bluuebunny/crossref_metadata_2025_split huggingface dataset:
Differential antiviral immune response in swine model of influenza vaccine-associated enhanced respiratory disease. (VIR2P.1026)
Authors: Loving Crystal , Vincent Amy , Gauger Phillip , Hughes Holly 
Published: January 2023

Abstract
Genetic drift and introduction of human seasonal influenza A virus (IAV) have resulted in six H1 phylogenetic clusters in swine. In humans reports suggest that prior vaccination against seasonal IAV (pre-2009) may result in enhanced disease following infection with pandemic 2009 IAV (pH1N1). Similarly, vaccine-associated enhanced respiratory disease (VAERD) has been reported in pigs that were vaccinated with one antigenic H1 subtype (human-like H1δ1) and subsequently challenged with pH1N1. To investigate the immune response associated with VAERD to delineate a mechanism for enhanced disease pigs were vaccinated with adjuvanted, inactivated H1δ1 and subsequently challenged with pH1N1 (Vx/Ch). Non-vaccinated (NV)/Ch and NV/non-challenged (NC) were included. Vaccination elicited IAV-specific IgG that cross-reacted with pH1N1 but did not neutralize infectivity. Proinflammatory cytokines IL-8, IL-1β and IL-6 were significantly elevated in lungs of Vx/Ch pigs compared to NV/Ch pigs. However, IFNα levels were significantly lower in lungs of Vx/Ch pigs compared to NV/Ch pigs indicating a difference in activation of antiviral immune pathway(s). IFNα mRNA levels were the same in tracheal epithelial cells collected from Vx/Ch and NV/Ch pigs; however, IFNα mRNA levels in alveolar macrophages (AM) from NV/Ch pigs were significantly increased over Vx/Ch pigs. We hypothesize vaccine-potentiated immunopathology through dysregulation of AM innate responses potentiates disease.
The role of T cell leptin signaling in 2009 pandemic H1N1 influenza infection mortality in obese mice (VIR2P.1013)
Authors: Milner J. , Meyers Matthew , Sheridan Patricia , Mancuso Peter , Beck Melinda 
Published: January 2023

Abstract
Obese humans are more susceptible to death from infection with the 2009 pandemic H1N1 influenza virus (pH1N1) compared with healthy weight individuals. To identify explanatory mechanisms, we utilized a mouse model of obesity and pH1N1 infection. Diet-induced obese C57BL/6J male mice and lean control mice were intranasally infected with influenza A/Cal/07/09 (pH1N1). Obese mice exhibited an 80% mortality rate, whereas no lean mice succumbed. During the infection, obese mice exhibited similar levels of lung viral titers but had elevated levels of lung inflammatory cytokines and greater lung airway damage. Further, obese mice had fewer activated lung CD4+Foxp3+CD103+ regulatory T cells. As a potential mechanism for the heightened inflammatory responses in the lungs of obese mice, we addressed the role of leptin, an immunomodulatory hormone chronically elevated in an obese state. Obese mice had more than twice as much leptin in serum and lung airways during the pH1N1 infection compared with lean mice. Given the regulatory role of leptin in T cell activity, we utilized mice lacking functional leptin receptor in T cells (LepRT-/-). LepRT-/- and LepRTfl/fl littermate controls were maintained on a high fat or low fat diet for 15 weeks. Preliminary studies indicate that disruption of leptin signaling in T cells limits pH1N1 mortality and infection severity in obese mice. Therefore, leptin signaling in T cells may be a critical mediator of pH1N1 severity in obese mice.
Deciphering and correcting impaired respiratory virus-specific immunity caused by vitamin A deficiency (VIR2P.1017)
Authors: Penkert Rhiannon , Surman Sherri , Jones Bart , Sealy Robert , Neale Geoffrey , Rudraraju Rajeev , Hurwitz Julia 
Published: January 2023

