bluuebunny/crossref_metadata_2025_split huggingface dataset:
Investigation of novel TLR7/8 ligands in combination with TLR4 ligands as adjuvants to drive cell mediated anti-influenza immunity
Authors: Miller Shannon M. , Cybulski Van , Walsh Lois , Livesay Mark , Bess Laura , Burkhart David J. , Bazin-Lee Helene , Evans Jay T. 
Published: January 2023

Abstract
Influenza is a highly communicative viral pathogen that infects 9–35 million individuals and results in 12,000–56,000 deaths in the US annually. For the most commonly used seasonal influenza vaccine, historical efficacy rates range from 10–60% thus improvements to the current vaccine are needed. We identified a novel series of synthetic TLR7/8 ligands that improve influenza vaccine efficacy when used alone or in combination with our synthetic TLR4 ligand. In human PBMCs, TLR7/8 ligands elicited secretion of the inflammatory cytokines TNFα, IL-6, and IL-1β as well as the Th1-polarizing cytokine IL12-p70. These responses can be altered by modification of novel structural features of the TLR7/8 ligands. The addition of a synthetic TLR4 ligand modified the cytokine expression profile, indicating that the structure of a TLR7/8 ligand and/or addition of a TLR4 ligand can drive substantive changes in the innate immune response. To evaluate the adjuventicity of these TLR ligands, Balb/c mice were vaccinated with split-flu vaccine containing TLR7/8 ligands alone or in combination with our TLR4 ligand. TLR7/8 ligands increased influenza-specific total IgG and IgG2a, but not IgG1, over antigen alone. Addition of a TLR4 ligand further increased influenza-specific total IgG and IgG2a. These data demonstrate that these ligands act as adjuvants to promote a Th1 skewed humoral response. The combination of TLR7/8 and TLR4 ligands elicited superior cell mediated immunity compared to either TLR7/8 or TLR4 ligand alone. These data demonstrate that heightened innate and adaptive immune responses can be elicited through a combination adjuvant using novel synthetic TLR7/8 and TLR4 ligands.
Poly-gamma glutamic acid/alum enhances the efficacy of vaccine antigen by modulating antigen transport to lymph nodes and the adaptive immune responses
Authors: Nguyen Quyen Thi , Yang Jihyun , Kim Jaemoo , Kwak Chaewon , Poo Haryoung 
Published: January 2023

Abstract
Vaccination is the most effective strategy to protect against infectious diseases and adjuvants are proven to be the key component in vaccines capable of improving antigen-specific immune responses. Conventional vaccine adjuvants, however, still have several limitations such as safety concerns and insufficient induction of vaccine efficacy. Here, we developed a novel adjuvant by combining poly-gamma glutamic acid (γ-PGA) with alum that is already approved for human use worldwide. The physiochemical properties, efficacy, and underlying mechanism of the PGA/Alum as an adjuvant were investigated using ovalbumin (OVA) as a model antigen in vivo and in vitro. PGA/Alum-OVA administered mice showed the robust increase of antigen-specific humoral and cellular immune responses compared to mice administered with γ-PGA-OVA or alum-OVA. Importantly, the PGA/Alum-OVA-induced antibodies had significantly higher antibody-dependent cellular cytotoxicity (ADCC) activity. The enhanced activation and antigen processing of dendritic cells (DCs) and the facilitated migration of antigen-loaded DCs from the injection sites to draining lymph nodes were observed in PGA/Alum-OVA administered mice. Finally, the efficacy of the PGA/Alum as a vaccine adjuvant was evaluated using pandemic H1N1 influenza vaccine antigen. The PGA/Alum drastically enhanced protective efficacy of the pandemic H1N1 vaccine against influenza virus infection. Taken together, PGA/Alum may be a promising adjuvant to improve the influenza vaccine efficacy.
CD8+ T cells control HSV-1 replication in the nervous system but not the cornea in HSV-1 0ΔNLS-vaccinated mice lacking virus-neutralizing antibody
Authors: Carr Daniel J. J. , Montgomery Micaela Lee , Royer Derek 
Published: January 2023

