bluuebunny/crossref_metadata_2025_split huggingface dataset:
Finding the balance between protective and pathologic vaccine induced immunity using LCMV specific T lymphocytes
Authors: Luna Evelyn 
Published: January 2023

Abstract
Vaccination remains one of the most effective strategies for preventing human diseases caused by infectious pathogens, yet developing an efficacious vaccine for persistent viral infections such as HIV remains a difficult aim of much research. Vaccines expressing pathogen T cell epitopes has been a widely employed strategy to try and improve the efficacy of vaccines against chronic viral infections. However, selectively engaging T cells has the potential to increase rather than prevent pathology during subsequent infection, consequently shifting a mild disease to a lethal one. Thus, determining the immune parameters that lead to protection versus those that mediate pathology is critical for developing a safe and effective vaccine against persistent viral infections. Using lymphocytic choriomeningitis virus (LCMV) we investigated how the precursor frequency of CD8 T cells affects the balance of protection vs. pathology during chronic viral infection. We found that the balance is based largely on the number of T cells responding to the pathogen. Intermediate numbers of responding CD8 T cells resulted in maximum pathology. We have also observed that increasing vaccine-induced CD4 T cell responses, unlike CD8 T cells, never leads to protection, but instead high host mortality. We have now began to study the interaction of CD8 and CD4 T cells during infection to determine what effect CD4 T cells have in protective versus pathologic vaccine-induced immunity and what exactly mediates such responses.
An multivalent vaccine elicits protective Th17 response via activation of C-type lectin receptor- and Card9-mediated signal against pulmonary Coccidioides posadasii infection
Authors: Hung Chiung-Yu , Zhang Hao , Campuzano Althea , Ostroff Gary , Yu Jieh Juen 
Published: January 2023

Abstract
Coccidioidomycosis is a potentially life-threatening fungal infection that is responsible for ~150,000 infections annually in the United States. Development of a vaccine against Coccidioides infection is urgent. We have created a multivalent coccidioidal antigen (rCpa1) that contains promiscuous human T cell epitopes. The rCpa1 was formulated with 5 types of experimental adjuvants including yeast cell-wall particles and CpG adjuvant. The rCpa1 formulated with glucan chitin particles (GCPs) derived from a non-pathogenic yeast demonstrated the best protective efficacy for susceptible C57BL/6 and HLA-DR4 transgenic mice against this disease compared to the other 4 tested vaccines. This is the first report of a subunit vaccine that can provide a comparable degree of protection to a live, attenuated vaccine against coccidioidomycosis. The GCP-rCpa1 vaccine elicited a robust and durable Th17 memory response. Depletion of Th17 cells significantly reduced the protective efficacy of this vaccine, indicating that Th17 cells play an indispensable role. Dectin-1 and Dectin-2 molecules can bind to the GCP-rCpa1 vaccine particles. Macrophages derived from mice lacking expression of Dectin-1, Dectin-2 and downstream immune adapter CARD9 secreted reduced amounts of IL-1β and IL-6 upon stimulation with GCP-rCpa1 that are essential for Th17 development. Furthermore, vaccinated Dectin-1−/−, Dectin-2−/− and CARD9 −/− mice recruited significantly reduced amounts of Th17 cells to the lungs compared to C57BL/6 mice and succumbed to coccidioidomycosis. Taken together, protection against Coccidioides provided by GCP-rCpa1 vaccine requires Dectin-1- and Dectin-2-CARD9-mediated signaling to activate Th17 immune response.
Memory T cell responses in survivors of the 2013–2016 West African Ebola outbreak
Authors: Sullivan Brian Martin , Sakabe Saori , Hartnett Jessica , Goba Augustine , Momoh Mambu , Sandi John Demby , Schieffelin John S. , de la Torre Juan Carlos , Grant Donald S. , Garry Robert F. , Oldstone Michael B. 
Published: January 2023