Abstract
Vitamin A deficiency (VAD) is a leading contributor to pediatric morbidity and mortality worldwide. Recently we have shown that VAD in mice impairs mucosal IgA responses in the upper respiratory tract during both paramyxovirus and influenza virus vaccination, thus impeding a first defense against these pathogens at their point of entry. The key vitamin A metabolite responsible for normal immune function is retinoic acid (RA). Previously, RA was believed to be produced predominantly by gut dendritic cells expressing aldehyde dehydrogenase (ALDH1A), an enzyme required for metabolism of RA from RA precursors. However, we found that epithelial cells of the respiratory tract autonomously produce ALDH1A. These cells also produce IL-6 and GM-CSF and can facilitate IgA production from activated splenocytes in vitro. Further in vitro analyses demonstrated that outcomes of vitamin A supplementation were affected by a variety of factors including concentration and type of vitamin A metabolite, as well as cells targeted. Based on these results, we supplemented a respiratory virus vaccine with a single intranasal dose of retinol, retinyl palmitate, or a combination of IL-6 and GM-CSF in VAD mice, and observed enhanced virus-specific mucosal IgA. In total, our data provide insight into the role of vitamin A in virus-specific immunity, while defining feasible methods for the correction of impaired mucosal immune responses in individuals with VAD.
Comparison of messenger RNA expression profile of antiviral innate immune response genes in peritoneal macrophages from BALB/c and C57BL/6 mice infected with ectromelia virus (INM3P.413)
Authors: Toka Felix , Dolega Patryk , Mielcarska Matylda , Bossowska Magdalena 
Published: January 2023

Abstract
Although a few mechanisms have explained how, for instance ectromelia virus (ECTV), is successful in causing fatal disease in certain strains of mice and how other strains are not susceptible, a global transcription overview of innate immunity genes is not entirely known. Poxviruses have evolved several mechanisms to avoid immune response of an infected host. Here we have studied the innate gene transcriptional response of BALB/c and C57BL/6 mice peritoneal macrophages to infection with ECTV Moscow strain (ECTV-Mos). Indeed, assessment of four categories of antiviral innate immune response receptors, downstream signalling and responsive components revealed generalized down regulation of many genes in both strains of mice. Of the 84 genes assessed in each mouse strain only 3 and 15 were significantly upregulated in BALB/c and C57BL/6 mice, respectively. The remaining genes were more or less down-regulated. Surprisingly, type I interferon genes were substantially upregulated. The observed upregulation strongly correlated with protein expression in the case of cathepsin genes as well as TLR genes. ECTV-Mos inhibits receptors and signalling components of the innate immune response in mice. Results provide an insight into initial factors that presumably lead to an ineffective antiviral immune response of BALB/c and C57BL/6 mice in the light of infection with ECTV.
Regulation of necroptosis as a viral immune antagonistic mechanism (INM3P.361)
Authors: Hartmann Boris , Albrecht Randy , Marjanovic Nada , Sealfon Stuart 
Published: January 2023

Abstract
Regulation of cell death is an important aspect of immune responses to human pathogens. We observed rapid mRNA degradation in human primary dendritic cells (DC) after infection with seasonal but not pandemic H1N1 influenza A viruses. Investigating the mechanism underlying this phenomenon, we found that virus-induced cell death is responsible for cellular RNA degradation. Our data showed that infection with seasonal H1N1 influenza induces caspase independent but RIPK3 dependent necroptosis in primary human DCs as early as 4 hours post infection. Additionally, we found that necroptosis induction is dependent on de novo viral RNA synthesis. To elucidate which viral proteins mediated necroptosis regulation, DC were infected DCs with recombinant viruses encoding segments from a pair of influenza viruses that differed in inducing necroptosis. These DC cell death assays indicated that HA or NA play a pivotal role in necroptosis regulation. Differences in necroptosis induction observed between the seasonal and pandemic influenza strains in DCs, the main antigen presenting cells in antiviral immunity, could have a significant impact on the adaptive immune response and offer a potential explanation for differences observed in clinical outcomes of infection with pandemic or seasonal influenza virus strains.
Discovery of huanglongbing (HLB) pre-symptomatic RNA biomarkers (INM3P.415)
Authors: Wren Melinda , Pardington Paige , Stover Ed , Gupta Goutam 
Published: January 2023