Abstract
HSV-1 is a successful human pathogen that can elicit benign pathology including cold sores to more severe to extreme life-threatening manifestations like blinding necrotizing stromal keratitis and encephalitis. To date, there is no commercially available vaccine for HSV-1 despite many failed experimental prototypes. We have evaluated the use of a live-attenuated HSV-1 strain (HSV-1 0ΔNLS) as a vaccine in a mouse model of ocular infection. This vaccine has been shown to prevent virus replication, spread, and establishment of latency while functionally preserving the visual axis and corneal integrity. The correlate of protection elicited by the vaccine is antibody, and optimal efficacy requires expression of the neonatal Fc receptor in the corneal epithelium. The present study was undertaken to determine if T cell receptor transgenic mice expressing CD8 T cells specific for glycoprotein B of HSV-1 (gBT-I.1) benefit from vaccination. gBT-I.1 mice were vaccinated with HSV-1 0ΔNLS or vehicle and subsequently ocularly challenged with HSV-1. The results showed HSV-1 0ΔNLS vaccinated gBT-I.1 mice had no measureable neutralizing antibody titer but did show enhanced survival compared to vehicle-vaccinated gBT-I.1 mice. The efficacy correlated with less infectious virus in the nervous system of HSV-1 0ΔNLS-vaccinated mice during acute infection (p &lt; 0.05). However, viral titers and pathology were similar in the corneas of both groups. Collectively, the results suggest in the absence of antibody, vaccine-primed HSV-specific CD8+ T cells enhance control of HSV-1 replication and spread in the nervous system but are not effective in the cornea.
A Bovine Adenovirus (BAdv) Expressing Mycobacterial Secreted Ag85B and a TLR-2 Stimulating Adjuvant Peptide Induces Robust Antigen Presentation In vitro and Improved Protection against Tuberculosis in Mice
Authors: Khan Arshad , Mani Arunmani , Hwang Shen-An , Mann Lovepreet , Papanna Ramesha , Won Jong Hak , Canaday David , Hunter Robert L. , Wang Jin , Mittal Suresh , Jagannath Chinnaswamy 
Published: January 2023

Abstract
Human Adenovirus (HAdv) vectors expressing Mycobacterium tuberculosis (Mtb) derived antigens, have been tested as candidate boosters for BCG vaccine in animal models and Phase I human studies but failed to provide significant additional protection. Presumably, pre-existing immunity to HAdv among humans has been suggested to limit their efficacy as vectors. We earlier reported that novel bovine adenovirus (BAdv)-vectors induced robust T cell mediated immunity in mice and carried less risk of interference by human innate immunity. Thus, we evaluated BAdv vectors expressing Mtb derived antigen 85B and a novel TLR-2 activating peptide as booster vaccines for BCG in vitro and in mouse model for tuberculosis. Both mouse and human APCs (macrophages and dendritic cells) infected with BAdv-85B showed robust presentation of p25 epitope to T cells within 18 hrs of infection. BAdv-Ag85B-TLR2 was better than BAdv-85B in inducing antigen presentation. Antigen presentation by both BAdv-Ag85B and BAdv-Ag85B-TLR2 peptide were significantly decreased when DCs were derived from atg7 knockout mice or when 3-methyladenine was used for blockade, indicating that autophagy played a role during adenovirus-induced antigen presentation. Consistent with in vitro data, BAdv-Ag85B-TLR-2 and BAdv-Ag85B vaccinated mice exhibited reduced lung CFUs of Mtb by 1.5 log and 1.7 log respectively whereas BCG vaccinated mice could reduce CFUs by 0.95 log as compared to unvaccinated mice. In addition, the BAdv vaccines also protected spleens better than BCG suggesting improved protection against disseminated tuberculosis. Since BAdv can be given through mucosal route, we propose that they offer a novel mean to enhance lung and systemic immunity against tuberculosis.
Polarization of Acellular Pertussis Vaccine-primed Immune Response to the TH17 Response
Authors: Kapil Parul , Merkel Tod J. 
Published: January 2023

