bluuebunny/crossref_metadata_2025_split huggingface dataset:
Surface and cytoplasmic tumor cell PD-L1 differentially mediate virulence in ovarian cancer and melanoma through mTOR activation
Authors: Hambright Heather Graham , Gupta Harshita B. , Padron Alvaro S , Vadlamudi Ratna , Chen Yidong , Osmulski Pawel A , Curiel Tyler J 
Published: January 2023

Abstract
Tumors express intracellular PD-L1 that we showed increases ovarian cancer (OC) and melanoma virulence by increasing mTORC1 and tumor stem cells (TSC). We made PD-L1KO(CRISPR) in ES2 human OC and B16 melanoma cells and re-expressed PD-L1 only on cell surface (PD-L1surf) or in cytoplasm (PD-L1cyto) with specific expression vectors. Subcellular PD-L1 location in all clones was validated by immunoblots, confocal microscopy, and co-IP/mass spec. We selected clones with PD-L1 surf or cyto expression similar to parental cells. PD-L1KO reduced cell diameter 30% which was restored partially in PD-L1surf and fully in PD-L1cyto in ES2 and B16. PD-L1KO significantly decreased viability in all cell lines tested which was fully rescued in PD-L1surf and PD-L1cyto. PD-L1surf ES2 and B16 grew slower in vitro and in vivo than PD-L1cyto and only PD-L1cyto rescued F-actin polymerization phenotype seen in PD-L1KO ES2 and B16. RNA-seq showed that surf and cyto PD-L1 differentially altered canonical signaling pathways, notably mTOR, stemness and gene regulation. PD-L1cyto grew much slower than PD-L1surf B16 in NSG mice but generated more TSC in vitro, and PD-L1surf but not PD-L1cyto B16 responded to αPD-L1 in WT. PD-L1cyto but not PD-L1surf induced mTORC1 activation (p-rpS6, p-P70S6K) through mTORC1 lysosomal docking through LAMTOR1/2 seen by confocal and confirmed by co-IP in ES2 and B16. Imaging CyTOF of human melanomas showed PD-L1cyto association with activated mTOR. Thus, surf versus cyto PD-L1 differentially affects tumor biology, signaling, pathology, TIL and treatment response in OC and melanoma. We define a mechanism for PD-L1-driven mTORC1 activation. Surface vs. cytoplasmic PD-L1 and/or mTORC1 could be response biomarkers for αPD-L1 or αPD-1.
Randomized Controlled Phase 2a Study Results Using Anti IL-33 in Food Allergy
Authors: Liu Cherie , Chinthrajah Sharon , Long Andrew , Lyu Shu-Chen , Londei Marco , Nadeau Kari Christine 
Published: January 2023

Abstract
Objectives of this placebo-controlled study were to assess the safety and tolerability of single dose ANB020 administration in peanut-allergic adult patients and to measure the response during a standardized oral food challenge (OFC) after ANB020 or placebo administration compared to baseline peanut food challenge. On Day 1, fifteen highly allergic adult patients were administered 300 milligrams of ANB020 by IV infusion, and five patients were administered placebo injections. To measure patient response, patients were administered ex-vivo whole blood peanut antigen challenges on Day 2 and Day 5 and were administered OFCs on Day 15 and Day 45. The clinical outcomes and cellular responses of patients were analyzed. For patients given ANB020, 0% at Baseline, 67% on Day 15, and 57% on Day 45 passed the OFC; no placebo patients passed the OFC at Baseline, Day 15, or Day 45. Patients given ANB020 also experienced fewer adverse events (abdominal pain, nasal congestion), compared to placebo patients (abdominal pain, vomiting, nausea, asthma, allergic reaction). The median percentages of IL-4 and IL-9 cells in CD69 T cells were lower for patients administered ANB020 compared to patients administered placebo at Baseline, Day 2, and Day 5, and higher at Day 15. Peanut-specific and histamine skin test wheal sizes among all patients stayed consistent, except at Day 15 for patients given ANB020, where both wheal sizes decreased significantly to less than 5 mm. Volumes of peanut-specific IgE and total IgE were smaller for patients given ANB020 at Baseline, Day 15, and Day 45. Thus, study results show ANB020 injections to be potentially helpful in increasing patient tolerability and safety during OFCs.
Prophylactic immunization prevents antiviral T cell subversion by a rat hepatitis C-like virus
Authors: Hartlage Alex , Murthy Satyapramod Srinivasa , Kumar Arvind , Trivedi Sheetal , Dravid Piyush , Sharma Himanshu , Walker Christopher M , Kapoor Amit 
Published: January 2023

