bluuebunny/crossref_metadata_2025_split huggingface dataset:
Filamentous phage as a model immunogen for tracking B-cell responses to infection and vaccination (154.30)
Authors: Murira Armstrong , Henry Kevin , Holland Jessica , Scott Jamie 
Published: January 2023

Abstract
Humoral immunity to infection can be categorized into four response stages: (i) innate-like, (ii) early-induced, (iii) adaptive, and perhaps (iv) the response to chronic infection (ChI). The first three stages are mediated by B-cell lineages distinguishable by phenotypic, genetic and functional characteristics. Our analysis of antibodies (Abs) produced during ChI indicates that “ChI Abs” have unique genetic features including high somatic mutation (SM) and usage of distal germline VH genes; ChI is also associated with aberrations in B-cell subsets. Here, we use filamentous phage as a model antigen to determine the genetic features and cellular origins of “ChI Abs” in the mouse. The phage’s surface consists of ~3,000 copies of the major coat protein, pVIII, and a majority of the anti-phage Ab response cross-reacts with a 12-aa peptide comprising the N-terminus of pVIII, allowing easy isolation of phage-specific B cells. After a single immunization, two “waves” of Ab-secreting cells (ASCs) appeared: first, IgM and IgG ASCs expressing proximal unmutated genes, followed by IgG ASCs expressing more distal genes bearing SMs. Phage-specific ASCs and serum IgG increased with repeated immunization, peaking after the fifth immunization and declining thereafter. Thus, we have validated the approach of combining cellular, flow cytometric, serological and immunogenetic analyses to characterize the dynamics of the B-cell response after initial and repeated encounter with antigen.
Vγ4+ T cells regulate host immune response to West Nile virus infection (154.33)
Authors: Wang Tian , Welte Thomas , Aronson Judith , Gong Bin , Rachamallu Aparna , Tesh Robert , Born Willi , O'Brien Rebecca 
Published: January 2023

Abstract
Vγ4+ cells, a subpopulation of peripheral γδ T cells are involved in West Nile virus (WNV) pathogenesis but the underlying mechanism is unclear. Here, we further investigated the role of Vγ4+ cells in WNV encephalitis and found that Vγ4+ cell-depleted mice had a lower viremia and reduced inflammation in the brain following WNV infection. Although Vγ4+ cells contributed to interleukin (IL-17) production during infection, blocking IL-17 signaling did not affect host susceptibility to WNV encephalitis. Furthermore, there was an enhanced magnitude of protective Vγ1+ cell expansion in the spleen and more Vγ1+ cell infiltration into the brains of Vγ4+ cell-depleted mice than controls during WNV infection. Vγ4+ cells of WNV-infected mice had a higher potential for producing transforming growth factor (TGF)-β. We noted that the difference in anti-CD3-stimulated γδ T cell proliferation between those of controls and Vγ4+ cell-depleted mice was diminished in the presence of TGF-β inhibitor. Moreover, Vγ4+ cells contributed to the production of IL-10, which is known to play a negative role in immunity against WNV infection, either directly or by increasing IL-10-producing αβ T cells. These results suggest that Vγ4+ cells may suppress Vγ1+ cell expansion via TGF-β and promote IL-10 production, which leads to higher viremia and enhanced brain inflammation during WNV infection.
The herpes simplex virus 1 encoded latency associated transcript promotes dysfunctional virus specific CD8+ T cells in latently infected trigeminal ganglia (154.39)
Authors: Alami chentoufi Aziz , Kritzer Elizabeth , Tran Michael , Dasgupta Gargi , Afifi Rasha , Jiang Xianzhi , Osorio Nelson , Carpenter Dale , Nesburn Anthony , Wechsler Steven , BenMohamed Lbachir 
Published: January 2023

