly higher expression of type I interferon (IFN) that restricted viral replication. Notably, the induction of type I IFN by m6A-deficient rhMPVs and virion RNA was dependent on the cytoplasmic RNA sensor RIG-I, not MDA5. Using RIG-I pull down and RIG-I limited digestion assay, we mechanistically demonstrated that m6A-deficient virion RNA exposed to cytoplasm has much high accessibility to the binding of RIG-I, which allows RIG-I’s translocation along the RNA strand and subsequential conformational change, oligomerization, activation of IFN signaling cascade, and then even higher RIG-I expression during anti-virus status. Furthermore, m6A-deficient rhMPVs triggered higher type I IFN in vivo and were significantly attenuated in the lower respiratory tract yet retained high immunogenicity in cotton rats. Collectively, our results highlight that (i) virus acquires m6A in their RNAs as a means of mimicking cellular RNA to avoid the detection by innate immunity; and (ii) viral m6A RNA can serve as a novel target to attenuate hMPV for vaccine purposes.
A Brazilian Zika virus isolate preferentially induces T follicular helper cell responses while suppressing Th1 immunity
Authors: Pardy Ryan D , Gentile Maria E , King Irah L , Richer Martin J 
Published: January 2023

Abstract
Zika virus (ZIKV) is a mosquito-borne pathogen that caused a series of increasingly severe outbreaks in Micronesia, French Polynesia, and South and Central America. Recent work from our laboratory has shown that, compared to a pre-epidemic isolate (ZIKV-CDN), a Brazilian ZIKV isolate (ZIKV-BR) possesses a novel capacity to suppress antigen-specific CD8 T cell responses, resulting in sustained infection. However, it is unknown whether ZIKV-BR also modulates CD4 T cell immunity. Thus, we investigated the CD4 T cell response to infection with each ZIKV isolate. Our data demonstrate that the CD4 T cell response to ZIKV-BR is reduced in magnitude compared to the response induced by ZIKV-CDN. Further, CD4 T cells are less polarized to the Th1 subtype, express less T-Bet, and are functionally impaired, as they produce less IFN-γ following ex vivo restimulation. Although we observed no alterations in the Th2, Th17 or T regulatory cell compartments, we observed a striking accumulation of PD-1hiCXCR5+ T follicular helper (Tfh) cells 10 days post-infection with ZIKV-BR. This response correlated with an enhanced germinal center B cell response, and increased detection of germinal center formation by confocal microscopy. Future studies will aim to determine the mechanism through which ZIKV-BR infection enhances the Tfh response, and the implications of promoting Tfh responses while dampening Th1 responses for antiviral immunity. Together, our data suggest that contemporary ZIKV strains have evolved to modulate CD4 T cell responses and this could provide a model for interrogating the signals required for Tfh development.
Risk assessment test for MAR ASD: a subtype of Autism
Authors: Celis Nora Alexandra Ramirez , Van de Water Judy 
Published: January 2023

Abstract

Background
Autism spectrum disorder (ASD) is an important health issue and affects 1 in 59 children in the US. Prior studies found that maternal autoantibody related autism (MAR ASD) is thought to be responsible for ~20% of ASD cases. We aimed to create a robust assay to identify ASD-specific autoantibody patterns of reactivity against the previously identified brain antigens CRMP1, CRMP2, GDA, LDHA, LDHB, NSE, STIP1, and YBOX1 in the blood of mothers whose children have ASD and determine their relationship with ASD behavioral outcome.

Methods
We obtained plasma enrolled in the CHARGE study from mothers of children diagnosed with ASD (n=481) and control mothers of typically developing children (TD, n=377). Maternal plasma was probed against the eight antigens by ELISA and WB. We then determined patterns of reactivity that had a strong association with ASD by permutation analysis.

Results
We found several ASD specific patters of reactivity (positives for several antigens) in 16% of the ASD samples and 0% in the TD group. From those, 4 patterns of reactivity were statistically significant using Fisher’s exact test 0.05% showing a significant association of having autoantibodies against a combination of those antigens and a higher risk of having a child with MAR ASD. Also, preliminary studies indicate a positive correlation between having reactivity to multiple antigens and higher Autism Severity Scores (ADOS composite).