Abstract
The resurgence of pertussis in the United States has stimulated interest in the development of improved pertussis vaccines. Studies in the baboon model demonstrated that responses induced by infection were dominated by TH1 and TH17 and resulted in near sterilizing immunity. In contrast, the response to vaccination with licensed acellular pertussis (aP) vaccine was dominated by TH2 responses that prevented clinical disease following challenge with pertussis, but did not prevent colonization or transmission. These results suggest that B. pertussis will circulate more freely in an aP-vaccinated population.
A conservative approach for addressing the resurgence of pertussis would be replacement of the aP booster vaccines with an acellular vaccine that generates a balanced TH1/TH2/TH17 response. Before pursuing this strategy, it will be important to understand the degree to which a booster vaccine can polarize an aP-primed TH2 immune response. In this study, aP-primed and unvaccinated baboons were challenged with wild-type B. pertussis. Six months following the first challenge, all baboons and additional unvaccinated, unexposed (naïve) baboons were challenged with wild-type B. pertussis. Our results demonstrated that natural infection of the aP-primed animals resulted in polarization of the TH2-dominated immune response towards a TH17 but not a TH1 response. In contrast to the convalescent animals that were not detectably colonized following the second challenge, the aP-primed, convalescent animals were transiently infected. This data indicates that the aP-primed immune response can be reprogrammed towards a more protective TH17 response albeit not to the same degree as induced by natural infection of unvaccinated animals.
Validation of a fluorescent microsphere multiplex serology assay for differential diagnosis of exposure to Zika virus and other closely related arboviruses
Authors: Venkateswaran Neeraja , Sarwar Jawad , Parameswaran Nishanth , Krishnan Krish VV. , Nelson William M. 
Published: January 2023

Abstract
Arboviruses cause a serious public health problem in tropical and subtropical countries and are emerging as a threat in western hemisphere also. Rapid and accurate detection of these infections can help in improving patient care and disease control. The cross-reactivity of immunoglobulin M (IgM) and immunoglobulin G (IgG) antibodies to ZIKV with dengue virus (DENV), West Nile virus (WNV), yellow fever virus (YFV) and some other related flaviviruses poses a significant challenge for an accurate detection of ZIKV infection in serological assay such as IgM capture ELISA. To overcome these challenges we developed a multiplex serological assay that will simultaneously detect antibody response to ZIKV, other related flaviviruses and Chikungunya virus (CHIKV). Various recombinant arboviral antigens were coupled to optically encoded microspheres from Luminex Corporation. This fluorescent microsphere immunoassay was used to differentiate between recent, past, and/or co-infections that may occur in endemic regions. We also developed an easy detection algorithm for quick multiplex data analysis to differentiate ZIKV IgM response from other arboviruses. This rapid assay can be performed from sample to answer in less than 2 hours. This assay was validated with more than 200 samples procured from commercial sources; ZIKV, DENV, CHIKV, and WNV positive samples for sensitivity; EBV, CMV, flu positive samples, and normal samples for specificity. We obtained good concordance with the results provided by the vendor. Results indicated that serological response to ZIKV NS1 antigen is more specific than ZIKV envelope antigen. A significant IgM antibodies to ZIKV envelope antigen was detected in samples that were positive for other flaviviruses.
Cytokine and chemokine profiles in a human respiratory disease model of Ebola virus
Authors: O’Brien Cecilia , Brannan Jennifer , Kuehne Ana , Josleyn Nicole M. , Parkhill Robert , Edwards Darin , Dye John M. 
Published: January 2023

Abstract
Category A agents, such as Ebola virus, pose a great risk to national security because of high rates of transmission and mortality and the gravity of impact to public health. The use of Ebola virus as a bioweapon is a significant concern, and rapid diagnostics, safe vaccines, and efficacious therapeutics are needed. The Mucosal Tissue Equivalent (MTE) component of the MIMIC™ lung mucosal model is an in vitro/ex vivo respiratory tissue model comprised of human lung epithelial cells that mimics the vascularized lower airway alveolar tissue micro-environment. The use of the MTE allows for the inclusion of human immune components, which may be a better predictor of the human immune response than animal models. In this study, Ebola virus was applied at the air-liquid interface of the differentiated human epithelium and expression of cytokines was measured. Peripheral blood mononuclear cells (PBMCs) were applied to apical layer of the MTEs prior to inoculation with Ebola virus (Kikwit). We quantified cytokines and chemokines using supernatants serially collected on days 0, 3, 6, 9, and 15 post infection. In the infected MTEs containing human PBMCs, we detected pro-inflammatory cytokines, colony stimulating factors and endothelial growth factors. This “cytokine storm” would be expected to play a role in inflammation, recruitment of cells to the site of infection, and induction of a specific immune response to acute viral infection in humans. This human lung infection model will be used to evaluate existing therapeutic antibody and vaccine candidates for Ebola virus. Going forward, this system may provide a more rapid, relevant and cost effective means to evaluate vaccine candidates than can be accomplished by using animal models.
Type I and III interferon signaling contributes to severe pathogenesis of human metapneumovirus clinical isolates
Authors: Xu Jiuyang , Zhang Yu , Tollefson Sharon J. , Manni Michelle L. , McHugh Kevin J. , Alcorn John F. , Sarkar Saumendra N. , Williams John V. 
Published: January 2023