Abstract
Following ocular herpes simplex virus type 1 infection, HSV-specific CD8+ T cells are induced, selectively retained in latently infected trigeminal ganglia and appear to decrease HSV-1 reactivation. The LAT gene increases HSV-1 reactivation. We hypothesized that increased numbers and/or function of HSV-specific functional CD8+ T-cells in TG might be involved in the decreased reactivation seen with LAT(-)mutants. Mice were ocularly infected with either LAT(+) or LAT(-) viruses and the number and function of CD8+ T-cells in TG were examined during latency. Although fewer total CD8+ T-cells were found with LAT(-) viruses, TG had more functional HSV-gB-specific CD8+ T cells compared to LAT(+) TG which had many exhausted HSV-gB-specific CD8+ T cells, as judged by high levels of PD-1, impaired cytotoxicity, and decreased IFN-γ and TNF-α production. In addition, mouse Neuro2A cells expressing LAT, had elevated PD-L1 and MHC-I compared to LAT(-) Neuro2A cells and were resistant to lysis by allogeneic CD8+ T cells. Collectively, our findings suggest that TG from mice latently infected with LAT(-) viruses had more HSV-specific functional CD8+ T-cells than did TG from mice infected with LAT(+) viruses. In addition LAT appeared specifically able to upregulate both PD-L1 and MHC-I. These findings may constitute a novel immune evasion mechanism whereby LAT promotes dysfunctional HSV-specific CD8+ T cells in latently infected TG, resulting in more virus reactivation
Differential regulation of post-transplant viral host defense by donor versus host regulatory T cells (154.40)
Authors: Lindell Dennis , White Maria , Lukacs Nicholas , Berlin Aaron , Torgerson Troy 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) infection is a significant cause of morbidity and mortality following hematopoietic cell transplant (HCT). We used a murine model of autologous HCT to investigate the roles played by regulatory T cells (Treg) in host defense against RSV infection post-transplant. Regulatory T cells were highly enriched in the CD4+ T cell compartment up to five weeks post-transplant (&gt;30% of lung CD4+ T cells at week 2 post-transplant, versus 5-10% in controls). The increased frequency of Tregs resulted from 1) survival recipient-derived cells, 2) increased proliferation of Tregs compared to Teff, and 3) differentiation of induced Treg (iTreg). Using Foxp3-DTR mice, DT- mediated ablation of recipient-derived Tregs led to increased lung leukocytes (CD45+, CD4+, CD8+, and CD11b+CD11c+ cells). Total numbers of IFNγ+ CD4+, IL-17+CD4+, IFNγ+CD8+ T cells were all increased in recipient Treg ablated mice. Remarkably, ablation of donor Tregs led to decreases in the same pulmonary leukocyte subsets, and decreased effector T cell (CD4+IFNγ+ and CD8+IFNγ+) responses. Ablation of donor (but not recipient) Tregs impaired viral clearance. In other studies, mature Foxp3+ CD4+ T cells co-transferred at transplant lost Foxp3 expression (&gt;30% by week 4), suggesting instability of Tregs in the post-transplant environment. Together, these studies indicate differential (and possibly, competing) functions for Tregs in post-transplant host defense.
Oligomeric procyanidins stimulate innate antiviral immunity (154.9)
Authors: Hedges Jodi , Kimmel Emily , Jerome Maria , Holderness Jeff , Snyder Deann , Kemoli Sharon , Jutila Mark 
Published: January 2023

Abstract
Oligomeric procyanidins (OPCs) have been shown to have antiviral and immunostimulatory effects. OPCs isolated from non-ripe apple peel, found in the dietary supplement Applepoly®, were tested for capacity to reduce dengue virus (DENV) titers. Similar to published accounts, OPCs exhibited direct antiviral activity. OPCs also enhanced expression of critical innate antiviral products during DENV infection of human PBMCs. Specifically, expression of MXI and IFNB transcripts in DENV infected cells, and phosphorylation of STAT2 in response to recombinant type I IFN (IFN I), were increased by OPC treatment. During low MOI infection, addition of OPCs also increased expression of STAT1 transcripts, MHC I and TNFα protein production. Thus, OPCs exhibited innate immune stimulation of DENV-infected human cells, bystander cells in infected cultures, and uninfected cells treated with IFN I. To test the effects of OPC ingestion in vivo, mice were fed a rich source of OPCs and injected with polyIC to mimic innate responses to viral infection. Ingestion of OPCs resulted in enhanced innate antiviral responses in vivo. While OPCs from a number of sources are known to exhibit antiviral effects, their mechanisms are not precisely defined. The capacity of OPCs to enhance innate antiviral immunity could be broadly applicable to many viral infections and two separate antiviral mechanisms, direct and immunomodulatory, suggest that OPCs may represent a novel, robust antiviral therapy.
VRC01 provides sterilizing protection to non human primates from mucosal SHIV challenges (155.11)
Authors: Pegu Amarendra , Yang Zhi-yong , Chen Xuejen , Todd John-Paul , McKee Krisha , Rao Srinivas , Mascola John , Nabel Gary 
Published: January 2023

