bluuebunny/crossref_metadata_2025_split huggingface dataset:
Induction of Innate Immune Factor Expression in A549 Lung Alveolar Type II Cells by Cytokines Interferon-g and Tumor Necrosis Factor-α
Authors: Gutierrez Lucas , Yoon Alexander , Faull Kym Francis , Porter Edith 
Published: January 2023

Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), continues to be a detrimental infectious disease that is estimated to infect one third of all people worldwide. The lack of TB control is in part due to the lack of protection of adults from the existing TB vaccine as well as an urgent need for novel vaccine design. Vaccines rely in part on interferon-γ (IFNγ), a cytokine secreted by T helper (TH) cells, which has been shown to be an important component of the adaptive host defense against Mtb. Tumor Necrosis Factor-α (TNFα) is also secreted by TH cells and has demonstrated protective effects on epithelial cells by increasing secretion of proinflammatory cytokines, chemokines such as IL-8, and antimicrobial effector molecules. We hypothesize that IFNγ and TNFα also affect expression of antimicrobial lipids including cholesteryl esters. A549 Alveolar Type II cells were stimulated with IFNγ and TNFα for 24 h. Gene expression of the IL-8, and sterol O-acyltransferase-1 (SOAT-1), a key enzyme for cholesteryl ester synthesis, was quantified by RT-PCR and SYBR green technology using ribosomal protein, large, P0 (RPLP0) as a reference gene. Cholesteryl esters in lipid extracts from culture supernatants were quantified by mass spectral analysis with multiple reaction monitoring. Our results showed a statistically significant upregulation of IL-8 and SOAT-1 gene expression in response to INFg (5 ng/mL) and for SOAT-1 to TNFa (10 ng/mL) (p &lt; 0.05 in OneWay ANOVA), which was accompanied by increased cholesteryl ester content. Augmentation of epithelial antimicrobial lipid production by cytokines from resident TH cells may be incorporated in a novel vaccine design against Mtb.
Immunization with synthetic LbL microparticle vaccine administered using a microneedle patch elicits humoral and cellular immune responses and protects mice from challenge with respiratory syncytial virus
Authors: Powell Thomas Jeff , Mistillis Matt , Palath Naveen , Tang Jie , Jacobs Andrea , Cardenas Edwin , Boyd James G. , Prausnitz Mark 
Published: January 2023

Abstract
Synthetic vaccines made by layer-by-layer fabrication of microparticles (LbL-MP represent a novel method of delivering peptide antigens to elicit protective immune responses in the absence of complex adjuvant and without concomitant inflammation. We incorporated LbL-MP into a microneedle patch that delivers the vaccine directly to the immunologically rich environment of the skin in a minimally-invasive manner. BALB/c mice immunized with microneedle patches loaded with LbL-MP bearing two conserved epitopes of respiratory syncytial virus (RSV) generated humoral and cellular immune responses and were protected from virus challenge. The vaccine contained a conserved CX3C chemokine mimic epitope from the RSV attachment (G) protein that contributes to Th2-skewed inflammatory responses. Patch-immunized mice developed RSV-G-specific antibody titers comparable to the titers induced by direct injection of the vaccine into the footpad. The mice developed T-cell responses, including effector CTL, against a CD8 epitope of the RSV-M2 protein included in the vaccine. While footpad injection elicited both Th2 (IL-5) and Th1 (IFNγ) responses, microneedle patch immunization elicited a dominant Th1 response with very low Th2 response. A similar pattern of Th1&gt;Th2 was seen in C57BL/6 mice immunized with a patch loaded with LbL-MP containing epitopes of the P. falciparum circumsporozoite protein, suggesting that the Th1 dominance was not antigen- or strain-specific, but rather an outcome of LbL-MP microneedle patch immunization. These studies demonstrate that LbL-MP retain their integrity and potency when delivered via microneedle patch, and favor Th1 immune responses that may be more effective against acute infection.
Parainfluenza virus spread into the lower respiratory tract of immunocompromised hosts: Antibodies but not G-CSF reduce viral load and accelerate clearance
Authors: Mostafa Heba , Vogel Peter , Srinivasan Ashok , Russell Charles J 
Published: January 2023