Abstract
The hepatitis C virus (HCV) is a leading cause of severe progressive liver diseases by virtue of its ability to evade host immunity and establish lifelong persistence in majority of infected individuals. Despite significant advancements in antiviral therapy, a vaccine to prevent HCV persistence and associated disease is not yet available, in part because there is no small animal model to experimentally dissect mechanisms of immune protection and viral subversion. Here, we used a novel rat model of HCV-related hepacivirus infection to define antiviral T cell immunity during viral persistence and after prophylactic vaccination. Challenge of lab rats with a rodent hepacivirus led to universal persistence characterized by minimal viral diversification and an absence of functional CD8+ T cell responses. Direct visualization of virus-specific CD8+ T cells with a class I tetramer revealed a premature contraction of responses prior to acquisition of antiviral effector functions. By contrast, immunization of rats with a recombinant adenovirus expressing hepacivirus non-structural proteins induced functional CD4+ and CD8+ T cell immunity and significantly prevented hepacivirus persistence in majority of rats after challenge. Loss of vaccine-conferred immunity and subsequent persistence in a single rat was associated with selection of MHC class I escape variants. Transient depletion of CD8+ cells from vaccinated animals prolonged viral replication after challenge, while CD4+ cell depletion led to virus persistence. These data provide direct in vivo evidence that T cells are important for resolution of persistent hepacivirus infection and that subversion of the response can be successfully prevented by prophylactic immunization.
Unraveling the mechanism of type-1 immunity induction by defective viral genomederived oligonucleotides
Authors: Fisher Devin G , Lopez Carolina B 
Published: January 2023

Abstract
Many newly developed vaccines use killed pathogens or pathogen subunits as antigens. Unfortunately, these inert antigens do not contain danger signals required to induce robust adaptive immunity. Adjuvants are added to vaccines to provide danger signals that help boost and shape the immune response. Currently, no approved adjuvants can effectively skew the immune response towards type-1 immunity including CD8+ T cells necessary for the clearance of viruses and other intracellular pathogens. Most viruses induce type-1 immunity and this process can be leveraged to generate type-1 immunity inducing adjuvants. The primary immunostimulatory molecules during paramyxovirus infections are defective viral genomes (DVGs). We identified the immunostimulatory motif of a Sendai virus DVG and created a DVG-derived oligonucleotide (DDO) to test as an adjuvant. Intramuscular injection of DDO with inactivated influenza virus induced robust protective type-1 immunity characterized by CD8+ T-cell responses and antibodies of the IgG2c isotype. This immune response was dependent on type I interferon signaling. Mice lacking MyD88, the adaptor for TLR and IL-1 signaling, did not produce type-1 humoral or cellular responses in response to a DDO-adjuvanted vaccine. Current studies focus on further understanding the molecular and cellular mechanisms mediating the type I interferon-dependent response to DDOs. This knowledge may allow for directed vaccine design for intracellular pathogens.
Antigen-specific CD8 T cell response following genital chlamydial challenge is a predictive biomarker of vaccine efficacy in protection against reproductive tract pathology
Authors: Murthy Ashlesh K , Warda Katerina , Moy Lindsay , Musunuri Tarakarama , Bui Nhi , Wright-McAfee Erika , Ramsey Kyle H , Li Weidang 
Published: January 2023