Abstract
VRC01 is an exceptionally broad neutralizing monoclonal antibody targeting the CD4 binding site of HIV gp120. It was isolated from an HIV-1 infected donor and is able neutralize over 90% of circulating HIV-1 isolates at high potency in vitro. Using a nonhuman primate lentiviral immunodeficiency virus infection model, we assessed the ability of VRC01 to protect animals from mucosal challenge with a pathogenic chimeric simian-human immunodeficiency virus (SHIV). The animals were first administered either VRC01 or a control IgG i.v. at a dose of 20 mg/kg and 2 days later were mucosally challenged with SHIV. We used two different mucosal routes - intrarectal (i.r.) and intravaginal (ivag) for mucosal challenge to mimic natural HIV exposures in humans. The plasma viral loads and sera VRC01 levels in animals were measured weekly by real time RT-PCR and ELISA, respectively. We observed that 3 out of the 4 animals in both the control groups were infected, with peak viremia occurring at week 2 for the i.r. challenge and at week 3 for the ivag challenge. In contrast, none of the 4 animals that received VRC01 got infected in both mucosal challenge groups (p=0.04). These results demonstrate that a broadly neutralizing CD4 binding site mAb, VRC01, protects against mucosal exposure to pathogenic viruses in vivo. This finding provides support for the CD4 binding site as a target of AIDS vaccine development and the possible use of VRC01 to prevent mucosal transmission of HIV-1 in humans.
The anti-infective Nitazoxanide shows strong immumodulating effects (155.21)
Authors: Clerici Mario , Trabattoni Daria , Pacei Michela , Biasin Mara , Rossignol Jean-Francois 
Published: January 2023

Abstract
Nitazoxanide (Alinia®, NTZ) and its active circulating metabolite tizoxanide (TIZ) are anti-infectives thiazolide with activity against parasites, anaerobic bacteria, and viruses. NTZ is licensed in the US for the treatment of diarrhea caused by Cryptosporidium parvum and Giardia lamblia. NTZ and TIZ also inhibit replication of RNA and DNA viruses including influenza A and hepatitis C viruses. In clinical trials, NTZ was shown to be effective in treating rotavirus gastroenteritis, norovirus gastroenteritis and chronic hepatitis C, and is in late-stage clinical development for treatment of influenza. We evaluated the immunomodulatory effect of TIZ. PBMC from 10 healthy donors were cultured in the presence/absence of 3 different doses of TIZ (0.5, 1.0 and 10 mg/ml) in both unstimulated and flu-stimulated conditions and analysed for T helper and CTL activity as well as for TLR7 and TLR8 expression and type I IFN responses. TIZ showed potent immunomodulatory effects inducing an increase in: 1) IFNg- and IL2-secreting CD4+ T cells, 2) CTL degranulation, 3) Fas-expressing CD8+ T cells, 4) TLR8-expressing monocytes, 5) IFNa- and IFNb- mRNA expression, 6) mRNA specific for type I IFN inducible genes (MXA, PRKCZ, ADAR, CXCL10, IRF1, PRKRA), and 7) mRNA specific for gene involved in MHC class I presentation (HLA-A, HLA-B, TAP1).The antiviral effects of TIZ result from immumodulatory activity stimulating a strong antiviral immune response mediated by both native and acquired mechanisms
Dual antigen target based immunotherapy for prostate cancer eliminates the growth of established tumors in mice (155.3)
Authors: Karan Dev , Dubey Seema , Thrasher Brantley 
Published: January 2023

Abstract
Generation of antigen-specific CD8 T cells is considered optimal for an effective immunotherapy against cancer. Knowing that heterogeneity of prostate cancer limits the therapeutic benefit, we developed a recombinant adenovirus type 5 (rAd5) co-expressing a fusion of PSA (prostate-specific antigen) and PSCA (prostate stem cell antigen) genes. The selection of these genes is based on their restricted distribution within the prostate and their association with the development and progression of prostate cancer. Immunization of mice with rAd5 vector co-expressing PSA and PSCA antigens (Ad5-PSPA) simultaneously induces the expansion of anti-PSA, and anti-PSCA T cells as measured by intracellular cytokine staining for IFN-y. To analyze the impact on therapeutic efficacy of Ad5-PSPA vaccine against the tumor cells co-expressing cognate antigens (RM11-PSA/PSCA cells), injection of mice with Ad5-PSPA vaccine inhibited the growth of established tumors. Initially, the mice developed slow growing tumors and eventually upto 80% of the mice remain tumor free following immunization with Ad5-PSPA vaccine. These data provide useful information that antigen-specific effector T cells can be generated simultaneously and their additive anti-tumor effect has the ability to eliminate the growth of established tumors. Therefore, the immunotherapy approach of using the simultaneous targeting of dual antigens associated with prostate cancer may have important implications for human clinical trials.
Signaling via neurokinin-1 receptor is required for cellular immunity induced by melanoma vaccines (156.12)
Authors: Larregina Adriana , Mathers Alicia , Tkacheva Olga , Morelli Adrian 
Published: January 2023

