bluuebunny/crossref_metadata_2025_split huggingface dataset:
Bioactive lipids serve as biomarkers of host immune response during severe influenza infection in pediatric patients
Authors: Anania Veronica G. , Randolph Adrienne , McBride Jacqueline M. , Yang Xiaoying , Rosenberger Carrie , Mathews Rodney 
Published: January 2023

Abstract
Influenza virus infects 5–20% of the population annually, leading to considerable morbidity and mortality especially in children. Robust biomarkers, reflecting the host immune response, are needed to identify patients at risk of prolonged illness or death. Eicosanoids, a family of bioactive arachidonic acid metabolites produced by the host in response to influenza infection, have pro- and anti-inflammatory properties. This study aimed to assess the relationship between the host lipid response at ICU admission with clinical outcomes in a multicenter cohort of 105 children with influenza-related illness (PICFLU study). We developed a mass spectrometry-based method to quantify &gt;100 lipid metabolites from nasopharyngeal swabs and endotracheal aspirates. The bioactive lipid profile in influenza infected children was impacted by multiple factors including patient age and bacterial coinfection. Patients coinfected with methicillin-resistant Staphylococcus aureus and influenza had significantly elevated levels of pro-inflammatory lipids and concomitantly lower levels of anti-inflammatory 15-lipoxygenase metabolites. Interestingly, children that presented with high levels of lipids including prostaglandin E2 and 12-hydroxyeicosatetraenoic acid were more likely to have fatal outcomes despite reports indicating these lipids have opposing immunomodulatory activity. These results suggest children at risk of mortality have an amplified bioactive lipid immune response that may negatively impact disease resolution. Our study provides evidence that bioactive lipids are potential prognostic biomarkers of patient immune response phenotype, and may help to identify children at risk of influenza-related death.
Toll-like receptor signalling protects against IL-33 led virus-induced asthmatic response in a Type I Interferon independent manner
Authors: Wali Shradha , Flores Jose R. , Goldblatt David , Tuvim Michael J. , Dickey Burton F. , Evans Scott E. 
Published: January 2023

Abstract
Respiratory viruses are frequent causes of asthma development and exacerbations. However, there are gaps in understanding how viral infections cause immuno-pathology in the host leading to asthma progression. We have previously shown that mice treated with a combination of Toll-like receptor (TLR) 2/6 and 9 agonists (Pam2-ODN) are protected against broad range of respiratory infections induced by viruses, fungi and bacteria. Pam2-ODN treatment one day prior to virus infection leads to enhanced survival with reduced lung viral burden in mice. Further, Pam2-ODN pretreatment also inhibits acute lung pathology caused by CD8+ T cells and prevents chronic asthmatic phenotype of eosinophilia, airway hyperreactivity and mucus metaplasia. This protective effect was accompanied by reduced virus-driven lung IL-33, which is necessary to induce chronic asthmatic phenotype. Interestingly, Pam2-ODN does not induce increased production of Type I or III Interferons (IFN), nor does the protective response require intact interferon signaling. Transcriptome profiling of the mouse lungs in the chronic phase of infection led to identification of genes involved in airway remodelling, epithelial cell differentiation and chemokine signalling. More importantly, we identified genes from the Pam2-ODN treatment group that are involved in reversing the viral infection effect on day 49. Taken together, our findings reveal novel type I IFN independent mechanisms to prevent virus-induced asthma, and may provide an opportunity to protect vulnerable populations.
Induction and isolation of protective influenza neuraminidase specific antibodies in humans following seasonal vaccination.
Authors: Kobie James , Piepenbrink Michael , Nogales Aitor , Martinez-Sobrido Luis 
Published: January 2023