Abstract
TNF-α producing antigen (Ag)-specific CD8 T cells induce upper genital tract (UGT) pathology following primary C. muridarum infection; therefore, we hypothesized that a vaccine regimen must subvert Ag-specific CD8 T cell response following immunization, and/or challenge to attenuate Chlamydia-induced UGT pathology. We evaluated three immunization regimens: live-chlamydial elementary body intranasal (EB-i.n.), live-EB i.m. (EB-i. m.), and irrelevant antigen bovine serum albumin i.n. (BSA-i.n.) that induced near-total (90%), partial (50%), and no (0% ) protection, respectively against oviduct pathology following i.vag. C. muridarum challenge in C57BL6/J animals. Live-EB-specific IFN-γ, TNF-α, and IL-17 response from purified splenic CD8 T cells was evaluated on days 7, 14, and 21 after immunization. There was no detectable reduction of Ag-specific CD8 T cell response following immunization with protective vaccine regimens. We evaluated splenic live-EB-specific CD8 T cell responses on days 3, 6, 9, and 12 following i.vag. chlamydial challenge. All groups of challenged animals displayed comparable induction of Ag-specific CD8 T cell cytokine responses on day 6 after challenge. As early as day 9 after challenge, Ag-specific IFN-γ and TNF-α production from CD8 T cells was significantly reduced in EB-i.n.-, compared to the EB-i.m.- or BSA-i.n.-immunized animals. On day 12, both EB-i.n.- and EB-i.m.-immunized animals displayed minimal Ag-specific TNF-α production, compared to enhanced TNF-α production from CD8 T cells in BSA-i.n. immunized animals. These results suggest that TNF-α producing CD8 T cell response could serve as a predictive biomarker of anti-chlamydia vaccine efficacy against reproductive pathology.
Combined PD-1 and LAG-3 Blockade Together with HLA-A*0201 Epitopes Immunotherapy Restore the Function of CD8+ TRM Cells and Reduce UV-B Induced Recurrent Ocular Herpes in HSV-1 Infected “Humanized” HLA Transgenic Mice
Authors: Benmohamed Lbachir , Coulon Pierre-Gregoire A , Srivastava Ruchi , Roy Soumyabrata 
Published: January 2023

Abstract
Exhaustion of herpes simplex virus type 1 (HSV-1)-specific CD8+ T cells is a notable cause that contribute to the frequency and severity of recurrent herpes. In the present study, we found that functionally exhausted HSV-specific CD8+ T cells, expressing both the programmed death-1 (PD-1) and lymphocyte activation gene-3 (LAG-3), two immune checkpoint receptors that promotes T cell exhaustion, were frequent in symptomatic (SYMP) patients with a history of numerous episodes of recurrent corneal herpetic disease. Similarly, using a novel “humanized” HLA-A*0201 transgenic mouse model of UV-B induced recurrent corneal herpetic disease, we demonstrated that SYMP mice with increased virus shedding and severe recurrent corneal herpetic disease had more exhausted HSV-specific tissue resident PD1+LAG-3+CD8+ TRM cells in both trigeminal ganglia (TG) and cornea. Dual blockade of both PD-1 and LAG-3 pathways restored the number and function of antiviral CD8+ TRM cells and appeared to be synergistically superior to blockade of either pathway alone. Moreover, blockade of PD-1/LAG-3 immune checkpoints in combination with therapeutic vaccination with a mixture of HLA-A*0201-restricted CD8+ T cell epitopes UL9196–204, UL25572–580, and UL44400–408, recently identified from HSV-1 proteins, significantly improved protection against UV-B induced recurrent herpes. This pre-clinical study indicate that dual blockade of Immune checkpoints combined with therapeutic vaccination with human epitopes identified from HSV-1 proteins is a promising strategy to protection against recurrent herpes in human.
High dimensional analysis of the GI tract as a long-term reservoir for chronic viral infection
Authors: Macleod Bethany L , Dickson Russell , Hezaveh Kebria , Elsaesser Heidi J , Guidos Cynthia J , Brooks David G 
Published: January 2023

Abstract
Chronic viruses such as HIV and hepatitis are a major health concern worldwide. As an organ constantly exposed to the external environment, the gastrointestinal tract (GIT) must constantly balance suppressive and inflammatory immunity, making it an ideal organ for virus persistence. Yet despite its importance, chronic virus infection of the GIT and its ramifications towards host immunity remains poorly understood. We recently discovered that the GIT is a long-term reservoir for chronic lymphocytic choriomeningitis virus (LCMV); persisting well after virus is cleared from the blood and other peripheral tissues.
To identify host and microbial alterations that facilitate chronic GIT infection we performed high dimensional CyTOF analysis, 16s rRNA-seq and next generation sequencing. Primary infection induced acute CD4 T cell ablation and chronic infection promoted Treg outgrowth, which was associated with viral persistence. Interestingly, chronic infection led to acute GI pathology and dysbiosis, with long-term infection enhancing susceptibility to IBD. Transcriptional signatures indicated enhanced type I interferon induced inflammation and metabolic changes associated with immune exhaustion. Interestingly, upstream regulators of GIT immunity were shared in chronic LCMV, HIV and SIV, indicating the induction of conserved pathways across multiple viral infections. Finally, we demonstrate the efficacy of immunotherapeutic targets and cell depletions to control the long-lived chronic GIT reservoir. Ultimately our studies define molecular, cellular and microbial impacts of chronic virus infection to alter GI function and identify potential immunotherapeutic strategies to control virus in this long-lived reservoir.
Structural and functional insights of the capsid protein from Zika virus
Authors: Song Hao , Shang Zifang , Qi Jianxun , Gao George F. 
Published: January 2023