Abstract
Tumor vaccines are promising alternatives to current therapies for melanomas. Yet, in spite of initial enthusiasm, melanoma vaccines not always provide the positive results expected. Hence, there is a need for in-depth study of the mechanisms underlying effective vaccines for melanocyte Ags. The neuroimmune function of the skin, is ideal for efficient cancer vaccines and agonistic signaling of skin cells via neurokinin-1 receptor (NK1R), by the inflammatory substance-P (SP) released by cutaneous nerves and immune cells, favor CD4+Th1 and CD8+Tc1 immunity to foreign Ags. Here, we demonstrate that elicitation of cellular immunity by skin gene gun (GG) immunizations needs agonistic signaling via NK1R.Indeed, GG-vaccines encoding the tyrosine-related-protein-2 (TRP-2) (GG-TRP-2), delivered to NK1RKO mice failed to induce TRP-2-specific immunity. Conversely, NK1R agonist (Sar9Met O2)11-SP (SarSP) used as adjuvant at the vaccination site in BL/6 WT mice significantly enhanced the ability of GG-TRP-2 to elicit TRP-2-specific effector and memory Th1 and Tc1 immunity. Importantly, this resulted in prevention of melanoma growth and increased survival of mice challenged with B16F0 melanoma cells and overcame a potential tumor promoting effect of SarSP. Our results shed light on the mechanisms involved in efficient elicitation of cellular immunity through cutaneous delivery of weakly immunogenic tumor self Ags are relevant for development of effective tumor vaccines.
Decitabine and Interferon-γ enhance neuroblastoma cells susceptibility to CTL-mediated killing (156.26)
Authors: Bao Lei , Dunham Kimberly , Lucas Kenneth 
Published: January 2023

Abstract
MAGE-A1, MAGE-A3, and NY-ESO-1 are cancer-testis (CT) antigens expressed on a number of malignant solid tumors, including neuroblastoma, but many tumor cell lines down-regulate the expression of CT antigens as well as major histocompatibility (MHC) antigens, precluding recognition by antigen specific T cells. If expression of cancer antigens as well as MHC molecules could be enhanced pharmacologically, the efficacy of CT antigen specific immunotherapy could be improved. We have demonstrated that the expression of MAGE-A1, MAGE-A3, and NY-ESO-1 can be upregulated on neuroblastoma cells following exposure to the demethylating agent 5-aza-2’-deoxycytidine (decitabine, DAC) in 10/10 neuroblastoma cell lines. Culture of neuroblastoma cell lines with IFN-γ was associated with an increased expression of either MHC Class I or II by cytofluorometry, with MHC Class I upregulated in 10/10 of these cell lines, although to varying degrees. MAGE-A1, MAGE-A3, and NY-ESO-1 specific CTL were cultured from volunteer donors by stimulating peripheral blood mononuclear cells with dendritic cells pulsed with overlapping peptide mixes derived from full length proteins, and these CTL lysed HLA partially matched, DAC treated neuroblastoma and glioblastoma cell lines. These studies confirm that DAC and IFN-γ can be used to increase the expression of CT antigens and MHC molecules on neuroblastoma cells, and pre-treatment with these agents makes tumor cell lines more susceptible to CTL mediated killing.
High avidity T cells have increased potential to convert to FoxP3+ T cells in vitro and in the tumor microenvironment (156.29)
Authors: Sklavos Martha , Zhu Ziqiang , Singh Vinod , Hurwitz Arthur 
Published: January 2023

Abstract
We have previously reported that CD8+ T cells that enter the tumor microenvironment and become tolerized can also acquire suppressive function. More recently, we reported that low avidity (TCRlo) T cells were unable to control B16 melanoma tumor growth, despite retention of effector function. In contrast, high avidity (TCRhi) T cells initially delayed tumor growth until they became tolerized, when tumor growth resumed. We hypothesized that TCRhi T cells may be more likely to differentiate into FOXP3+ regulatory T cells, which could contribute to restored tumor growth. To examine our hypothesis, B16 tumor-infiltrating TCRlo and TCRhi T cells were tested for FOXP3 expression. An increased frequency of intratumoral FOXP3+ TCRhi T cells (p=0.012 vs. FOXP3+ TCRlo cells) were detected approximately 2.5 weeks after T cell transfer, suggesting that conversion to a FOXP3+ phenotype contributed to restored tumor growth. We next tested the potential of TCRlo and TCRhi T cells to differentiate into FOXP3+ T cells. After a 10 day in vitro culture with TGF-β, an increased frequency of TCRhi T cells expressed FoxP3 compared to TCRlo T cells (p=0.019). On-going studies are characterizing the function of these unique tumor-infiltrating CD8+ T cells. Circumventing the conversion of high avidity T cells to FoxP3-expressing T cells in vivo may extend the beneficial effects of adoptive T cell therapy and produce more effective cancer therapies.
Autophagy of Listeria monocytogenes within macrophages is dependent on Nod/Rip2 pathway (157.2)
Authors: Anand Paras , Kanneganti Thirumala-Devi 
Published: January 2023