Abstract
Human metapneumovirus (HMPV) is a leading cause of respiratory tract infection in infants and children. The disease outcome of HMPV infection ranges from mild infection to severe bronchiolitis and fatal pneumonia. HMPV was discovered in 2001 and its disease mechanisms are not fully understood. To gain insight into HMPV pathogenesis, we tested nine HMPV clinical isolates in an established C57BL/6 mouse model. HMPV clinical isolates induced variable disease severity ranging from mild to fatal disease. Mice infected by non-virulent strain TN/94-49 did not show significant weight loss, but mice infected with virulent isolate C2-202 showed dramatic weight loss and 40% mortality within 5 days post-infection. These findings were confirmed in other inbred mouse strains. C2-202 infected mice also suffered from impaired pulmonary function post-recovery. Lung virus replication did not correlate with disease severity, suggesting immune-mediated pathogenesis. Further investigation revealed increased type I and III interferons, pro-inflammatory cytokine production, and neutrophil infiltration in C2-202 infected mice. HMPV C2-202 infection also inhibited dendritic cell recruitment and down-regulated MHC-II surface expression on macrophages. Stat1/Stat2 double knockout mice lacking interferon signaling exhibited reduced weight loss, lessened disease severity, and increased dendritic cell recruitment after C2-202 infection. Our results indicate that severe disease caused by HMPV clinical isolates was due to exuberant interferon response leading to immuno-pathological tissue damage. These data suggest interferon signaling plays an important role in HMPV pathogenesis, and thus serves as a potential therapeutic target.
A single infection with a malaria parasite protects mice from lethal autoimmune glomerulonephritis
Authors: Bolland Silvia , Kole Hemanta K. , Scott Bethany , Amo Laura 
Published: January 2023

Abstract
Infections can alter the prevalence of autoimmune diseases such as SLE. Epidemiological studies have showed a relative absence SLE in West Africa (areas of endemic malaria), even though SLE is highly prevalent in populations of African descent living outside of Africa. We hypothesize that malaria infections might reduce the incidence of autoimmune lupus. In the present work, we assess the effect of the non-lethal Plasmodium yoelii 17XNL in a well-characterized animal model of SLE (FcγRIIB−/−). Mice deficient in the inhibitory Fc receptor for IgG (FcγRIIB) develop spontaneous disease driven by the production of anti-nuclear autoantibodies, a broad immune activation, splenomegaly, anemia and lethal glomerulonephritis with a pathology similar to human SLE. We infected FcγRIIB−/− mice at 2 months of age with P.yoelii and followed the progression of autoimmune disease for 5 months. Infection with P. yoelii increased the titer of a broad range of autoantibodies, with concomitant immune-complex deposition and complement fixation in the kidney. While lupus-prone mice succumbed from renal disease detected by protein in urine and serum urea nitrogen, malaria-infected lupus-prone mice did not develop proteinuria or lethal disease. Infection with the parasite did not alter tolerance mechanisms leading to lupus but instead prevented end-point tissue pathology. P. yoelii infection seems to inhibit pathogenic leukocyte infiltration without affecting the autoimmune inflammation of glomeruli. These results indicate a possible route for lupus protection that specifically targets renal function, which remains a cause of the substantial morbidity and mortality in SLE patients.
Lupus-suppressing effect of VSV-primed CD8+ T cell subsets
Authors: Kole Hemanta K. , Scott Bethany , Crampton Steve , Sule Gautam , Deane Jonathan , Bolland Silvia 
Published: January 2023

