bluuebunny/crossref_metadata_2025_split huggingface dataset:
Antigen experienced and memory T cell correlates of protection in peripheral blood following administration of a whole parasite blood stage malaria vaccine (P4479)
Authors: Reiman Jennifer , McPhun Virginia , Ito Koichi , Lee Moses , Good Michael 
Published: January 2023

Abstract
One of the greatest obstacles to a malaria vaccine is the lack of peripheral blood correlates of protection for all candidate vaccines. We have developed a novel vaccine using chemically attenuated parasitized erythrocytes. Plasmodium chabaudi ring stages were treated in vitro with seco-cyclopropylpyrroloindole (CPI) analogs which bind parasite DNA. Mice were immunized and protection was assessed. T cell phenotypes in peripheral blood were monitored utilizing CD11a+ and CD49d+ as markers of antigen experienced T cells as well as additional memory markers and intracellular cytokine staining. Specific antibodies were assessed but were undetectable. Mice that received three vaccinations were all strongly protected when challenged 113 days after last vaccination. However, only some mice that received a single dose of vaccine were protected. We observed a direct correlation between levels of CD11a+CD49d+ cells at day 21 post vaccination and subsequent protection, for CD4+ (r2=0.704, p=0.002) and CD8+ (r2=0.888, p=0.005) T cells. Immunity was abrogated if CD4+ T cells were depleted prior to challenge. Subsequently, we have observed generation of effector memory cells in blood and the boosting of CD4+CD49d+CD11a+ cells with a second and third dose of vaccination. We have also detected IFNγ positive CD4 and CD8 T cells in response to vaccination. Additional experiments are being performed to better understand the immune phenotype and properties of these T cells.
Self-assembling peptide nanofiber vaccines elicit robust cytotoxic T cell responses (P4515)
Authors: Rudra Jai , Chesson Brent , Huelsmann Erica , Lacek Andrew , Zloza Andrew 
Published: January 2023

Abstract
Vaccines that elicit robust CTL responses are desirable for protection against infectious diseases and cancer. However, clinical vaccine adjuvants like alum elicit robust antibody responses but poor T cell responses. We recently reported that self-assembling peptides that form nanofibers in physiological buffers act as powerful immune adjuvants. When peptide antigens (OVA323-339) were linked to self-assembling peptides, strong adjuvant-free and antigen-specific antibody responses were observed in mice. The protective efficacy of antibodies induced with self-assembling peptide vaccines, was confirmed in a murine malaria model. In this study, we investigated whether self-assembling peptides bearing a CD8+ T cell epitope (OVA257-264) would elicit antigen-specific effector and memory T cell responses. Our results indicate that OVA257-264-nanofibers elicit significantly higher levels of antigen-specific T cells, IFN-γ, and protected against OVA-influenza compared to alum or IFA. These results suggest that self-assembling peptide nanofibers may be useful as adjuvants for vaccines where CD8+ T cell-mediated protection is desirable.
Temporal effects of intestinal ischemia/reperfusion in phagocytosis and inflammatory mediators release (P5054)
Authors: Vitoretti Luana , Ferraz-de-Paula Viviane , Gimenes-Júnior João , Acceturi Beatriz , Ligeiro-de-Oliveira Ana Paula , Breithaupt-Faloppa Ana Cristina , Lino-dos-Santos-Franco Adriana , Tavares-de-Lima Wothan 
Published: January 2023

Abstract
Intestinal ischemia/reperfusion (i-I/R) can induce acute lung inflammation. Furthermore, injuries seen in i-I/R may cause deterioration of the immune system. Studies have demonstrated that dendritic cells present lower responsiveness to bacterial components, while peritoneal macrophages reduce the levels of MHC-II and release less IL-12. Male Wistar rats were subjected to 45 min of ischemia of the superior mesenteric artery and then to 2 h, 3, 5 or 20 days of reperfusion. After these times, the phagocytosis and oxidative burst of peritoneal macrophages and blood monocytes were evaluated by flow cytometry. In addition, inflammatory mediators were quantified in lung culture. We observed that after 5 days of reperfusion the phagocytosis of monocytes was lower than in basal and in the other periods studied. On the other hand, the oxidative burst in this time increased. The phagocytosis of peritoneal macrophages increased after 3 and 5 days of reperfusion, while the oxidative burst increased only after 3 days. Lung explants culture from reperfused rats revealed that while the levels of IL-1β increased during the days of reperfusion, the levels of IL-10 decreased. Furthermore, the amount of IL-17A, TNF-α and IL-4 were higher after 5 days of reperfusion than in the others times. Our data indicate the i-I/R as a promoter of temporal changes in the immune system that alter its ability to maintain the homeostasis and to respond appropriately to pathogens.
Decreased expression of receptor for advanced glycation end-products (RAGE) on neutrophils following surgery necessitating cardiopulmonary bypass (snCPB) (P5058)
Authors: Nikolakopoulou Zacharoula , Creagh-Brown Benedict , Burke-Gaffney Anne , Quinlan Gregory 
Published: January 2023

