bluuebunny/crossref_metadata_2025_split huggingface dataset:
High IL-4 expression and IL-4 gene polymorphisms are associated with susceptibility to human paracoccidioidomycosis (164.21)
Authors: Rodrigues Virmondes , Sawan-Mendonça Monica , Peraçoli Terezinha , Ribeiro Silvio , Silva-Vergara Mario 
Published: January 2023

Abstract
Paracoccidioidomycosis is caused by the dimorphic fungus Paracoccidioides brasiliensis. After invasion, the fungi are immediately destroyed or overcome the local defenses of the host and begin multiplication, causing initial injury. Previous studies have demonstrated that the severity of disease is associated with a Th2 immune response characterized by high IL-4 production. In the present study, we analyzed two polymorphisms in the IL-4 gene, -590 C/T and the intron-3 microsatellite, in 76 patients with paracoccidioidomycosis and in 73 control individuals from an endemic area. A significant correlation was observed between the RP2/RP2 intron-3 genotype and infection with P. brasiliensis (p=0.011), while the RP1/RP1 genotype was correlated with resistance. The IL-4 promoter polymorphism showed a significant correlation of the presence of T allele with the disease (p=0.030). Furthermore, high IL-4 expression observed on the patient group compared with control and was associated with TT genotype. This result suggests that IL-4 polymorphisms are associated with the ability of the host to control P. brasiliensis infection. The potential biological role of this polymorphism is supported by our observation that patients with disease produce high levels of IL-4 after mitogen or antigen stimulation and the association of high IL-4 levels with TT genotype. IL-4 gene is located in the cytokine cluster region of chromosome 5, where other polymorphisms have been described.
Type II interferon gamma is detrimental to the host in Streptococcus suis infections caused by an epidemic strain (164.6)
Authors: Lachance Claude , Segura Mariela , Pereyra Gerber Pehuen , Bergman Eugenia , Lacouture Sonia , Xu Jianguo , Gottschalk Marcelo 
Published: January 2023

Abstract
S. suis is a major swine pathogen that can be transmitted to humans causing severe symptoms. A large human outbreak was described in China, where approximately 25% out of 215 infected humans developed an unusual streptococcal toxic shock-like syndrome (STSLS). Albeit increased expression of inflammatory mediators following infection by the Chinese S. suis strain was suggested as responsible for STSLS case severity, the mechanisms involved are still poorly understood. Therefore, we investigated the host innate immune response to infection by either one of 3 strains of S. suis: 89-1591 (Canadian, intermediate virulence), P1/7 (European, high virulence), and SC84 (Chinese, epidemic strain). Using Illumina microarray, qPCR, and Luminex assay, infected mice showed elevated expression of mainly pro-inflammatory chemokine and cytokine genes. Generally, pro-inflammatory genes were expressed at a higher level in mice infected with strain SC84 &gt; P1/7 &gt; 89-1591. Interestingly, IFNγ was expressed at much higher levels only in mice infected with strain SC84, which could potentially explain some of the STSLS symptoms. IFNγ-KO mice infected with epidemic SC84 strain showed significantly better survival than WT mice while no difference was observed in mice infected with highly virulent P1/7 strain. Overall, our results show an important role of IFNγ in S. suis infections and might explain in part the increased virulence of the epidemic SC84 strain responsible for the outbreak in China.
The negative feedback mechanism between SLPI and IFNγ is impaired in tuberculosis patients (164.7)
Authors: Tateosian Nancy , Pasquinelli Virginia , Hernandez del Pino Rodrigo , Garcia Veronica , Chuluyan Eduardo 
Published: January 2023