Abstract
HLB is the most devastating citrus disease and is associated with vector-borne Liberibacter. Currently there is no cure for HLB. Visual disease symptoms appear in only a few leaves months after initial Liberibacter exposure compromising disease management by tree removal. Since infected but non-symptomatic trees are inoculum sources, a robust platform for early diagnosis of HLB is urgently needed. Here, we describe our studies on the discovery of HLB pre-symptomatic RNA biomarkers. For this, we infected greenhouse citrus using Liberibacter inoculum delivered by psyllid vectors confined to branch cages for a single week. Total RNA was extracted from leaves at three distances from the point of inoculation and for a range of early post-exposure times. Gene expression data by RNA-seq was collected for all leaf samples. We expect citrus genes belonging to pattern recognition, plant hormone, and stress pathways to be expressed early during infection. The RNA-seq data will be analyzed to identify which citrus genes are altered in leaves during early infection. It is our hypothesis that pre-symptomatic citrus biomarkers will be systemically expressed during the early stages of infection even in leaves distant from the site of Liberibacter inoculation. We will validate the expression of the candidate pre-symptomatic biomarkers by qPCR. The candidate biomarkers will reflect citrus genes that are systemically expressed and the Liberibacter genes that are indicative of bacterial growth.
Cyclo(L-phe-pro), Vibrio vulnificus produced metabolite, suppresses innate immune response (INM3P.418)
Authors: Jang Sung , Kim Kiwan , Lee Gap 
Published: January 2023

Abstract
Cyclo(Phe-Pro)(cFP), known as a secondary metabolite of some bacteria and fungi, is also produced by Vibrio vulnificus. It has been suggested that cFP has a role in bacterial cell-to-cell communication. However, the role of cFP in host immune response has not been reported yet. In this study, we investigated whether cFP modulates host innate immune responses. cFP suppressed production of pro-inflammatory cytokines, TNFa and IL6, nitric oxide, and reactive oxygen species in LPS-induced macrophages and bone marrow-derived macrophages. cFP also inhibited IKK phosphorylation, IkBa degradation, and NF-kB translocation to the nucleus, indicating that cFP affects the NF-kB pathway. These results provide evidences that cFP has immune suppressive effects that enhance the pathogen’s ability to infect and survive in host environment. Moreover, it may contribute to reveal the role of cFP in host-pathogen interaction and establish potential therapeutic strategies for the diseases related to Vibrio vulnificus.
Identification of an E3 ubiquitin ligase that regulates cellular resistance to influenza virus infection by controlling levels of the antiviral protein IFITM3 (INM3P.363)
Authors: Chesarino Nicholas , McMichael Temet , Hach Jocelyn , Yount Jacob 
Published: January 2023

Abstract
Interferon (IFN)-induced transmembrane protein 3 (IFITM3) is a cellular antiviral restriction factor that is able to inhibit infection by a wide variety of viruses, including influenza and Ebola. We previously showed that IFITM3 turnover is promoted by its ubiquitination, though the ubiquitin ligase responsible for this modification was not identified. Here we demonstrate that the E3 ubiquitin ligase NEDD4 ubiquitinates IFITM3 in vitro and in cells. Accordingly, we found that NEDD4 knockout mouse fibroblasts accumulate IFITM3, and that this accumulation is lost upon reconstitution of these cells with NEDD4. Importantly, IFITM3 accumulation results in enhanced resistance of NEDD4 knockout cells to influenza virus strains. Similarly, knockdown of NEDD4 in several human lung cell lines resulted in a buildup of IFITM3 and resistance to infection, demonstrating an evolutionary conservation of this regulatory mechanism in mice and humans. Further supporting a role for NEDD4 as a regulator of IFITM3 turnover, overexpression of the NEDD4 inhibitory protein, interferon stimulated gene 15 (ISG15), led to increased IFITM3 levels in human lung cells but decreased IFITM3 ubiquitination, demonstrating a new synergistic link between ISG15 and IFITM3. This work implicates NEDD4 as a therapeutic target for the prevention or treatment of influenza virus infections, and introduces a new paradigm for up-regulating the cellular level of an IFN-inducible antiviral protein independently of IFNs.
IL-33 promotes innate IFN-γ production and controls multi-functional T cell responses in viral hepatitis (IRC7P.429)
Authors: Liang Yuejin , Jie Zuliang , Soong Lynn , Sun Jiaren 
Published: January 2023