Abstract
Surgery necessitating cardiopulmonary bypass (snCPB) is associated with systemic inflammation which can be severe. Systemic inflammation is common in the critically ill, is linked to adverse outcome and currently has no specific therapy. Insight into the pathogenesis of systemic inflammation may lead to therapies. The receptor for advanced glycation end-products (RAGE) is an ubiquitous receptor that is up-regulated in the presence of its ligands which are glycated proteins, S100 proteins and high mobility group box 1 (HMGB1). It causes a pro-inflammatory response via NF-κB and the MAP kinases. RAGE inhibition has been associated with improved outcomes in animal models of inflammation and may represent a novel target for intervention. In this study, blood was obtained pre- and post-operation from patients having cardiac surgery involving CPB. The surface and intracellular expression levels of RAGE in neutrophils and monocytes were assessed by flow cytometry and mRNA was obtained for RT-PCR. Preliminary results showed that although snCPB made little difference to intracellular RAGE, cellular RAGE decreased significantly, suggesting that the operative procedure could have initiated shedding of the receptor. There was no significant difference in the RAGE mRNA levels pre- and post-operation. This study provides a better understanding of the involvement of RAGE in systemic inflammation suggesting that shedding of the surface RAGE might contribute to the inflammation process.
Transient receptor potential melastatin 2 is a critical mediator of lipopolysaccharide-induced pulmonary inflammation and injury (P5076)
Authors: Botta Davide , Ballesteros-Tato André , Mudunuru Uma , Martin Kyle , Randall Troy , Stevenson Christopher , Lund Frances 
Published: January 2023

Abstract
Lipopolysaccharide (LPS)-induced production of Reactive Oxygen Species (ROS) leads to lung inflammation and damage associated with several respiratory diseases, including Acute Respiratory Distress Syndrome (ARDS). The link between oxidative stress and inflammation in ARDS led us to hypothesize that the non-selective, redox-sensitive TRPM2 cation channel contributes to the pathogenesis of this syndrome. Following intranasal LPS challenge, Trpm2-/- mice had attenuated alveolar hemorrhage compared to wild-type mice. Flow cytometric analyses showed a modest increase in PMNs and alveolar macrophages (AMs) in the lung tissue and airways of Trpm2-/- mice at the early phase (3-12 hours) of inflammation but significant reductions in PMNs, monocytes, monocyte-derived cells and lymphocytes at the mid (1-2 days) and late (3-7 days) phases. Furthermore, Trpm2-/- mice had decreased expression of proinflammatory/chemoattractant factors and matrix metalloproteases in the lung. Irradiated bone marrow chimeric mice revealed that the protective, TRPM2-deficient phenotype is mainly due to defects in irradiation-resistant lung cells, suggesting that TRPM2 may play an important role in non-hematopoietic cells (e.g. pulmonary endothelial and epithelial cells), as well as AMs. Our data support a harmful role for TRPM2 in ARDS and highlight its pharmacological inhibition as a potential therapeutic approach in treating acute pulmonary inflammation and injury in patients with bacterial infections.
A novel role for IL-15 in the regulation of redox state in stressed mouse skin (P5086)
Authors: Lee Tsung-Lin , Yie Jr-Chi , Chuang Che-Ming , Kung John , Ku Chia-Chi 
Published: January 2023