Abstract
Mycobacterium tuberculosis increases IFNγ secretion which plays an important role in granuloma formation and clearance of it. Also, the exposure of macrophages to M. tuberculosis increases secretory leukocyte protease inhibitor (SLPI), a serine protease inhibitor with antimycobacterial activity. Therefore, the aim of the present study was to determine the role of a putative interaction between IFNγ and SLPI in PBMC derived from healthy donors (HD) and tuberculosis patients (TB). Peripheral blood mononuclear cells (PBMC) from TB and HD were treated with Mtb antigen and IFNγ and SLPI was determined by ELISA. Our results showed that the stimulation with Mtb of PBMC from HD, it decreased SLPI (p&lt;0.01) while increased IFNγ secretion. Furthermore, the blockage of IFNγ reversed the effect of the Mtb antigen on SLPI secretion in PBMC-derived HD. Surprisingly Mtb antigen did not modify the SLPI secretion in PBMC-derived from TB, although it increased IFNγ. Furthermore, the mAb against IFNγ did not affect the SLPI secretion. When plasma levels of SLPI and IFNγ were measured, we found a positive correlation between them in TB but not in HD. Moreover, tuberculosis patients showed more SLPI in plasma, being the levels higher with the severity of the disease. Overall, these results suggest that there is a negative cross talk between IFNγ and SLPI in HD that it is not present in TB patients. Therefore, the higher concentration of IFNγ and SLPI might contribute to control the infection.
A novel iNKT-mediated vaccine maneuver overcomes PD-1-mediated T cell exhaustion in cancer (165.13)
Authors: Varghese Bindu , Lynch Lydia , Vriend Lianne , Kissick Haydn , Dunn Laura , Varghese Sharlin , Arredouani M. Simo , Balk Steven , Exley Mark 
Published: January 2023

Abstract
Our immune system plays an important role in preventing cancer. However, tumor-derived immuno-suppression hinders effective anti-tumor immunity. T cell dysfunction or exhaustion in tumor-bearing hosts is one such mechanism. Numerous studies have identified PD-1 and Tim-3 as markers of exhausted T cells, and antibodies blocking PD-1 and Tim-3 have been shown to partially restore T cell function. We have found that both Tim-3 and PD-1 are expressed on CD8+ tumor-infiltrating lymphocytes (TILs) in an animal model of B cell lymphoma and that these cells represent the predominant fraction of T cells infiltrating tumors. We find that iNKT stimulation using the ligand, alpha-galactosylceramide, combined with TLR9 stimulation using the ligand, CpG, can down-regulate Tim-3 and PD-1 expression in TILs, restore TIL function as measured by proliferation and production of TNF and IFNg in response to tumor, and induce long-lasting therapeutic immune responses in mice with large advanced (&gt;1cm2) tumors.
Markers of effective anti-tumor CTL populations for adoptive cell therapy (165.5)
Authors: Yang Jianping , He Shujie , Peng Lifeng , Rawson Pisana , Perret Rachel , Jordan Bill , Ronchese Franca 
Published: January 2023

Abstract
Adoptive transfer of in vitro activated, tumor-specific CTL is a useful strategy for cancer immunotherapy. We compared in vitro culture conditions for ability to generate tumor-specific CTL that reject tumours in vivo, and for expression of molecular markers associated with effective anti-tumor activity. Specific CTL were obtained in short-term in vitro cultures of naïve CD8+ T cells and bone marrow DC loaded with peptide antigen, and were expanded in IL-2 for 2 days before transfer in vivo. The conditions of DC activation did not appear to affect the recovery, phenotype or effector function of cultured CTL, but had a substantial effect on the CTL’s ability to prevent tumour growth in vivo. Proteomic analysis of the total and surface proteome of different CTL populations was carried out using liquid chromatography and tandem mass spectrometry. Among more than 1,000 identified proteins, several were expressed with different abundance in CTL populations with varying anti-tumour activity. The functional significance of proteins showing the greatest differential expression is currently being examined using a combination of gene silencing and in vivo transfer studies. The identification of markers associated with effective anti-tumor function will provide useful means to understand and predict the functional activity of CTL populations for in vivo transfer.
Intratumoral delivery of liposome-anchored anti-CD137 and IL-2 induces highly potent local and systemic anti-tumor immunity while minimizing toxic inflammatory side effects (165.6)
Authors: Kwong Brandon , Liu Haipeng , Irvine Darrell 
Published: January 2023

Abstract
Immunostimulatory cytokines and antibodies induce potent anti-tumor immune responses in animal models, but also elicit dose-limiting systemic inflammatory toxicity, limiting their effectiveness in the clinic. To address this limitation, we developed a strategy to anchor immunotherapeutics to the surface of lipid nanoparticles (NPs), thus restricting their biodistribution following local injection. We previously demonstrated that NP-coupled anti-CD40 and CpG oligos significantly inhibited growth of s.c. B16F10 tumors, while minimizing systemic exposure to these agents and eliminating the symptoms of inflammatory toxicity associated with soluble agent delivery. Here we have modified this strategy to deliver NP-conjugated anti-CD137 and IL-2. Following local injection into established B16F10 tumors, NP-coupled anti-CD137 + IL-2 therapy enabled complete cure of the primary tumor in nearly 50% of mice and significantly delayed tumor progression in all mice, without systemic inflammatory effects. Importantly, anti-CD137/IL-2-NP therapy also delayed the growth of simultaneous distal untreated tumors, and induced the complete rejection of secondary tumor challenges in 100% of mice. Ongoing experiments are aimed at determining the cellular mechanisms of the combined local and systemic anti-tumor immune response. These results suggest that locally potent immunostimulation can drive systemic anti-tumor immunity without the severe toxicity typically associated with systemic therapy.
Immunomodulatory actions of lanthionine synthetase C-like protein 2-based drugs (165.9)
Authors: Lu Pinyi , Hontecillas Raquel , Viladomiu Monica , Pedragosa Mireia , Carbo Adri , Bevan David , Lewis Stephanie , Bassaganya-Riera Josep 
Published: January 2023