Abstract
Recently, experimental vaccine based on replication-defective lymphocytic choriomeningitis virus (rLCMV) has been shown to induce effective protection in several models, suggesting that rLCMV may show utility as a vaccine vector against infectious diseases and cancer. However, the key molecules in regulating the LCMV-induced immunity and controlling tissue damage are not clear. Here, we report that IL-33 promotes the innate and adaptive immune responses in LCMV-infected mice. Deficiency of IL-33 resulted in fewer IFN-γ+ innate immune cells (e.g. γδ T and NK cells) at 16 hours post-infection and lower levels of IFN-γ and IL-12 in the liver at 3 days post-infection (dpi). Impaired anti-viral T cell responses were observed in IL-33-/- mice at 7 dpi, as evidenced by fewer multi-funtional CD4 and CD8 T cells and lower level of anti-viral cytokines (e.g. IFN-γ, IL-12 and IL-2). In contrast, recombinant IL-33 (rIL-33) facilitated IFN-γ-producing gd T and NK cells, but inhibited proliferation of IL-17+ γδ T cells. rIL-33 treatment also promoted anti-viral T cell responses in both wild-type (WT) and IL-33-/- mice, and attenuated liver injury at 6 dpi. Moreover, we found that type 2 innate lymphoid cells (ILC2), induced by rIL-33, were dispensable for anti-viral T cell response in LCMV-induced acute hepatitis. Our data revealed the key role of IL-33 in regulating innate immune cells, and subsequently enhancing the plurifunctionality of anti-viral T cell responses in LCMV infection.
Mature dendritic cells secrete functionally active CTLA-4 in microvesicles (IRC7P.430)
Authors: Halpert Matthew , Konduri Vanaja , Liang Dan , Chen Yunyu , Wing James , Paust Silke , Levitt Jonathan , Decker William 
Published: January 2023

Abstract
Cytotoxic T-Lymphocyte Associated protein-4 (CTLA-4), the target of the blockbuster cancer immunotherapeutic ipilimumab, is a regulatory molecule of the B7 superfamily known to inhibit T-cell responses by a variety of different mechanisms. While CTLA-4 expression and function have been well-characterized in T-cells, very little is known about the presence and/or role of CTLA-4 in other hematopoietic lineages. Previous reports have indicated that myeloid lineage dendritic cells (DC) might express the CTLA-4 mRNA transcript and that transcript levels could be regulated by external stimuli. In the present study, we substantially build upon these critical observations, definitively demonstrating that mature DC express significant levels of intracellular CTLA-4 which are constitutively secreted in Rab5+Rab11- microvesicular structures. We further demonstrate that CTLA-4-containing microvesicles are capable of competitively binding B7 costimulatory molecules with significant functional consequences for downstream T-cell responses both in vitro and in vivo. The data indicate a previously-unknown role for DC-derived CTLA-4 in the physiologic regulation of T-cell responses and have significant implication for the design and implementation of immunomodulatory strategies intended to treat cancer and infectious disease.
Extracellular matrix protein 1 plays a critical role in driving Th2 cell migration and controlling Th17 cell differentiation (IRC7P.434)
Authors: Sun Bing 
Published: January 2023

Abstract
Abstract: Extra-Cellular Matrix Protein 1 (ECM1), a secreted protein, is highly and selectively expressed in Th2 cells. ECM1 deficiency caused impaired Th2 responses and reduced allergic airway inflammation in vivo. Functional analysis demonstrated that ECM1 deficient Th2 cells exhibited a defect in migration and were retained in peripheral lymphoid organs. Based on the cross-inhibition between Th2 and Th1/Th17 cells, we discovered a novel function of ECM1 in ameliorating Experimental autoimmune encephalomyelitis (EAE) which is mediated by Th1/Th17 cells. After the recombinant ECM1 were administrated i.v during EAE induction, the development of Th17 cells was decreased. In mechanism study we found that ECM1 could interact with integrin αv and block the interaction of integrin αv and latent TGF-β, which is critically for activating latent TGF-β maturation and then consequently to determine Th17 cell differentiation. To confirm the novel function of endogenous ECM1 in vivo, ecm1 transgenic mice was used to induce EAE. The data showed that EAE induction was suppressed significantly as compared with control group, which was associated with the failure of Th17 cell development. Our clinical observation indicated that ECM1 function is correlated with the pathogenesis of MS. This discovery offers new concept that ECM1 has potential in clinical application for understanding the pathogenesis of MS and its diagnosis.
Control of T cell proliferation, differentiation, and effector function by the adaptor protein BCAP (IRC8P.449)
Authors: Singh Mark , Srivastava Shivani , Duggan Jeffrey , Hamerman Jessica , Campbell Daniel 
Published: January 2023