Abstract
Influenza’s propensity for antigenic drift and shift, and to elicit predominantly strain specific antibodies (Abs) leaves humanity susceptible to waves of new strains with pandemic potential for which limited or no immunity may exist. Subsequently new clinical interventions are needed, particularly those with broad activity against diverse strains. Although hemagglutinin (HA) specificity dominates the humoral response to seasonal inactivated influenza vaccines and infection, Abs targeting neuraminidase (NA) are also generated. NA-specific Abs are suggested to act primarily through inhibiting its enzymatic activity and preventing release of virus from infected cells. Relative to HA, there is substantially less diversity among NA from different influenza types and subtypes, suggesting it is a valuable target for inducing broad protective immunity. To determine if humans generate NA-specific Abs with protective activity we examined plasmablasts from subjects that were immunized with the seasonal influenza inactivated vaccine, and isolated several NA-specific human monoclonal Abs (hmAbs), including those with potent in vitro viral neutralizing activity. One of the NA B–specific hmAbs, KPF2 recognized NA from both the Yamagata and Victoria lineages, and when administered prophylactically to mice resulted in sterilizing immunity. These results suggest seasonal influenza vaccine induces protective NA-specific mAbs in humans. Analysis of other NA-specific hmAbs is ongoing.
Viral MHC class I inhibition evades protective tissue-resident memory CD8+ T cells (TRM) and influences TRM immunodominance within specific niches
Authors: Lauron Elvin James , Yang Liping , Bern Michael D. , Williams Graham D. , Boon Adrianus C.M. , Yokoyama Wayne M. 
Published: January 2023

Abstract
Tissue-resident memory CD8+ T cells (TRM) confer rapid protection and immunity against viral infections. Many viruses have evolved mechanisms to inhibit MHCI presentation in order to evade effector CD8+ T cells, suggesting that these mechanisms may also apply to TRM-mediated protection. However, the effects of viral MHCI inhibition on the function and generation of TRM is unknown. We show that viral MHCI inhibition dampens immunodominance within the lung TRM pool, indicating an effect on the TRM repertoire, but this effect was not observed in the skin. In the presence of viral MHCI inhibition, the overall development of TRM is unaffected, yet is unexpectedly enhanced with local cognate antigen, while local cognate antigen is not required for TRM maintenance. Moreover, viral MHCI inhibition efficiently evades TRM effector functions. These findings suggest that vaccine strategies involving pure T-cell approaches may provide poor efficacy against viruses that target the MHCI pathway.
Disease manifestations with immune alteration by bacterial neuraminidases in influenza virus infection with Streptococcus pneumoniae superinfection
Authors: Dutta Avijit , Huang Ching-Tai , Hseih Yu-Chia , Chen Tse-Ching , Lin Chun-Yen , Lin Yung-Chang , Chang Chia-Shiang , He Yueh-Chia , Huang Yu-Lin , Chen Ting-An 
Published: January 2023

Abstract
Streptococcus pneumoniae often causes superinfection in influenza and exacerbates the disease with more severity and even mortality. In our influenza hemagglutinin (HA) antigen-specific transgenic mouse model, mice suffered from severe disease and died with increased virus titer and pathology in the lungs upon serotype-3 Streptococcus pneumoniae superinfection on day 4- post PR8 strain H1N1 influenza virus infection. Same dose viral or bacterial infection caused mild disease in control mice. Streptococcus pneumoniae supreinfection attenuated anti-influenza T cell immunity in the lungs. There was less clonotypic expansion, T-bet induction and effector cytokines IFN-γ and TNF-α production in HA-specific CD4+ T cells on day 2- and 3- post bacterial superinfection, with impaired viral clearance. Streptococcus pneumoniae strains with different combinations of bacterial neuraminidase (NA) demonstrated varied degrees of T cell immunity attenuation. Streptococcus pneumoniae with NA-B only was the most suppressive with up-regulated active TGF-β and down-regulated IFN-γ expression in HA-specific CD4+ T cells, followed by those with both NA-A and NA-B. Streptococcus pneumoniae with both NA-A and NA-B and inserted NA-C was least suppressive. With in vitro experiments, recombinant bacterial NA-A or NA-B augmented TGF-β and attenuated IFN-γ in HA-specific CD4+ T cells in overnight culture with PR8 virus. Recombinant bacterial NA-C mitigated TGF-β and increased IFN-γ in HA-specific CD4+ T cells. Our results demonestrates distinct immune alteration by different bacterial neuraminidases, which may play a significnt role of disease manifestation in influenza with bacterial superinfection.
IFITM3 is cardioprotective during influenza virus infection
Authors: Kenney Adam , Imas Alexander , Rajaram Murugesan , Yount Jacob 
Published: January 2023