Conclusion
We developed the first risk assessment test to predict ASD with 100% specificity based on reactivity to different combinations of brain antigens. We are currently working on the development of multiple MAR ASD animal models.
Insights into the role of Epstein-Barr virus infection in multiple sclerosis using a novel humanized mouse model of disease
Authors: Allanach Jessica R. , Hardman Blair K , Fettig Naomi M , Mouat Isobel , Gu Yu , Jean-Baptiste Virginie , Shanina Iryna , Osborne Lisa C , Vorobeychik Galina , Horwitz Marc S 
Published: January 2023

Abstract
Multiple sclerosis (MS) is an autoimmune disease of the central nervous system without a clear cause. Epstein-Barr virus (EBV) is proposed to contribute to the pathogenesis of MS through unknown mechanisms. Evidence for a role of EBV infection in MS comes from both epidemiological and experimental studies, however, due to its narrow host tropism, there are currently few suitable animal models of MS that incorporate EBV infection. Recent advancements in humanized mouse modelling has enabled direct infection for the study of EBV-associated malignancies. We therefore chose to evaluate the role of EBV infection in humanized mice with experimental autoimmune encephalomyelitis (EAE), a widely used model of MS. Immunocompromised mice were engrafted with peripheral blood mononuclear cells (PBMC) derived from individuals with relapsing MS (RRMS) or from matched healthy EBV seropositive or seronegative donors. We observed that HuPBMC mice induced with EAE developed ascending paralysis, weight loss and signs of discomfort consistent with classical EAE models. Further, HuPBMC EAE showed significant T cell infiltration of both the brain and spinal cord, notably of IFN gamma-expressing CD4 and CD8 T cells, resulting in spinal cord and cerebellar demyelination. HuPBMC EAE mice derived from EBV seropositive donors developed earlier disease onset with more severe clinical symptoms compared to EBV seronegative donor-derived mice. We also observed increase disease severity among mice derived from RRMS patients compared to healthy controls. With continued improvement and characterization of this novel humanized EAE model, additional environmental and genetic risk factors can be evaluated in a system with human immune-mediated pathology.
Macrophage cannabinoid 1 receptor promotes obesity-induced insulin resistance and inflammation
Authors: Han Ji Hye , Kim Wook 
Published: January 2023

Abstract
NLRP3 inflammasome plays a crucial role in immune responses, promoting the maturation of proinflammatory cytokines interleukin 1β (IL-1β) and IL-18, and has been associated with a variety of inflammatory conditions, including obesity and type 2 diabetes. Our recent studies have figured that inhibition of cannabinoid 1 receptor (CB1R) improves metabolic abnormalities and suppresses macrophage infiltration into white adipose tissue, activation of NLRP3 inflammasome, and production of proinflammatory cytokines. Macrophages are implicated in this process. To test the role of CB1R, we established mice with selective CB1R-defeciency in macrophages (MacCB1R KO). We investigate that feeding a Western-type diet to control and MacCB1R KO mice caused similar obesity, but only mice with MacCB1R KO remained insulin sensitive. The protection of mice with macrophage-specific CB1R-deficiency against insulin resistance was associated with reduced tissue infiltration by macrophages. Immunophenotypic parameters have been proved that CB1R is involved for pro-inflammatory macrophage polarization. These studies demonstrated that CB1R in macrophages is associated to establish obesity-induced insulin resistance and inflammation.
The role of Interleukin-22 and its receptor Interleukin-22Rα on the regulation of inflammatory responses in the brain
Authors: Lee DaHae , Kim Yejin , Jo Hyejung , Kang Jae Seung 
Published: January 2023

Abstract
Interleukin (IL)-22 is a member of IL-10 family, is a potent mediator of inflammatory responses. It is produced by activated CD4+ T cells and natural killer (NK) cells and takes effect on non-hematopoietic cells mainly stromal and epithelial cells. And, IL-22 receptor consists of IL-22Rα and IL-10Rβ. It is known that IL-22Rα expression is restricted to non-hematopoietic cells in the skin, pancreas, intestine, liver, lung and kidney. Even though IL-22 is mainly involved in the development of inflammatory responses, but there is a no report regarding their roles on inflammatory responses in the brain. In the present study, I investigated the role of IL-22 and its receptor on inflammatory responses in the brain using mouse microglia cell line, BV2 and mouse hippocampal neuronal cell line, HT22. When BV2 and HT22 were treated with rIL-22 (20 ng/ml), expression of cyclooxygenase (COX)-2, was increased and its expression is followed by the increased of PGE2 production. Next, I examined whether production of pro-inflammatory cytokines, such as such as IL-6 and TNF-α, and pro-inflammatory chemokines by IL-22 treatment. As a result, I confirmed that IL-6, TNF-α, and MIG/CXCL9 are remarkably increased. Taken together, IL-22α is spontaneously expressed on the cells, especially microglia and neuron and it is closely involved in the development of inflammatory responses in the brain.
Role of C-C Motif Chemokine Ligand 20 in the Regulation of Epidermal γδ T Cells
Authors: Bshara-Corson Savannah , Gonzalez Isaac , Jameson Julie M 
Published: January 2023