Abstract
Current inflammatory bowel disease (IBD) treatments are associated with significant side-effects. We identified lanthionine synthetase component C-like protein 2 (LANCL2) as a target for abscisic acid, a naturally occurring compound with potent anti-inflammatory effects. The goal of this study was to determine the role of LANCL2 as a therapeutic target for developing novel anti-inflammatory drugs. Structure-based virtual screening was performed using a compound library from National Cancer Institute Diversity Set II. To validate the anti-inflammatory efficacy of the top-ranking compound 61610, a series of in vitro and pre-clinical efficacy studies were performed using a mouse model of dextran sodium sulfate-induced colitis. Our findings showed that oral administration of 61610 (20 mg/kg/day) ameliorated experimental colitis by down-modulating colonic inflammatory gene expression and favoring regulatory T cell responses. We also investigated the cell specificity and molecular targets underlying the anti-inflammatory mechanism of 61610. Our in vivo findings indicate that anti-inflammatory efficacy of 61610 depends on macrophage expression of peroxisome proliferator-activated receptor γ, a receptor downstream of LANCL2. In summary, we used an integrated drug discovery platform consisting of molecular modeling approaches followed by experimental validation to confirm LANCL2 as a novel therapeutic target against IBD and demonstrated that 61610 is a novel anti-inflammatory drug.
Synthetic LbL microparticle vaccines containing the conserved T1BT* epitope of Plasmodium falciparum elicit protective antibody and cellular immune responses with minimal inflammation (166.11)
Authors: Powell Thomas , Tang Jie , DeRome Mary , Jacobs Andrea , Palath Naveen , Cardenas Edwin , Boyd James , Mitchell Robert , Nardin Elizabeth 
Published: January 2023

Abstract
Microparticle vaccines containing the conserved T1B repeat and T* epitopes from the P. falciparum CS protein were synthesized via layer-by-layer (LbL) fabrication on a solid core; microcapsules were prepared by dissolution of the particle core. Mice immunized with microparticles or microcapsules yielded T1B-specific antibody responses that neutralized Plasmodium parasite in vitro. The mice also developed T1BT*-specific cellular responses, including Th1, Th2, and CD4+ cytotoxic effector cells. When challenged with PfPb, a recombinant P. bergheii expressing the T1B repeats from P. falciparum, 70-80% of the mice immunized with microparticle, and 40-50% immunized with microcapsule, showed &gt;90% reduction in liver parasite burden compared to naïve challenged mice. A minority of mice with reduced parasite burden did not have potent PfPb-neutralizing antibody activity. Since depletion of either CD4+ or CD8+ cells prior to challenge did not ablate protection, the vaccine-induced protection appears to be primarily associated with antibody responses but may also involve other mechanisms not yet defined. An examination of cytokine and chemokine gene expression in the liver post-challenge did not reveal any evidence of inflammatory responses following LbL vaccination and PfPb challenge. These results demonstrate that synthetic LbL vaccines bearing the conserved T1BT* epitopes can elicit protective immunity against Plasmodium without triggering unwanted inflammatory responses.
Modulation of protection against Mycobacterium tuberculosis by adjuvants that elicit different T cell responses. (166.18)
Authors: Baldwin Susan , Bertholet Sylvie , Reese Valerie , Ching Lance , Reed Steven , Coler Rhea 
Published: January 2023