Abstract
Primary infection with Ebola virus protects against subsequent challenge, thus an optimal vaccine should generate immune responses similar to those found in disease survivors. To this end, we characterized CD8 and CD4 T cell responses in Ebola survivors to uncover the immunogenicity of seven of eight Ebola virus proteins. T cell responses of 33 Sierra Leonean Ebola survivors were examined. Nearly all individuals studied harbored nucleoprotein (NP)-specific CD8 T cell responses. Moreover, NP-specific T cells responded more strongly and were more numerous in 65% of NP responders compared to responses to other EBOV proteins in the same individual. Conversely, we found glycoprotein (GP) CD8+ T cell responses in only 37% of EBOV responders. GP responses were also weaker and less numerous than other responses in the same individual. Specificity of the CD4+ T cell responses were more evenly distributed. Altogether, our data indicate that NP is among the most immunogenic EBOV proteins while only VP30 was less immunogenic than GP in our cohort of Sierra Leonean survivors. An optimal vaccine designed to elicit both humoral and cell mediated immune responses in a broad human population should contain both NP and the GP.
Dynamics of adaptive natural killer cells in longitudinal analysis of CMV vaccine recipients
Authors: Gyurova Ivayla E. , Schlums Heinrich , Bernstein David , Bryceson Yenan , Waggoner Stephen N. 
Published: January 2023

Abstract
Classical vaccine efforts focusing on the induction of B- and T-cell memory have proven ineffective in the protection against pathogens such as cytomegalovirus (CMV). Thus, CMV remains a significant public health threat. There is clear evidence that patients lacking natural killer (NK) cells suffer recurrent, severe infections with multiple herpesviruses, including CMV, highlighting the importance of NK cells in controlling this pathogen. In addition, several studies describe the expansion and persistence of phenotypically and functionally distinct murine (Ly49H+) and human (NKG2C+, FcRγneg, EAT-2neg, SYKneg) NK-cell subsets with putatively enhanced antiviral effector function upon CMV infection. Therefore, one potentially pioneering approach to creating an efficacious CMV vaccine would include the induction of such NK cell adaptations. To test this, we used longitudinal PBMC samples collected during a vaccine trial with HCMV gB in MF59 adjuvant administered to CMV negative adolescent females. We observed several patterns of transient and sustained elevations in the frequency of FcRγneg, EAT-2neg, and SYKneg subsets at various time points despite absence of detectable CMV infection in any trial participants. Surprisingly, these patterns were apparent in participants regardless of administration of vaccine or placebo. In contrast to previous cross-sectional studies, we present evidence that these CMV-reactive adaptive NK cells exhibit continuous oscillations in the blood of CMV negative individuals, suggesting that they may react to unknown environmental or inflammatory cues.
Rig-I-Like Receptors (RLRs) regulate humoral immunity to West Nile Virus (WNV) infection.
Authors: Schenten Dominik , O’Ketch Marvin 
Published: January 2023

Abstract
Rig-I-like Receptors (RLRs) comprise a family of pattern recognition receptors that recognizes microbial RNA in the cytosol. RLR activation induces an anti-viral state in infected cells and leads to the release of proinflammatory cytokines and interferons. RLRs are therefore important mediators of innate immunity to many viral infections. However, the role of RLRs in the regulation of adaptive immunity is still poorly understood. Infection of MAVS-deficient mice, the essential signaling adaptor for RLRs, with West Nile Virus (WNV) results in a defective adaptive immune response. While this finding suggests a role for RLRs in the regulation of adaptive immunity to WNV, it is difficult to interpret due to a high WNV viremia in the absence of a MAVS-dependent innate immune response. In order to overcome this caveat, we have infected MAVS-deficient mice with a mutant form of WNV that is unable to assemble infectious virions and is therefore limited to a single round of infection. Here, we show that MAVS-deficient mice display increased numbers of antigen-specific CD4 T cells as well as an enlarged germinal center (GC) B cell compartment. Importantly, these mice fail to produce an effective neutralizing antibody response to WNV despite normal levels of WNV-specific antibodies. Together, these findings suggest that RLR-dependent signals regulate humoral immunity to WNV.
Endothelial dysfunction in the pathogenesis of acute Lassa Fever
Authors: Horton Lucy Elise , Sullivan Brian , Garry Robert F. , Grant Donald S. , Oldstone Michael B. 
Published: January 2023