Abstract
Zika virus (ZIKV) emerged as a global public health concern, and is distinct from other flaviviruses in many aspects, e.g., causing transplacental infection, fetal abnormalities and vector-independent transmission through body fluids in humans. The capsid (C) protein is a multifunctional protein, since it binds to viral RNA in the process of nucleocapsid assembly and plays important roles in virus infection processes by interacting with cellular proteins, modulating cellular metabolism, apoptosis and immune response. Here we solved the crystal structure of ZIKV C protein at a resolution of 1.9 Å. The ZIKV C protein structure contains four α helices with a long pre-α1 loop, and forms dimers. The unique long pre-α1 loop in ZIKV C contributes to the tighter association of dimeric assembly and renders a divergent hydrophobic feature at the lipid bilayer interface in comparison with the known C structures of West Nile and dengue viruses. We reported the interaction between the ZIKV C protein and lipid droplets through confocal microscopy analysis. Substitutions of key amino acids in the pre-α1 loop of ZIKV C disrupted the interaction with lipid droplets, indicating the loop is critical for membrane association. We also recognized ZIKV C protein possesses broad binding capability to different nucleotide types, including single-stranded and double-stranded RNAs or DNAs. Furthermore, the highly positively charged interface, mainly formed by α4 helix, is proposed to be responsible for nucleotide binding. These findings will greatly enhance our understanding of ZIKV C protein, providing information for anti-ZIKV drug design targeting the C protein.
Can Age-Associated B cells (ABC) Contribute to Anti-Viral Immunity?
Authors: Kugler-Umana Olivia Antonia , Kuang Yi , Zhang Wenliang , Devarajan Priyadharshini , Xia Jingya , Swain Susan L 
Published: January 2023

Abstract
With age, follicular helper T cell (TFH) dependent B cell responses erode, reducing germinal center formation, follicular B cell antibody responses and memory. Aged mice and humans develop an additional B cell population, termed age-associated B cells (ABC), that lack CD21 and CD23 and may produce TFH independent antibodies. The aged ABC population is heterogeneous, with some expressing transcription factors and adhesion molecules suggesting antigen exposure, and such ABC have been implicated in autoimmunity. Similarly, we found a unique population of responding B cells following influenza A virus (IAV) infection of aged mice that was Fas+/GL7− and we called infection induced-ABC (iABC). We asked if the CD21−CD23− ABC are progenitors of these non-follicular iABC. Upon IAV infection, transferred ABC gave rise to an iABC (Fas+GL7−) population in T and B deficient RAG KO and TFH deficient SAP KO hosts. This ABC-derived iABC population shared the phenotype of iABC in infected aged mice and could become T- cell independent Ab-producing cells. We found that aged ABC can be separated into sIgD+ (putative naïve B cells) and sIgD−(memory-like B cells). When transferred to SAP KO hosts, the sIgD+ ABC efficiently gave rise to iABC, some of which become CD138+ Ab-secreting cells. This suggests that upon T-independent stimulation, the population of sIgD+ABC in aged mice can develop into IAV-specific Ab secreting cells and may thus provide an alternate B cell-mediated pathway of protection against IAV infection. Studies are underway to evaluate the contribution of iABC-produced Ab to IAV protection.
Early Cancer detection in the Pacific
Authors: Sika-Paotonu Dianne , Liligeto Urijah , Guilford Parry 
Published: January 2023