Abstract
Influenza virus annually infects more than one million individuals worldwide and causes severe pandemic outbreaks. Myocarditis and cardiac dysfunction can be observed in particularly severe cases of influenza. Humans with polymorphisms in the gene encoding interferon-induced transmembrane protein 3 (IFITM3), an antiviral restriction factor, experience severe influenza virus infections. Thus, we hypothesized that IFITM3 deficiency leads to cardiac dysfunction during influenza virus infection. We found that Ifitm3−/− mice generated in our laboratory exhibited increased morbidity, mortality, and viral lung titers compared to WT mice when infected with influenza A virus. Ifitm3−/− and WT mice showed identical cardiac function and electrical activity prior to infection as confirmed by echocardiogram and electrocardiogram. While major alterations were not observed early in infection for WT mice, Ifitm3−/− mice exhibited aberrant electrical activity, including decreased heart rate, decreased QRS interval, and irregular R/R interval. These changes were further exacerbated as infection progressed, likely contributing to the complete lethality observed in knockout mice. In contrast, WT mice exhibited only mild cardiac dysfunction late in infection that resolved following recovery. Minimal viral replication was observed in the hearts of WT and Ifitm3−/− mice. Heart sectioning and staining suggests a role for lymphocyte infiltration and tissue damage underlying the cardiac dysfunction observed in Ifitm3−/− mice. These data identify a novel cardioprotective role for IFITM3 during influenza virus infection and establish Ifitm3−/− mice as a tool for studying molecular events leading to virus-induced cardiac dysfunction.
Characterization of Peptides Associated with Molecules of the Major Histocompatibility Complex using Mass Spectrometry
Authors: Ford Michael J. , Jones Richard , Amunugama Ravi , Allen David , Pisano Michael , Mobley James L. , Domanski Paul , Bochar Daniel 
Published: January 2023

Abstract
The major histocompatibility complex (MHC) is a region of highly polymorphic genes encoding for glycoproteins (MHC molecules) that form part of the cell-mediated branch of the acquired immune system. In the cytosol, cellular self and foreign (non-self) proteins are constantly being degraded; it is the peptides generated that are presented, non-covalently bound to MHC molecules, on the surface of cells for inspection by cytotoxic T-lymphocytes (CTLs). Non-recognition of the presented peptide ultimately leads to cell destruction.
Characterizing the factors associated with non-recognition is an attractive proposition for anyone interested in generating tools for targeted cell destruction. In the field of oncology the obvious application then is the targeted destruction of cancerous cells. To enable the molecular level characterization of peptides associated with molecules of the major histocompatibility complex requires a targeted protein complex enrichment, an unbiased peptide elution and finally a peptide analysis method. Most frequently an immunoprecipitation is used to isolate the target complex. The peptide elution is performed under conditions minimizing protein contamination and finally peptide analysis is accomplished by mass spectrometry.
Here we present a case study of our recent work optimizing and performing a workflow for the analysis of peptides associated with Class I and Class II MHC molecules.
Extraction and intracellular trafficking of membrane associated antigen distinguishes human germinal center B cells from naïve B cells and memory B cells
Authors: Kwak Kihyuck , Saniee Avva , Quizon Nicolas , Sohn Haewon , Pierce Susan 
Published: January 2023

Abstract
Protective antibody responses to vaccination or infection in humans depend on the competitive selection of high-affinity germinal-center (GC) B cells into the long-lived memory B cell compartment. Selection is determined in large part by the ability of GC B cells to gather, process and present antigen to T follicular helper T cells (TFH cells). We have shown that human GC B cells are better able to distinguish their affinity for antigen as compared to naïve B cells in the gathering and internalization of antigen. Here we provide evidence that human naïve B cells and GC B cells rely on different endocytic processes for antigen internalization and trafficking. We found that the Microtubule Organizing Centers in activated GC B cells were not polarized toward the immune synapse with the antigen-containing membrane as in naïve B cells but rather dispersed large distances from the immune synapse in GC B cells. GC B cells trafficked antigen-bound BCRs from the synapse outside the sides of the cells to distal sites for internalization whereas naïve B cells internalized antigen from the immune synapse. Moreover, as compared to naïve B cells, LAMP-1+ vesicles in GC B cells were less polarized and less internalized antigen was colocalized with LAMP-1+ vesicles. We also found that the expression of SNX9 and SNX18, key components of the endocytosis machinery and modulators of clathrine mediated endocytosis, was significantly lower in GC B cells as compared to naïve B cells and SNX9 and SNX18 were poorly polarized toward the immune synapse in activated GC B cells. We propose that these differences in endocytosis processes for antigen internalization contribute the higher affinity thresholds of GC B cells.
Subversion of antigen presentation by Adenoviruses
Authors: Bouvier Marlene , Li Lenong , Deng Hui 
Published: January 2023