Abstract
The use of an adjuvant within a vaccine can influence and direct the immune response to enable a desired outcome. A T helper 1 (Th1) response, including antigen-specific production of interferon-gamma (IFN-γ), is needed to protect against Mycobacterium tuberculosis. A successful subunit vaccine should include not only an appropriate antigen but also a proper adjuvant to ensure that a Th1 mediated cellular response is induced. Only a few adjuvants have been approved for use in human vaccines such as Alum and oil-in-water (o/w) based emulsions, including MF59 (Novartis), AS03 (GSK Biologics), AF03 (Sanofi) and liposomes (Crucell). These adjuvants primarily induce humoral responses. A new adjuvant in approved products is AS04, which combines the TLR-4 agonist monophosphoryl lipid A (MPL) with Alum. In this study we combine our candidate TB vaccine, ID93, with a synthetic TLR-4 agonist, glucopyranosyl lipid adjuvant (GLA) mixed with a stable o/w emulsion (SE). Both SE and GLA-SE induce potent cellular responses when combined with ID93 in mice. ID93/GLA-SE induced multifunctional CD4+ Th1 cell responses (IFN-γ, TNF-α, IL-2) in mice and protected both mice and guinea pigs against M. tuberculosis. In contrast, ID93/SE in the absence of GLA induced IL-5 and provided no protection, as assessed by bacterial burden, survival, and pathology. These results demonstrate the importance of properly formulating subunit vaccines with effective adjuvants for use against TB.
A zebrafish model to develop DNA-based vaccines - identification of cdh as a protective antigen against mycobacterial disease (166.19)
Authors: Rämet Mika , Oksanen Kaisa , Harjula Sanna-Kaisa , Halfpenny Nicholas , Milka Vuoksio , Pajula Elina , Parikka Mataleena 
Published: January 2023

Abstract
Mycobacterium tuberculosis, the causative agent of human tuberculosis, is an intracellular pathogen killing nearly two million people annually. The current live vaccine is controversial and thus novel preventive approaches are needed. DNA vaccines represent an alternative for immunizing against tuberculosis. As a vertebrate model organism with a fully developed immune system, zebrafish (Danio rerio) presents itself as an attractive and ethical option for screening novel vaccine antigens. Here we show that antigens can be expressed in the adult zebrafish as DNA-based vaccines. Furthermore, introduction of DNA plasmids expressing a combination of three previously characterized mycobacterial antigens (Ag85B, ESAT-6, CFP-10) was protective against M. marinum challenge in adult zebrafish. Using a low-dose intra peritoneal infection with 19-28 bacteria, both the number of granulomas and the amount of affected organs were reduced. Likewise, using a lethal infection dose of 20,000 cfu, vaccination significantly reduced both mortality and bacterial counts. In addition, a putative diacylglycerol pyrophosphatase cdh was protective against lethal M. marinum infection with 25, 000 cfu decreasing mortality by more than 50% compared to controls. In summary, DNA-based vaccination protects adult zebrafish against experimental Mycobacterium marinum infection and cdh is a promising novel protective antigen in this model.
Oral polio vaccination failure in urban slum children is associated with malnutrition and evidence of chronic inflammation (166.2)
Authors: Newell Evan , Sigal Natalia , Haque Rashidul , Kidd Brian , Tse Tiffany , Petri William , Davis Mark 
Published: January 2023

Abstract
Oral vaccines for polio (OPV) and rotavirus have been shown to be much less effective in poor children in the developing world. The reason(s) for oral vaccine failure in this setting has been unknown. We hypothesized that failure of orally administered vaccines such as OPV was due to tropical enteropathy and resultant inflammation from endotoxin exposure. We tested this hypothesis in a cohort of children followed from birth in an urban slum of Dhaka Bangladesh. Response to oral poliovirus vaccine was measured in the children who received the recommended minimum of three doses of OPV by age 6 months. Diminished antibody responses to OPV were associated with malnutrition, serum endotoxin-specific antibodies, and shorter breastfeeding duration. In a subset of these children, we investigated the mechanism for vaccine failure using a systems-immunology approach, performing comprehensive cellular assays on peripheral blood mononuclear cells, including a single-cell mass-spectrometry based assessment of cellular phenotypes and functional capacities. From this analysis, children with vaccine failure exhibited globally reduced cellular responsiveness to a range of cytokine stimulations, as well as elevated pro-inflammatory cytokine expression. These data indicate that oral vaccine failure in this at-risk group is related to malnutrition, gut barrier dysfunction and shorter duration of breast-feeding in early childhood, and is associated with a chronic inflammatory immune phenotype.
Adaptive immunity against Francisella tularensis elicited by an adenovirus-based vaccine (166.21)
Authors: Zeng Mingtao , Kaur Ravinder , Chen Shan , Arévalo Maria , Xu Qingfu , Chen Yanping 
Published: January 2023