Abstract
The PI3K network is required for a robust effector T cell response. However, the molecular mechanisms involved in regulating PI3K function during T cell activation are poorly understood. The adaptor protein B Cell Adaptor for PI3K (BCAP) has previously been detected in B cells and myeloid cells, and there is evidence suggesting that BCAP is involved in the regulation of PI3K signaling pathways in these cell populations. We have generated novel data demonstrating the role of BCAP in ensuring optimal T cell activation, proliferation and differentiation. BCAP is not expressed in naïve T cells but is detected in effector memory T cell populations, and can be rapidly induced in naïve T cells upon T cell activation in vitro. BCAP deficient T cells are hypo-proliferative, and have attenuated signaling cascades downstream of PI3K in vitro. To study the role of BCAP in T cells in vivo, we infected wild type and BCAP deficient mice with the pathogen Lymphocytic Choriomeningitis Virus (LCMV). At 7 days post infection, notable skewing in the effector CD8+ T cell populations was observed, with an increased frequency of KLRG1loCD127hi memory precursor cells (MPCs) at the expense of KLRG1hiCD127lo terminal effector cells (TECs). Finally, use of mixed bone marrow chimeras showed that wild type T cells have a significant competitive advantage over BCAP deficient T cells in vivo. Collectively, these data suggest that BCAP may have a non-redundant role in determining T cell fate in vivo.
Enhanced IL-7 responsiveness provides competitive advantage to recent thymic emigrants in peripheral T cell survival and homeostasis (IRC8P.451)
Authors: kim hye kyung , Castro Ehydel , Voong Nga , Telford William , Gress Ronald 
Published: January 2023

Abstract
Recent thymic emigrants (RTE) are newly generated T cells that are necessary to replenish T cell antigen receptor diversity and rejuvenate the peripheral naïve T cell pool. Both naïve T cells and RTE require IL-7 to survive in the periphery, but it is not known how RTE successfully compete with resident T cells for IL-7 signaling. To address this question, we assessed IL-7 receptor (IL-7Ra) expression on RTE, and found that RTE expresse substantially lower levels of IL-7Ra than naïve T cells. Because IL-7 signaling downregulates expression of its own receptor, lower IL-7Ra expression suggest that RTE are potentially more responsive to IL-7 than naïve T cells. Indeed, in vitro IL-7 stimulation showed significantly increased STAT5 phosphorylation in RTE compared to naïve T cells. To understand the molecular basis for increased IL-7 responsiveness, we assessed STAT5 phosphorylation and IL-7R expression upon IL-7 re-stimulation, and found that RTE are significantly more responsive to IL-7 re-stimulation. Contrary, adoptive transfer of RTE cells into lymphopenic host mice resulted in less efficient proliferation and expansion than of naïve donor T cells, which was not rescued by increasing in vivo IL-7 levels by implanting IL-7 osmotic pumps. Collectively, these data indicate that increased IL-7 responsiveness in RTE maximizes their survival while decreasing their proliferative capacity such as under lymphopenic conditions.
Plasmacytoid dendritic cell activation is dependent upon type I IFN-driven fatty acid oxidation (IRM9P.456)
Authors: Wu Duojiao , Everts Bart , Qiu Jing , Pearce Erika , Cella Marina , Pearce Edward 
Published: January 2023

Abstract
Plasmacytoid dendritic cells (pDCs) are specialized for the secretion of type I interferons (IFN-I) and thus are considered mediators of antiviral responses. pDCs selectively express endosomal Toll-like receptor (TLR) 7 and TLR9 and the ligation of TLR7/9 leads to rapid cellular activation. Recently, we found that stimulation of pDCs with the TLR9 agonist CpG resulted in a marked increase in mitochondrial oxygen consumption rates (OCR) dependent on increased fatty acid oxidation (FAO). FAO is essential for full activation of CpG-stimulated pDCs because etomoxir or carnitine palmitoyltransferase 1A shRNA (short-hairpin RNA) severely attenuated IFN-alpha production by these cells. Using RNA-seq, we identified the expression of many interferon-stimulated genes (ISG) in CpG-stimulated pDCs, amongst which were genes encoding FAO pathway components. We found that IFNAR -/- pDCs failed to increase mitochondrial OCR in response to TLR9 agonists. Taken together, our data indicate that IFN-alpha-induces FAO which is essential for full pDC activation in response to CpG.