Abstract
The association of IL-15 with a range of inflammatory disorders has implicated its function in innate immune response. Several isoforms of IL-15 mRNA generated by alternative splicing have been found constitutively expressed in normal mouse tissues at low level. An ENU mutagenized mouse (pedigree 191) bears a mutation in the exon 7 of IL-15 mRNA. Although the transcriptional level of the canonical IL-15 mRNA in P191 was comparable with B6 wild type skin, a transcript generated from alternatively spliced exon 7 of IL-15 mRNA (IL-15_ASE7) was increased by 8 folds in the epidermis of mutant mice. Mechanical stimulation induced downregulation of IL-15 mRNA in B6 but less reduced in P191 abraded skin which also exhibited attenuated dermal cellular infiltration and reduced expression of IL-1β, TNF-α and IL-6 transcripts. Moreover, genome-wide transcriptional profiling of B6 and P191 abraded skin by DNA microarray analysis showed that genes involved in oxidative phosphorylation and glutathione metabolism were distinguishably expressed between B6 and P191 abraded skin. Particularly, transcriptional levels of Uqcrb gene encoding components of the mitochondrial respiratory chain complex III and anti-oxidant Sod-1 gene were significantly reduced in P191 skin at 48 hours after abrasion. Detailed mechanisms by which IL-15 controls the redox state in epidermal keratinocytes as well as the regulatory role of IL-15_ASE7 on IL-15 action will be elucidated.
Interleukin 16 induces intestinal inflammation via PepT1 upregulation in a pufferfish model (P5050)
Authors: Wang Ping , Lu Yi-qi , Shao Jian-zhong , Dong Wei-ren , Xiang Li-xin 
Published: January 2023

Abstract
Interleukin 16 (IL-16) is a chemoattractant cytokine with various effects on cellular activities and diseases. Inflammatory bowel disease (IBD) has long been a worldwide health care problem. Although its clinical features have been well described, its etiology and pathogenesis remains unclear. Moreover, the involvement of IL-16 in IBD is still far from comprehension. Here, we report for the first time, the mechanism by which IL-16 induces intestinal inflammation by up-regulating the expression of oligopeptide transporter member 1 (PepT1) in a Tetraodon nigroviridis fish model. A dextran sulfate sodium (DSS)-induced IBD model in this species revealed that the IL-16 level significantly increased accompanied by the elevation of PepT1 in the colon. Moreover, the signs of IBD were dramatically attenuated by IL-16 depletion using anti-IL-16 antibodies. In vivo administration of IL-16 induces remarkable intestinal inflammation with typical IBD features, including a series of histological damages, increased MPO activity and pro-inflammatory cytokines expression, which corresponds with significant PepT1 upregulation in the colon. Our study provides the first evidence of the connection between IL-16 and PepT1, which provides new insights into the molecular mechanism underlying IBD development. We hope that this study would provide a better understanding of IL-16 biology from fish to mammals, and the development of IL-16-based therapies for IBD.
CD1d-restricted invariant natural killer T cells mediate airway inflammation through IL-25 and IL-18. (P6257)
Authors: Watarai Hiroshi 
Published: January 2023

Abstract
CD1d-restricted iNKT cells are characterized by their expression of an invariant Vα14-Jα18 antigen receptor in mice and of an invariant Vα24-Jα18 in humans that recognizes glycolipid antigen presented by MHC class I-like molecule CD1d. Another distinguishing feature of iNKT cells is their promiscuous production of Th1, Th2, Th9 and Th17 cytokines. Here we identified iNKT cells consist from distinct functional subtypes based on the expression of IL-17 receptor B (IL-17RB), a receptor for IL-25: IL-17RB+ iNKT cells produce robust IL-13 and IL-9 with moderate IL-17A in response to IL-25, which is phenotypically and functionally distinct from classical IL-12-reactive IFN-γ-producing iNKT cells bearing CD122 without IL-17RB. In the in vivo experimental settings, IL-17RB+ iNKT cells play a crucial role in the induction of airway inflammation both of OVA and of RSV model. Through the elucidation of the mechanisms in the activation of IL-17RB+ iNKT cells, IL-18 instead of IL-25 is responsible for the activation of these cells in RSV model, resulting in an acute and robust production of Th2 and Th17 cytokines. Our findings reveal that IL-17RB+ iNKT cells and leading effector cells as target cells of IL-25 and IL-18 in the pathogenesis of airway diseases, illustrating the clinical potential of severe exacerbation of developing asthma by IL-17RB+ iNKT cell-dependent cellular cascade targeted therapy in humans.
The interplay of macrophages and dendritic cells with WNV-specific T cells during single-cycle flavivirus immunization. (P6332)
Authors: Winkelmann Evandro , Xia Jingya , Widman Douglas , Gorder Summer , Mason Peter , van Rooijen Nico , Bourne Nigel , Milligan Gregg 
Published: January 2023