Abstract
The cell-surface presentation of viral antigens by MHC class I molecules to CD8+ T-cells is critical for eliminating virus-infected cells. In turn, viruses have evolved numerous strategies to interfere with the generation and presentation of class I antigens. Human adenoviruses (Ads) comprise more than 70 different types classified into seven species (A to G); Ad infections cause diseases of the respiratory track (species B, C, and E), eyes (species D), and gastrointestinal track (species F). Ads encode the E3-19K protein that targets MHC class I molecules for retention in the endoplasmic reticulum of infected cells, thereby suppressing cell-surface presentation of Ad-derived antigens. In recent years, we determined the x-ray structures of Ad2 (species C) and Ad4 (species E) E3-19K bound to HLA-A2, which together with biochemical and functional data allowed to explain the mechanism of immunomodulation. Interestingly, in comparison to other Ads, species F Ads lack a gene for the common E3-19K protein and instead have two unique and uncharacterized genes, E3-19.4K and -31.6K. We are using a biochemical and functional approach to investigate how species F Ads modulate various cell surface immune proteins, including MHC I molecules, and what role of E3-19.4K and -31.6K proteins play in these effects.
Synthetic Peptide Nanofiber Adjuvants Engage Mechanisms of Autophagy in Antigen Presenting Cells
Authors: Rudra Jai S. , Khan Arshad , Clover Tara , Endsley Janice , Zloza Andrew , Wang Jin , Jagannath Chinnaswamy 
Published: January 2023

Abstract
A crucial challenge in subunit vaccine development is to minimize adjuvant-associated toxicity and balance immunogenicity with safety. Due to the chemical heterogeneity and toxicity associated with most plant- or pathogen-derived adjuvants, those clinically approved in the U.S. are limited to alum and AS04 (alum combined with MPLA). Therefore, there is a compelling clinical need for new adjuvant strategies that potentiate strong immune responses and are chemically defined and minimally toxic. We have previously demonstrated that supramolecular peptide nanofibers are potent adjuvants that elicit protective antibody and cellular immune responses in animal models of infectious diseases, cancer, and addiction. Critically, the adjuvant potential was non-inflammatory and the exact mechanism of action was unknown. Here, we report that self-assembling peptide nanofibers bearing CD4+ or CD8+T cell epitopes are processed through mechanisms of autophagy in antigen presenting cells (APCs). Using in vitro antigen presentation assays, we confirmed loss and gain of adjuvant function using pharmacological modulators of autophagy and APCs deficient in multiple autophagy proteins. Incorporation of microtubule associated protein 1A/1B-light chain 3 (LC3-II) into the autophagosomal membrane, a key biological marker for autophagy, was confirmed using microscopy. Our findings indicate that autophagy plays an essential role in the mechanism of adjuvant action of supramolecular peptide nanofibers.
Comprehending the phenotypic and functional diversity of γδ T cell subtypes in autoimmune skin disease Pemphigus Vulgaris
Authors: Das Dayasagar , Santosh KV , Sharma Alpana , Arava Sudheer 
Published: January 2023