Abstract
Pathogenic infections are important environmental modifiers of autoimmune disease as they can alter the immune system in a way that either promotes or reduces autoimmune responses. We tested the effect of infection with vesicular stomatitis virus (VSV) on the FcγR2B−/− (R2) mouse strain that spontaneously develops lupus disease. Infecting FcγR2B−/− mice with live VSV reduces autoantibody levels and inflammatory pathology, and prolongs survival. We showed that VSV-mediated protection can be transferred in a CD8 cell adoptive transfer experiment. Legend screening for surface markers on CD8 T cells indicated that CD8 T cells from VSV infected mice express high level of markers linked to exhausted and regulatory phenotypes. After testing the transfer of various CD8 T cell subsets, we have identified CD8+CD122+NKG2D+ cells as mediator in VSV-induced Lupus amelioration. Preliminary analysis of RNA Sequencing data for gene expression profiles among various CD8 subsets, indicate that the protective cells express higher level of genes linked to memory phenotype. Our working hypothesis is that the viral infection may induce the expansion of long lived CD8 populations that regulate the humoral response.
Bacterial biofilm product Curli/eDNA induces NETs and serum anti-Curli/eDNA levels correlate with bacteriuria and lupus activity.
Authors: Pachucki Ryan J. , Corradetti Chelsea , Tursi Sarah , Kohler Lynne , Nicastro Lauren , Gallucci Stefania , Kilpatrick Laurie , Tükel Çagla , Caricchio Roberto 
Published: January 2023

Abstract
Infections are a major contributor to lupus disease. We have previously demonstrated that bacterial amyloid curli, produced by E.coli, can accelerate disease in mouse models of lupus. Interestingly curli incorporates extracellular DNA, which in turn can be both adjuvant and a self-antigen in lupus. Finally, uropathogenic E. coli (UPEC) is responsible for the majority of urinary tract infections in SLE. Based on our previous results, we hypothesize that exposure to UPEC triggers anti-curli/eDNA antibodies and curli/eDNA complexes can stimulate the innate immune system. We investigated 98 lupus patients who met at least 4 SLICC criteria. Results were compared to 54 age, sex and race matched healthy controls. We tested the production of anti-curli/DNA complex of both IgG and IgA subclasses. We than correlated the levels of anti-curli/DNA antibodies with clinical parameters. Finally, we stimulated human neutrophils with curli/eDNA complexes. We found that anti-curli/eDNA IgG levels were detected in both lupus and controls plasma. In lupus patients, anti-curli/eDNA levels correlated with persistent bacteriuria and disease flares (p&lt;0.05). In addition, anti-curli/eDNA antibodies recognized dsDNA suggesting a potential molecular mimicry mechanism for curli/eDNA with self-antigens such as dsDNA. We also found that IgA anti-curli/eDNA levels were higher (p&lt;0.01) in lupus donors compared to controls. Finally we found that curli/eDNA induced neutrophil extracellular traps (NETs) and the induction was ROS-dependent. We conclude that curli/eDNA complexes from UTIs can activate the innate immune system and IgG and IgA anti-curli/eDNA are strong biomarkers for disease activity and severity.
The REV-ERBs: Negative Regulators of Th17 Cell Development and Autoimmunity
Authors: Amir Mohammed , Chaudhari Sweena M. , Wang Ran , Campbell Sean , Kamenecka Theodore M. , Solt Laura A. 
Published: January 2023

Abstract
Th17 cells have been associated with the pathogenesis of several autoimmune diseases, including multiple sclerosis. While the nuclear receptor (NR) RORγt is considered the lineage determining transcription factor for Th17 cells, the REV-ERBs (REV-ERBα and REV-ERBβ), two other members of the NR superfamily, are often co-expressed in the same tissues as members of the ROR subfamily of NRs (i.e. RORγt) and bind to the same DNA response elements. In contrast to the RORs, which are transcriptional activators, the REV-ERBs are transcriptional repressors, suggesting mutual cross talk and co-regulation of their shared target genes. While the REV-ERBs are best known for their roles in the circadian rhythm and metabolic processes, their role in Th17 cell development and Th17 mediated inflammatory diseases is largely unexplored.
Our data indicates that over expression of the REV-ERBs inhibits Th17 cell differentiation whereas genetic deletion of the REV-ERBs perturbs Th17 cell differentiation. Using two commonly used mouse models of autoimmunity known to be Th17 driven [experimental autoimmune encephalomyelitis (EAE) and adoptive transfer model of colitis], we found that loss of REV-ERB expression exacerbates EAE and colitis compared to WT controls, largely as a consequence of an increased number of pro-inflammatory Th17 cells. Finally, using REV-ERB-selective small molecules that we have developed, we discovered that pharmacological modulation of REV-ERB activity significantly inhibits the development of autoimmunity. Overall, our data suggests that the REV-ERBs are potent negative regulators of Th17 differentiation and identifies the REV-ERBs as viable therapeutic targets for the treatment of Th17-mediated autoimmune diseases.