Abstract
Lassa fever (LF) is an acute disease characterized by enhanced vascular permeability resulting from infection with Lassa virus (LV), a non-lytic, Old World arenavirus. Animal models of arenavirus-induced vascular damage suggest that cytotoxic CD8+ T cells serve a critical role in the destruction of vascular endothelium by destroying LV infected endothelial cells as well as impairing platelet aggregation. Using plasma samples from acute LF patients, we sought to identify predictive biomarkers associated with endothelial integrity and platelet aggregation in fatal versus non-fatal LF cases by testing platelet function and measuring hemostasis markers with ELISA. We discovered a significant increase in plasminogen activation inhibitor-1 (PAI-1), endothelial protein C receptor (EPCR) and thrombomodulin in LF Ag+ cases compared to LF IgM+ and febrile non-LF controls. In addition, platelets from uninfected controls displayed decreased aggregation when mixed with plasma from 28 of 33 acute LF patients compared to plasma from uninfected controls. Our results demonstrate that severe LF (determined by Ag positivity) is associated with platelet dysfunction and abnormal regulation of coagulation, and suggest that similar to the LCMV Clone 13 model, immune-mediated endothelial activation leading to loss of barrier function, impaired hemostasis, and altered thrombogenicity may be an important mechanism in the pathogenesis of acute LF. Studies are underway to relate these biomarkers to the state of T cell activation in this cohort of patients.
West-Nile virus replicon particles infect 293T cells expressing DC-SIGNR
Authors: Kunkel Hannah L. , Budimlic Emin , Keilty John , Schmitz Madilyn R. , Madigan Amanda , Crowson Nicole , Leonard Nathan L. , Schwarzinger Victoria R. , Meyer Alyssa J. , Soderlund Mary , Martinez Osvaldo 
Published: January 2023

Abstract
West-Nile virus (WNV) is an arbovirus usually transmitted to humans via a mosquito vector. Less than one percent of cases result in a serious neurological illness such as meningitis or encephalitis Studies have shown that WNV infection efficiency is enhanced by expression of DC-SIGNR on target cells, which normally do not express DC-SIGNR. To investigate WNV tropism, we established 293T kidney epithelial cell lines that stably express vector or DC-SIGNR. We demonstrated uniformly high levels of DC-SIGNR expression in selected cells. Virus replicon particles (VRPs), replication-incompetent viral particles containing necessary structural proteins for infection and a viral plasmid including a GFP reporter are used to safely and conveniently study viral entry. Entry assays using WNV (NY99) VRPs as well as a variant of WNV (NY99) which contains the beta-lactamase enzyme show significant entry into DC-SIGNR expressing cell lines, but not in controls that do not express DC-SIGNR. Future studies will focus on discovering which regions of the DC-SIGNR surface glycoprotein are required for WNV entry.
Cytomegalovirus blockade of TRAIL-mediated type 1 ILC defenses regulates viral persistence
Authors: Picarda Gaelle Genevieve Alice , McDonald Bryan , Dodard Garvin , Verma Shilpi , Ghosh Raima , Morabiti Rachid , Thiault Nicolas , Brossay Laurent , Griffith Thomas S. , Benedict Chris A. 
Published: January 2023

Abstract
Tumor necrosis factor related apoptosis-inducing ligand (TRAIL) regulates cellular apoptosis and inflammation, and growing evidence indicates a key role in antiviral defense. Cytomegalovirus (CMV, a b-herpesvirus) establishes a lifelong persistent/latent infection that depends upon viral subversion of host innate and adaptive defenses. We have shown that both human and mouse CMV inhibit signaling by the TRAIL death receptors (DR) through the use of specific viral proteins. MCMV m166 blocks TRAIL-DR expression and promotes early viral replication by evading TRAIL-mediated natural killer (NK) cell defenses. After one week of systemic replication, MCMV spreads to the salivary glands (SG), the major mucosal organ responsible for horizontal transmission of the virus. We show that a MCMVΔm166 mutant replicates at lower absolute levels in the SG, but, surprisingly, persists for much longer times. Recent evidence suggests a role of type 1 Innate Lymphoid cells (ILC1) in control/clearance of MCMV. We investigated the role of the 2 main ILC1 populations (conventional and tissue resident (tr) NK cells) in controlling MCMV SG persistence. Depleting ILC1 prior to infection, or infection of TRAIL−/− mice, restored MCMVΔm166 SG replication to normal levels. In addition, SG trNK cells display a unique phenotype and express high levels of TRAIL during MCMV infection when compared to their conventional counterparts. Together our data reveal a key role for m166 inhibition of TRAIL-DR expression in promoting viral persistence by blocking ILC1 effector functions mediated by TRAIL, highlighting this TNF-family cytokine as an important factor regulating innate defenses in mucosal tissues.
Structural characterization of broadly neutralizing alphavirus antibodies
Authors: Basore Katherine , Earnest James T. , Diamond Michael S. , Fremont Daved H. 
Published: January 2023