Abstract
Innate immunity is important to control the early phase of infection. Macrophages and dendritic cells (DCs) play a critical role in the initial stages of immune responses to several viruses, serving as antigen-presenting cells (APCs), especially DCs, which are potent APCs and play an essential role in the induction and control of the cell-mediated immune response. Here we investigated the role of macrophages in dissemination of single-cycle flavivirus (SCFV) particles to draining lymph nodes (LN) following footpad (FP) inoculation and evaluated the APC function in the absence of macrophages. Our results demonstrated higher virus replication in the absence of macrophages and a wider spread of the particles from the initial site of infection, demonstrating that macrophages were important in the early control of the virus. On the other hand, we demonstrated that macrophages were not critical for the induction of WNV-specific CD8+ T cell response, since similar responses were observed in the presence or absence of macrophages. Further, we began to investigate the function of the TLR3, IRF3 and IFNαβR signaling pathways in the migration and activation of specific DC populations into the regional LN of mice inoculated with SCFV via FP injection. Although we found differences in the number of DCs recruited to the site of infection, our preliminary results suggest similar activation and APC function of DC from mice lacking these innate pathways.
Early events dependent on the suppression of IPS signaling are necessary for persistent viral infection (P6300)
Authors: Sullivan Brian , Teijaro John , de la Torre Juan Carlos , Oldstone Michael 
Published: January 2023

Abstract
Persistent infections are characterized by evasion of innate and adaptive immune responses controlled by the upregulation of immunosuppressive cytokines. However, little is known whether events during the first day of infection form the environment necessary for the establishment of a persistent infection. Using a novel in vivo competition approach by priming a persistent lymphocytic choriomenengitis virus (LCMV) infection with a non-propagating LCM virus, we found that suppression of the intracellular RNA sensing pathway and not the TLR7 pathway is necessary for establishing a persistent infection. Furthermore, signaling through IPS/MAVS up to six hours before LCMV inoculation changes the nature of the immune response within the first 24 hours. Increased cytokine expression, normally observed in the first 18-24 hours during a persistent LCMV infection, is markedly reduced upon priming. Reduced cytokine expression is associated with complete clearance of the virus within 2 weeks, suggesting that LCMV initiates persistence through immune disregulation. Interestingly, localization of viral antigen in the spleen is markedly different in primed and unprimed mice despite similar viral titers in the serum and organs three days post-infection. Thus, our data are the first to document how early events after LCMV inoculation serve to establish persistent infection and suggest that early intervention can modify the pathogenesis and course of a persistent infection.
Age-dependent decline of B cell-mediated immunity contributes to West Nile virus susceptibility in mice (P6338)
Authors: Richner Justin , Diamond Michael 
Published: January 2023

Abstract
With aging, the ability of the immune system to mount an efficient response declines, leading to the increased susceptibility of elderly individuals to succumb to infectious diseases. West Nile virus (WNV) is an emerging mosquito-borne flavivirus that causes fatal encephalitis in several vertebrate animals including humans. Despite similar infection rates across all ages, elderly individuals have a higher rate of WNV associated encephalitis and death, and similar results have been documented in laboratory mice. While defects in T cells have been implicated in increased WNV disease severity in aged mice, the contribution of B cell-mediated immune responses has not been addressed. In this study, we compared the immunological response in adult and old mice infected with WNV. We discovered that during the acute phase post infection old mice have delayed germinal center responses that include reduced number of T follicular helper cells and fewer activated germinal center B cells. Consequently, aged mice develop a blunted humoral response with lower serum antibody titers, altered epitope specificity, and reduced serum neutralization. These findings support a model in which decreased B cell-mediated immune responses in elderly animals failed to control viral replication at early times post infection, which resulted in rapid dissemination to the central nervous system, encephalitis, and death.
A combination of provirus stimulants with blockers of regulators of complement activation represents a novel approach for purging HIV-1 latently infected cells (P6342)
Authors: Lan Jie , Byrd Daniel , Amet Tohti , Yu Qigui 
Published: January 2023