Abstract
Pemphigus vulgaris (PV) is an atypical form of mucocutaneous autoimmune disease caused due to the formation of auto-antibodies against desmoglein3 (Dsg3) and anomalous T cell function. Gamma Delta T cells (γδ T cells) are evolutionary conserved distinctive cells that maintain the immune surveillance at the epithelial surface. The role of γδ T cells and their plasticity is not yet illustrated in the immunopathogenesis of PV. γδ T cells isolated from the PV patients showed diverse phenotypes (γδ1, γδ2, γδ17, γδreg) and functionality, such as migration, and multiple cytokine productions. Significantly higher frequency of γδ T cells producing IFN-γ & IL-17 (8.5% vs. 5.2%) was found in the circulation PV patients compared to control. Circulation of PV patients indicated higher number of CCR6+ γδ T cells suggesting their migratory potential. Cytotoxic activity of γδ T cells from PV patients (30±8%) was observed to be higher as compared to control (16±5%). Primary culture of γδ T cells from PV patients showed increased mRNA expression of inflammatory cytokines (IL17, ROR γt, IL-23) and co-stimulatory markers (CD27 and CD70). The regulatory markers associated with regulatory γδ T cells (TGFβ, FoxP3) were downregulated. At the tissue level, γδ 17 T cells in patient skin showed increased IL-17, CCR6 expression while CCR4 receptor associated with γδ reg T cells has shown lower expression indicating their imbalance and possible involvement in the immunopathogenesis of PV. These maiden findings suggest the versatile nature of γδ T cells that will help to find a better approach for novel therapeutics for PV.
Thpok suppresses pathogenic cytokine production by Th17 cells in autoimmune disease
Authors: Marks Kathryne E , Flaherty Stephanie , Reynolds Joseph M 
Published: January 2023

Abstract
CD4+ T cells, including Th17 cells, are instrumental in the development and progression of autoimmune diseases such as multiple sclerosis. While pathogenic Th17 cells drive inflammation in autoimmunity, the molecular programming underlying their pathogenicity remains insufficiently understood. Through RNA-sequencing, we have identified the transcription factor Thpok (Zbtb7b), also known as the CD4 lineage determination factor, as an apparent negative regulator of Th17 pathogenicity. Thpok expression is maintained in peripheral CD4+ T cells and assists in formation of memory CD4+ T cells. Furthermore, Thpok expression in CD4+ T cells represses cytotoxic genes and contributes to the Th17 response during intestinal inflammation. Herein we show Thpok is upregulated in pathogenic Th17 cells both in vitro and in vivo. In addition, we show increased expression of Thpok results in reduced production of IL-17, while conversely, loss of Thpok results in higher inflammatory potential of Th17 cells. Moreover, we have demonstrated that Thpok expression in Th17 cells in vivo functions to inhibit the development of experimental autoimmune encephalomyelitis, a mouse model of multiple sclerosis. Altogether this study establishes Thpok as a suppressor of the autoimmune inflammatory function of Th17 cells.
CNS-specific autoregulatory CD8 T cells rely on IFNγ signaling for optimal suppression of pathogenic CD4 T cell responses during inhibition of demyelinating disease
Authors: Boyden Alexander , Brate Ashley A. , Laageide Leah G. , Karandikar Nitin J. 
Published: January 2023

Abstract
Investigating the complex cellular interplay controlling immunopathogenic and immunoregulatory responses is critical for understanding multiple sclerosis (MS) pathogenesis and for developing successful immunotherapies for patients. We have shown previously that CNS-specific CD8 T cells (CNS-CD8) have an unexpected regulatory role in the MS mouse model experimental autoimmune encephalomyelitis (EAE). CNS-CD8 fail to transfer or exacerbate disease but rather protect mice from EAE, and use IFNγ and perforin production to exert suppression. However, the cellular target and downstream effects of IFNγ are less well understood. Here, we evaluated IFNγ dynamics, its receptor and perforin during inhibition of CNS-specific DTH and EAE and show that both IFNγ and perforin production by CNS-CD8 were required at different times to suppress CD4 responses and inhibit EAE disease. Interestingly, while WT CNS-CD8 suppressed CD4 responses in IFNγR-deficient mice, IFNγR-deficient CD8 T cells showed suboptimal inhibition of CD4 responses in WT mice. Likewise, IFNγR-deficient CD8 T cells also exhibited delayed and suboptimal EAE suppression. These data suggest that autoregulatory CD8 T cells’ ability to suppress pathogenic responses during demyelinating disease is influenced by different mechanisms during different phases of disease. Moreover, the results suggest that IFNγ may have an effect on the CD8 T cells themselves, revealing a potential previously unappreciated autocrine/paracrine IFNγ-mediated pathway. Results from these studies have mechanistic implications for the interaction between IFNγ-mediated and perforin-mediated suppression pathways, which may help educate future adoptive immunotherapeutic approaches for MS.