Abstract
Mayaro is a mosquito-borne single-stranded positive RNA alphavirus endemic to tropical regions of South America. It is closely related to other arthritogenic alphaviruses, such as Chikungunya, Semliki Forest, Ross River, and Sindbis viruses. Although there are currently no available vaccines or therapies for alphaviruses, previous studies demonstrate that cross-protection between different alphaviruses could be mediated by antibodies that map to conserved epitopes. For example, a class of monoclonal antibodies against Chikungunya were recently shown to neutralize other alphaviruses by blocking viral entry and egress, all with epitopes on the surface E2 glycoprotein. A panel of antibodies generated against Mayaro infection and boosted with recombinate E2 protein were also found to be cross-neutralizing against other alphaviruses. Currently, epitope mapping and structural studies are being performed on these antibodies in order to determine the vital residues for binding, as well as to determine the mechanism of cross-neutralization.
A nuclear receptor involved in cholesterol metabolism regulates herpesvirus latency and reactivation
Authors: Reese Tiffany A. , Tao Lili , Lowe Alexandria , Wang Guoxun , Zarek Christina M. 
Published: January 2023

Abstract
Herpesviruses are a component of our virome, and infect virtually everyone. They establish chronic latent infection that is punctuated with periods of viral reactivation. Reactivation is thought to drive herpesvirus pathologies, including lymphomas and tumors. However, the signals that promote herpesvirus reactivation are poorly understood. We previously showed that parasite co-infection could induce herpesvirus reactivation through the induction of the cytokines IL-4 and IL-13, and activation of Stat6. Stat6 directly binds to a viral promoter and induces virus reactivation, suggesting that the virus has evolved to sense immune signals from the host to modulate reactivation. We sought to identify other factors that induce herpesvirus reactivation through the modulation of inflammation. We found that peroxisome proliferator-activated receptor (PPAR)-a, a ligand-activated nuclear receptor, is upregulated during g-herpesvirus infection. PPAR-a is activated by endogenous fatty acids to regulate cholesterol metabolism. PPARs also regulate inflammation, although these functions are less well understood. We found that agonist activation of PPAR-a induces herpesvirus reactivation. PPAR-a activation dampens type I interferon signaling, by inhibiting genes that modulate the DNA sensing pathway. These data suggest that in addition to evolving cytokine-sensitive promoters, herpesviruses induce cellular machinery that sense fatty acids as a means of regulating viral reactivation.
MDA5, a Janus-faced dsRNA sensor in Coxsackievirus-accelerated autoimmune diabetes
Authors: Tse Hubert Ming , Burg Ashley R. , Chen Yi-Guang 
Published: January 2023

Abstract
While microbial infections can trigger autoimmune diabetes, ultimately, innate immune activation and the synthesis of free radicals, proinflammatory cytokines, and Type I interferons contribute to pancreatic β-cell destruction in Type 1 diabetes (T1D). We previously demonstrated that Coxsackievirus B3 (CB3) infection of Non-Obese Diabetic (NOD) mice can accelerate T1D, partly due to the induction of oxidative stress and antiviral signaling pathways including melanoma differentiation-associated protein 5 (MDA5). Single-nucleotide polymorphisms within Ifih1, the gene encoding for MDA5, is associated with multiple autoimmune diseases including T1D, but the molecular mechanism contributing to innate immune dysregulation is not known. Since T1D is a chronic proinflammatory autoimmune disease involving MDA5, we hypothesized that aberrant MDA5 expression and signaling can contribute to diabetogenic viral-accelerated T1D. NOD mice mutated in Ifih1 that resulted in loss of MDA5 expression (NOD.Ifih1_m1) or an in-frame truncation in the helicase domain of MDA5 (NOD.Ifih1_m4) exhibited a delay in spontaneous T1D. Interestingly, CB3-infected NOD and NOD.Ifih1_m1 mice displayed accelerated virus-induced T1D, but NOD.Ifih1_m4 mice were significantly (p &lt; 0.001) delayed. CB3-infected NOD.Ifih1_m4 mice were efficient in pancreatic viral clearance and exhibited decreases in circulating Type I interferons in contrast to NOD and NOD.Ifih1_m1 mice. The protective Ifih1_m4 mutation may establish an acute level of Type I interferons sufficient to inhibit CB3 replication without mediating bystander activation of autoreactive T cells in autoimmune diabetes.
Salmonella infection induces autoantibody production in MyD88-deficient host: Identification of candidate bacterial proteins with homology to murine antigens
Authors: al-Ramadi Basel K. , Issac Jincy M. , Mohamed Yassir A. , Bashir Ghada , Al-Sbiei Ashraf , Conca Walter , Khan Taj A. , Iqbal Asif , Cabral-Marques Otavio , Fernandez-Cabezudo Maria J. 
Published: January 2023