Abstract
Francisella tularensis is a highly infectious organism that causes tularemia. A live attenuated vaccine strain (LVS) has been developed, but it has not been licensed for public use by the FDA due to safety concerns. Thus, there exists a need for a safer and improved vaccine. In this study, we have constructed a replication incompetent adenovirus, Ad/opt-Tul4, encoding a codon-optimized gene for expression of the membrane protein, Tul4, of LVS. Its ability to protect against lethal challenge and its immunogenicity were evaluated in a murine model. An intramuscular injection of a single dose (1×107 PFU) of Ad/opt-Tul4 elicited a robust Tul4-specific antibody response. Assays suggest a Th1-driven response. A single dose elicited 20% protection against challenge with 100×LD50 LVS; two additional boosters resulted in 60% protection. In comparison, three doses of 5µg recombinant Tul4 protein did not elicit significant protection against challenge. Therefore, the Ad/opt-Tul4 vaccine was more effective than the protein vaccine, and protection was dose-dependent. Compared to LVS, the protection rate is lower, but an adenovirus vectored vaccine may be more attractive due to its enhanced safety profile and potential mucosal delivery. Furthermore, simple genetic modification of the vaccine may potentially produce antibodies protective against a fully virulent strain of F. tularensis. Our data support the development and further research of an adenovirus-based vaccine against tularemia.
Vaccination with a novel Yersinia pestis single component, two-valent LcrV-F1 vaccine protects against lethal intranasal challenge. (166.23)
Authors: Parent Michelle , Guth Kerri , Waters Stephanie , Chichester Jessica 
Published: January 2023

Abstract
Yersinia pestis, a category A select agent is the causative agent of pneumonic plague. Currently, an effective vaccine has yet to be developed to protect against pneumonic infection therefore, Y. pestis weaponization and aerosolization is considered a bioterrorism threat. Here, we investigated the efficacy of a novel plague vaccine containing the low-calcium-response V ( LcrV) and the Fraction 1 capsular (F1) proteins, expressed as fusions to the thermostable lechinase enzyme (LicKM) of Clostridium thermocellum and purified from Nicotiana benthamiana plants. BALB/c mice primed and boosted with 1μg of this single component two-valent LcrV-F1 vaccine in alhydrogel provided protection against a lethal intranasal challenge with Y. pestis KIM D27. We determined this protection was antibody mediated as vaccination generated high IgG antibody titers. Additionally, adoptive transfer of serum from vaccinated mice to naïve mice protected against a lethal challenge while treatment of this serum using a Protein G column negated this serum-mediated protection. In order to determine if this vaccination regimen also resulted in memory T cell production, CD4 T cells isolated from vaccinated mice and subjected to in vitro restimulation with either LcrV or F1-LicKM fusion resulted in IL-2 production. Here, we have determined that vaccination using this novel LcrV-F1 LicKM fusion results in humoral immunity and protection against lethal Y. pestis KIM D27 infection.
Adjuvanted influenza vaccines in young and aged BALB/c mice (166.25)
Authors: Yam Karen , Gupta Jyotsana , Allen Elizabeth , Ward Brian 
Published: January 2023

Abstract
Although the available influenza vaccines are generally safe, they are far from ideal. They have reduced efficacy in the most at risk groups: the very young and the elderly. To address such concerns, the vaccine industry is increasingly turning its attention to the use of adjuvants to enhance the immune responses generated by these vaccines. During the 2009 pandemic H1N1 influenza outbreak, an adjuvanted influenza vaccine was selected for administration to Canadians; it was formulated with the oil-in-water adjuvant AS03 and consisted of 1/4 the usual antigen dose of vaccine. This study investigated the immune responses generated following immunization with adjuvanted influenza vaccines in aged and young mice. We tested two ages of BALB/c mice (2 months, 1.4 years), two doses of Influenza A/Uruguay H3N2 split vaccine (0.75ug, 3ug), and two adjuvants (alhydrogel, AS03). The use of an adjuvant increased serum HAI titers compared to vaccination with unadjuvanted vaccine. We found no significant difference in using the high dose of vaccine antigen with both adjuvants. At the low dose of vaccine, the AS03 adjuvant gave significantly higher HAI titers in both age groups. Finally, aged mice given a low dose of the AS03-adjuvanted split vaccine showed significantly lower HAI titers than young mice. We are identifying additional differences between the immune responses of young and aged mice with an overall goal to be able to design more effective vaccines, especially for the elderly.