Abstract
The epidermis provides a barrier that protects against environmental damage and infection by pathogens. Epidermal T cells and keratinocytes work together to maintain skin homeostasis upon damage. During tissue repair, epidermal γδ T cells become activated to secrete cytokines, chemokines and growth factors to initiate inflammatory responses. Previous work in our lab has shown that during obesity and type 2 diabetes, Chemokine Receptor 6 (CCR6) is downregulated by murine epidermal T cells. The ligand for CCR6, C-C Motif Chemokine Ligand 20 (CCL20), is produced by keratinocytes and is responsible for cellular migration. Little is known about how CCR6 and CCL20 ligation affects epidermal γδ T cells. In this study, murine epidermal γδ T cells were harvested and stimulated in the absence or presence of CCL20 to discover how CCL20 affects activation and function of the cells. Epidermal γδ T cells that have been stimulated with anti-CD3ɛ and CCL20 downregulate their T cell receptor and upregulate CD25 showing cell activation. Interestingly, CCL20 costimulates T cell receptor stimulation to activate epidermal γδ T cells. Immunofluorescent microscopy was used to visualize the impact of CCL20 on activated cells verses non-activated cells in situ. Epidermal γδ T cells treated with CCL20 did not migrate within or out of the epidermis unlike previous studies on dermal γδ T cells. Flow cytometric analysis and Luminex assays were performed to determine which cytokines and chemokines are produced in response to CCL20. We show that CCL20 skews epidermal γδ T cells to produce pro-inflammatory cytokines and chemokines. Future studies will determine how CCL20 and CCR6 ligation affects murine models with obesity and type 2 diabetes.
CXCL13-CXCR5 signaling and its co-expression network are associated with colorectal cancer cell growth and poor prognosis
Authors: Nunez Sha’Kayla K , Griffen Tiara L , Young Corey D , Wu Ji Yuan , Davis Jennifer , Kopetz Scott , Lillard James W 
Published: January 2023

Abstract
The heterogeneity of colorectal cancer (CRC) and its microenvironment has molecular traits of immune cells, and is driven by dysregulated WNT, RAS-RAF-MAPK, TGF-β, and PI3K-AKT pathways. CXCL13-CXCR5 signaling has been shown to induce PI3K- and Ras-dependent activation of MAPK/ERK1-2 to promote cancer cell survival, invasion, and growth. The hypothesis tested in this study is CXCL13-CXCR5 signaling and co-expression networks mediate CRC progression, cell growth, and survival. RNAseq data from CRC cases, along with matched controls, were acquired from The Cancer Genome Atlas (TCGA). Weighted gene co-expression network analysis (WGCNA) elucidated gene networks that significantly correlated with CRC poor prognosis. CXCL13, CXCR5, and other co-expressed genes were identified in the WGCNA designated brown module (M3). The canonical pathways and their upstream regulators of this module were analyzed using Ingenuity Pathway Analysis (IPA). M3 hub genes XCL1, CCL19, PIK3AP1, FLT3, and WNT1 were significantly and positively correlated with PI3K, WNT, ERK1 and ERK2 activation, which promotes cell proliferation and survival. Next, we measured the CRC cell line growth effected by CXCL13 using a XTT assay. In confirmation, CXCL13 treatment of CRC cell lines significantly increased CRC cell line proliferation, but had no direct influence on cell survival. Our findings strongly support CXCL13-CXCR5 signaling and its co-expression networks activates important pathways associated with CRC progression and tumor growth.
PD-1/PD-L1 signaling regulates the thymic niche size of agonistly selected T cells
Authors: Moran Amy , Emlen Ester , Caruso Breanna 
Published: January 2023

Abstract
Effective peripheral T cell responses rely upon a diverse T cell repertoire, generated during thymic selection. Signaling through the TCR establishes thresholds for thymocyte selection in order to create this repertoire. Because co-stimulation modifies TCR signaling, it may contribute to the regulation of T cell development by determining signal strength thresholds that direct thymocytes into specific lineages. Programmed death-1 (PD-1), a member of the B7/CD28 family of costimulatory/inhibitory receptors, has been implicated in the development of thymocytes because it is expressed in CD4− CD8− double-negative thymocytes during TCRb rearrangement. Further, the ligands for PD-1, PD-L1 and PD-L2, are expressed on thymic epithelial cells. PD-L2 is restricted to the medulla whereas PD-L1 is expressed throughout the thymus. Here, we show that PD-1 modulates agonist selection, a process in which some high-affinity thymocytes will mature into unconventional T cell lineages (e.g. regulatory T cells, NKT cells). Transgenic mice lacking either PD-L1 or PD-1 have increased numbers of agonistly selected T cells compared to wildtype animals. Interestingly, loss of PD-L1 increases the selection of conventional and agonistly selected T cells whereas loss of PD-1 limits the phenotype to agonist lineages. These data demonstrate that PD-1, PD-L1, and possibly PD-L2 interactions, potentially within the thymic microenvironment in which they are expressed, play a role in determining T cell fate and shaping the final T cell repertoire.