Abstract
Persistent bacterial infections have been causally linked to the development of autoimmune diseases, but the precise mechanisms underlying this remain largely unknown. Of note, we demonstrated that systemic infection by attenuated Salmonella enterica serovar Typhimurium induces a breakdown in B cell tolerance in MyD88-deficient mice, as evidenced by the production of autoantibodies to nuclear and cytoplasmic antigens and immune complex deposition in the kidneys. The splenic niche of infected MyD88−/− mice revealed increased counts of activated myeloid cell subpopulations as well as CD4+ and CD8+ T cells. Moreover, this was associated with increased Th21 cell differentiation and the appearance of CD4+ T cells co-expressing IFN-g/IL-4 and IFN-g/IL-10. Importantly, infection with other bacteria (e.g. Acinetobacter baumanii, Streptococcus agalactiae or Escherichia coli) was unable to trigger the autoimmune phenomenon. We reasoned that the autoimmune response could be triggered by a process of molecular mimicry between mouse and Salmonella proteins. Bioinformatic analysis was used to identify potential Salmonella antigens with a high degree of homology to mouse proteins. This analysis revealed several candidate bacterial proteins with high homology to murine immune system proteins. The identified bacterial proteins were all uniquely expressed by Salmonella but not by the other three bacterial species that were incapable of inducing the autoimmune response in MyD88−/− mice. Therefore, our data suggest a mechanism for pathogen-specific induction of autoantibody production in the absence of MyD88 signaling pathway and provide important clues concerning the genotype-environmental factor correlations.
Transcription factor T-bet drives the pathogenesis of TH17-mediated neuroinflammation
Authors: Loo Tiffany Taylor , Shinoda Akane , Lazarevic Vanja 
Published: January 2023

Abstract
Emergingdata demonstrate that exposure to pro-inflammatory cytokines IL-12 and IL-23 convertsnon-pathogenic IL-17A-producing CD4+ TH17 cells intopathogenic effectors, though the molecular mechanism remains undefined. Here, we show that T-bet, a transcription factor normally associated with IFN-γ-producing TH1 cell differentiation, is an IL-23-induced critical regulator of pathogenic TH17 cells. Using the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis (MS), we report that IL-23-treated T-bet-deficient TH17 cells were not pathogenic and failed to induce neuroinflammation. We found that T-bet expression in TH17 cells was required to disrupt the blood-brain barrier (BBB) upon migration to the CNS. Following in vivo reactivation, T-bet-sufficient TH17 cells co-expressed IFN-γ and GM-CSF cytokines, upregulated expression of myelo monocytic-specific chemokines (Ccl1, Ccl3, Ccl4 and Ccl5), and attracted neutrophils, inflammatory monocytes and dendritic cells to the CNS. Conversely, T-bet-deficient TH17 cells failed to cross the BBB and invade CNS tissue, showing decreased cytokine and chemokine expression and reduced myelomonocyte recruitment. Interestingly, pharmacological BBB disruption via adjuvant administration bypassed the requirement for T-bet expression in TH17 cells, resulting in disease induction by T-bet-deficient TH17 cells. Collectively, these data demonstrate that autoreactive TH17 cells permeabilize the blood-brain barrier in a T-bet-dependent manner, resulting in a cascade of damaging inflammatory infiltrates.