Abstract
HIV-1 latently infected cells are recognized as the last barrier towards viral eradication and cure. To purge these latently infected cells, we developed an “activation-killing” approach by combining provirus stimulants (SAHA, prostratin or both) with a blocker of human CD59, a key member of regulators of complement activation (RCA), to facilitate anti-HIV-1 antibodies to trigger antibody-dependent complement-mediated lysis (ADCML) of latently-infected cells. We found that both SAHA and prostratin activated proviruses in ACH-2 cells, a well-characterized cellular model of HIV-1 latency, resulting in expression of HIV-1 gp120 on the cell surface. To prevent new rounds of infections by virus released from the stimulated cells, we treated ACH-2 cells with provirus stimulants plus antiretroviral drugs. We found that reverse transcription inhibitors had no effect on virion production, whereas protease inhibitors (PIs) significantly reduced the production of mature virions, but not gp120 expression on the cell surface. ACH-2 cells post-activation of provirus became sensitive to ADCML in the presence of a human CD59 blocker plus anti-HIV-1 gp120 antibodies or sera from HIV-1-infected patients. The lysis resulted from specific cell killing by anti-HIV-1 antibodies because the lysis did not occur using irrelevant antibodies or inactivated complement. Thus, a combination of provirus stimulants with RCA blockers represents a novel approach for purging HIV-1 latently infected cells.
Immune mediated Arenaviral Hemorrhagic disease in a novel mouse model (P6304)
Authors: Schnell Fred , Mourich Dan , Iversen Patrick 
Published: January 2023

Abstract
Viral hemorrhagic fever viruses (VHF) are a group of RNA viruses that can cause severe multisystemic illness in humans. Development of efficient countermeasures to this disease has been hampered by the lack of clinically relevant animal models. A better understanding of mechanisms behind disease progression would illuminate therapeutic targets. To this end, we have identified the FVB mouse strain which succumbs to a hemorrhagic fever like illness when infected with lymphocytic choriomeningitis virus (LCMV). Hemorrhagic FVB mice demonstrate increased IFN-gamma, IL-6 and IL-17, along with increased chemokine production, at early times after LCMV infection, which suggests that a viral-induced host immune response is the cause of the pathology. Antisense-targeted reduction of IL-17 cytokine responsiveness provided significant protection from hemorrhagic pathology. F1 mice derived from FVB x C57BL/6 mating were generated to better characterize immune-mediated hemorrhagic disease. LCMV-13 infected F1 mice displayed reduced numbers of LCMV specific T cells compared to both LCMV-Armstrong infected F1 and LCMV-13 infected C57BL/6 mice. This report reveals a possible immune component to Arenaviral Hemorrhagic disease and offers a potential therapeutic target in IL-17.
MHC Class I Dk expression in hematopoietic and non-hematopoietic cells is essential to NK cell licensing and murine CMV resistance (P6308)
Authors: Wei Hairong , Brown Michael 
Published: January 2023

Abstract
Ly49G2 inhibitory receptor-bearing NK cells are essential to viral control in murine (M)CMV infected MA/My and MHC class I Dk-expressing C57L mice. In bone marrow chimeric (BMT) mice, highly effective NK cell-mediated viral control requires Dk expression in both hematopoietic and non-hematopoietic cells. Because Dk is a licensing ligand for Ly49G2, we reasoned that Dk expression in discrete cell lineages modulates NK responsiveness and viral control. To address the question, we generated additional BMT mice and measured the effect of Dk expression on NK effector competency and virus control. As expected, G2+ NK cells in Dk-transgenic (Dk-Tg) mice reconstituted with Dk-Tg bone marrow were fully licensed and conferred MCMV resistance. Conversely, in BMT recipients with Dk expression restricted to only hematopoietic or non-hematopoietic cells, G2+ NK cells displayed reduced activation receptor stimulation and significantly less viral control. These data demonstrate that NK cell licensing is regulated by MHC class I expression in hematopoietic and non-hematopoietic cells and this corresponds to the extent of G2+ NK cell-mediated viral control. Whereas recent data has shown that licensing of adoptively transferred mature NK cells is sensitive to MHC I expression on non-hematopoietic recipient cells, ongoing adoptive transfer experiments with Dk-Tg and non-Tg mature NK cells further examines the relationship between NK cell licensing and their capacity for viral control.
T-bet: a key player in a novel type of B cell activation essential for effective viral clearance (P4333)
Authors: Rubtsova Kira , Rubtsov Anatoly , Kappler John , Marrack Philippa 
Published: January 2023

Abstract
IgG2a is known to be the most efficient antibody isotype for viral clearance. Here we demonstrate a novel pathway of B cell activation, leading to IgG2a production, and involving synergistic stimulation via B cell antigen receptors, TLR7 and interferon-gamma receptors. This leads to induction of T-bet expression in B cells, driving their differentiation into age-associated B cells (ABCs). T-bet positive ABCs appear during anti-viral responses and produce high titers of anti-viral IgG2a antibodies which are critical for efficient viral clearance. The results thus demonstrate a previously unknown role for T-bet expression in B cells during viral infections. Moreover the appearance of ABCs during anti-viral responses and during autoimmunity suggests a possible link between these two processes.