Abstract
Listeria monocytogenes is an intracellular pathogen that escapes from the phagosome and replicates in the cytosolic compartment. Intracellular bacteria are often targeted for autophagy, an essential component of the innate immune response. Autophagy involves engulfment of the pathogen within double-membrane structures called autophagosomes wherein the contents are degraded by acidification upon fusion with the lysosomes. The role of innate immune receptors, such as the Nod-like receptors, in autophagy of Listeria monocytogenes is not well known. We observed that upon Listeria infection autophagy is induced within macrophages as observed by LC3-II immunoblotting, GFP-LC3 puncta formation and electron microscopy. However, in macrophages deficient in Nod1 or Nod2, autophagy induction upon Listeria infection was found to be inefficient. Further, autophagy induction was dependent on the Nod1/Nod2 downstream adaptor Rip2 kinase. Defective autophagy in Nod2-/- macrophages resulted in fewer bacteria co-localizing with the GFP-LC3 autophagosomes. Furthermore, Nod2-/- macrophages were found to be more susceptible to Listeria replication. These findings demonstrate a mechanistic link between the innate immune receptors and antibacterial autophagy.
Sequential phosphorylation and ubiquitination regulate NOD2:RIP2 signaling (157.7)
Authors: Tigno-Aranjuez Justine , Abbott Derek 
Published: January 2023

Abstract
NOD2, the Crohn’s Disease and sarcoidosis susceptibility protein, is an intracellular sensor of muramyl dipeptide (MDP), a breakdown product of bacterial peptidoglycan. Upon exposure to MDP, NOD2 binds to the kinase RIP2 to modulate cytokine responses. We have recently described that NOD2 activation results in the tyrosine autophosphorylation of RIP2 and have demonstrated that pharmacologic inhibition of RIP2’s tyrosine kinase activity blunts activation of downstream NOD2 signal transduction pathways. In complementarly work, the E3 ubiquitin ligase, ITCH, downregulates NOD2 signaling, and in ITCH-/- macrophages or ITCH knockdown cells, both MDP-induced cytokine release and RIP2 tyrosine phosphorylation are aberrantly high. Our current work extends these findings by demonstrating that ITCH-/- mice are hypersensitive to sarcoidosis models. We molecularly map the direct site of ITCH-induced downregulation of the NOD2:RIP2 pathway and find that ITCH mediates regulation of NOD2 signaling and RIP2 tyrosine phosphorylation through ubiquitination and degradation of cIAP1. Lastly, we show that by mimicking the action of ITCH through the use of pharmacological inhibitors of cIAP1 (MEBS), we can decrease levels of cIAP1, decrease RIP2 tyrosine phosphorylation, and negatively regulate downstream NOD2 signaling. Agents such as MEBS may be useful in hyperactive NOD2 states such as in individuals with Crohn’s Disease harboring WT NOD2, Early Onset Sarcoidosis, and ITCH-deficiency.
Analysis of phosphorodiamidate morpholino oligomer chemisrty CpG effects in murine and human cells (158.12)
Authors: Hauck Laura , Mourich Dan , Iversen Patrick 
Published: January 2023

Abstract
Many RNA-based therapeutic oligomer backbone chemistries will elicit undesirable immunological response through a number of pathways. Additionally, it has been shown that certain sequences can also elicit cellular pro-inflammatory responses in the form cytokine and chemokines production. For example, non-methylated CpG DNA motifs are considered pathogen-associated molecular patterns (PAMPS) due to their abundance in microbial genomes and their recognition by TLR-9 receptors. Some synthetic oligonucleotides, containing modified backbone or other synthetic nucleotide motifs, will still retain potent immunostimulatory activity which may be inappropriate within the desired therapeutic effect. The purpose of this study was to look in vitro for immune activation resulting from exposure to optimized CpG sequences incorporated into the phosphorodiamidate morpholino oligomer (PMO) chemistry. Human and murine dendritic cells (DCs) were treated with varying concentration of PMO and culture media was assayed by multiplex cytokine and chemokine detection platform for simultaneous detection of multiple analytes. There was no evidence for a sequence- or chemistry-specific activation of the DCs indicating that PMO do not provide an innate stimulus to the immune system.