Abstract
Cancer is now the second leading cause of death across the South Pacific Region, and leading cause of death in at least two Pacific nations. As Pacific countries are also operating health systems with constrictive budgets and constrained resourcing, it can be difficult to quantify and obtain precise cancer measures and estimates such as incidence, morbidity, survival and mortality figures over time. It is acknowledged that within this resource constrained environment, the diagnosis, treatment and management of cancer patients is fraught with challenges and difficulties where routine tests and equipment may be unavailable and even vary from hospital to hospital. Circulating tumour DNA (ctDNA) refers to tumour DNA fragments found in the blood circulation. Using a simple blood test, these fragments can be identified by the presence of mutations in cancer genes and can be isolated and quantified to provide information concerning cancer’s size and progression. It is anticipated this simple method of detecting and monitoring cancer will enhance the precision of cancer diagnostics and surveillance and also lead to improved cancer health outcomes for Pacific Peoples in the Region. Preliminary engagement efforts with clinical and research persons were undertaken in order to understand the local context and explore the potential utility of ctDNA technology for early cancer detection to support and improve the diagnostics, care and health outcomes of cancer patients in the Solomon Islands. Interest was expressed in the possibility of utilizing a simple blood sample to allow detection and monitoring of cancer growth. The potential utility of ctDNA for early cancer detection remains a promising approach for cancer diagnostics.
CXCR5+ST2+memory Th2 cell reduced maturation and fecundity of Nippostrongylus brasiliensis through increase of expression of Major Basic Protein in eosinophils
Authors: Obata-Ninomiya Kazushige , Ishiwata Kenji , Endo Yusuke , Ichikawa Tomomi , Onodera Atsushi , Hirahara Kiyoshi , Okamoto Yoshitaka , Kanuka Hirotaka , Ziegler Steven F , Nakayama Toshinori 
Published: January 2023

Abstract
Once mice experience the infection of helminth, the mice acquired resistance to the helminth. We have studied about memory responses against Nippostrongylus brasiliensis (Nb) in mice. Nb penetrates into skin, passes through the lungs and finally reaches to the gut. It has been reported that IL-33 contributes to the immune responses against re-infection of helminth. However, the IL-33-dependent immunity to Nb has not been fully defined. In this study, we identified subsets of memory Th2 (mTh2) cells; CXCR5+ST2+CD44hiTh2 cells and ST2−CD44hiTh2 cells producing IL-4 and IL-13, and increasing accumulation of eosinophils in the lungs in helminth infection. CXCR5+ST2+mTh2 cells rather than ST2− mTh2 cells strongly expressed IL-5 and increased the expression of Major Basic Protein (MBP) in eosinophils in the lungs, which is important for reduction of maturation and fecundity of Nb in the intestine. Notably, we also found ST2+Treg cells but not ST2− Treg cells can suppress the ST2+mTh2 cell-mediated reduction of fecundity of Nb. Taken together, these findings indicate that we identified a mechanism against helminth elicited by a subpopulation of IL-5-producing Th2 cells through the accumulation of eosinophils strongly expressing MBP in the lungs. This would be helpful to establish the drugs and/or vaccination against helminth,
Structural and Functional Investigations Into B7-1:NGFR
Authors: morano nicholas , Garret Sarah , Almo Steven 
Published: January 2023

Abstract
Although Nerve Growth Factor Receptor (NGFR, TNFSFR16) is traditionally thought of as a receptor that regulates the growth of neurons, it is also widely expressed throughout the immune system in response to inflammation where its function is poorly characterized. In addition to binding the four neurotrophins (NGF, BDNF, NT3, NT4), the Almo lab and others have recently discovered that NGFR can also act as a receptor for B7-1 (CD80). B7-1 is a major costimulatory molecule expressed on antigen presenting cells (APCs) such as dendritic cells, macrophages, and microglia in response to inflammation. B7-1 can bind to CD28 on naïve T-cells, which induces T-cell activation. It can then bind CTLA4 (upregulated on T cells after CD28 activation), which reduces activation. B7-1 also interacts with PD-L1. The structure and function of the B7-1-NGFR interaction is currently unknown. We have recently conducted epitope mapping experiments that suggest the NGFR binds to B7-1 on the same interface that CD28 and CTLA4 bind to B7-1. This interface appears to be independent of the PD-L1-B7-1 binding interface. NGFR epitope mapping data suggests that B7-1 binds to NGFR near the binding site for NGF, and similarly to other TNFRSF receptor-ligand interactions. Furthermore, our data shows that NGFR and CTLA4 can compete for binding to B7-1. In addition, we are investigating the role the B7-1:NGFR binding plays in neurons.