Abstract
In immunocompromised patients, parainfluenza virus (PIV) infections have a higher potential of spread to the lower respiratory tract (LRT), increasing morbidity and mortality. Understanding the immunological defects that facilitate the spread of the infection to the LRT among high-risk populations will help developing better management protocols. In this study, we suppressed the immune system in mice using the widely used anti-leukemic drugs: dexamethasone and/ or cyclophosphamide. We monitored the spread of viral infection into the LRT by non-invasive bioluminescence imaging system using a reporter Sendai virus (murine PIV type 1). Our results show immunosuppression leads to a delay in clearance of infection and higher lung viral loads. A rebound in the peripheral neutrophils counts coincided with initiation of viral clearance. However, treatment of immunosuppressed mice with neutrophil-specific antibodies to delay neutrophil rebound did not delay clearance, and treatment with G-CSF to increase neutrophils counts did not accelerate clearance. On the other hand, treating immunocompromised mice with either Sendai virus-specific polysera or monoclonal antibodies reduced viral progression to the lung and accelerated viral clearance. This study demonstrates the strength of non-invasive bioluminescence in both studying respiratory viral progression and evaluating candidate intervention strategies. The findings challenge the potential benefit of using G-CSF in PIV pneumonia and suggest a therapeutic potential of virus-specific antibodies.
Blood microRNAs correlate with plasma cytokines and clinical severity in patients infected with Influenza B and Rhinovirus/Enterovirus.
Authors: Rosas-Taraco Adrian Geovanni , Arredondo-Loza Erick Roel , Martinez-Castilla Azalia M. , Mata-Tijerina Viviana Leticia , Salinas-Carmona Mario C 
Published: January 2023

Abstract
Acute respiratory infections (ARI) are the leading causes of infectious disease morbidity and mortality in the world. Two of the most common etiological agents are Influenza B virus (IBV) and Human Rhinovirus (HRV). The IBV is responsible for about 25% of laboratory-documented influenza; meanwhile HRV is responsible for 33% to 50% of common cold cases in adults. Little is known about immunological biomarkers in the early stages of the infection caused by this RNA virus and their possible association with symptoms in those patients. The aim of this study was to identify miRNAs and their correlation with cytokines and clinical severity. Adult patients clinically diagnosed with ARI were sequentially recruited from Medical Service and University Hospital of Universidad Autonoma de Nuevo Leon. The study was conducted with approval of the bioethics committee of the School of Medicine of the Universidad Autonoma de Nuevo Leon. Virus was detected by Luminex xTAG RVP kit, levels of nine miRNAs and twenty six plasma cytokines were analyzed by RT-qPCR and multiplex immunoassay, respectively. The severity of symptoms was daily monitored throughout seven days by surveys. The IBV-positive patients showed lower expression levels of miR-146, miR-16 and increased levels of CCL20 when compared with non-IBV. HRV/Enterovirus(EV)-positive patients showed lower expression levels of miR-132, miR-146 and miR-29. Expression levels of miRNAs and plasma cytokines correlated with symptoms severity in both patient groups. In conclusion, our findings suggest that blood miRNAs and plasma cytokines may regulate systemic immune response against IBV and HRV/EV and many of them may be associated with symptoms severity.
Macrophage Bcl6 expression promotes viral dissemination and host inflammation during influenza infection
Authors: Yao Shuyu , Jiang Li , Lu Qingbo , Dent Alexander L. , Sun Jie 
Published: January 2023

Abstract
The role of Bcl6 in regulating anti-viral immune responses is relatively unclear currently. Further investigation was hindered by the development of lethal inflammation in global Bcl6 deficient mice. To circumvent this and explore the cell type-specific role of Bcl6 in regulating anti-viral immunity, we have generated myeloid cell-specific Bcl6 deficient mice (Bcl6 cKO) by crossing Bcl6 fl/fl mice to LysMcre mice. In contrast to global Bcl6 deficient mice, Bcl6 cKO mice exhibited no signs of autoimmunity and tissue inflammation under homeostatic conditions. Using a murine influenza A/PR8 (IAV) infection model, we found that Bcl6 cKO mice showed drastically increased host resistance to IAV. We observed that although airway virus titers are comparable between control and Bcl6 cKO mice, Bcl6 cKO mice had greatly diminished IAV spreading in the lungs. Correspondingly, Bcl6 cKO mice developed milder pulmonary inflammation compared to control mice, characterized by the decreased levels of airway cytokines/chemokines and diminished inflammatory cell infiltration into the lungs. Interestingly, alveolar macrophage depletion abrogated the phenotype of decreased host morbidity and mortality to IAV infection in Bcl6 cKO mice, suggesting that Bcl6 deficiency in tissue resident alveolar macrophages mediates the effects of enhanced host resistance to IAV infection. Together, our data suggest that Bcl6 expression in lung resident macrophages dampens the efficient development of pulmonary anti-viral immune responses. Current studies are focused on the cellular and molecular mechanisms by which macrophage Bcl6 expression inhibits host innate and adaptive immunity during IAV infection.
Role of T cell receptors in suppressing HIV infection in elite controllers
Authors: Joglekar Alok , Lamothe Pedro A , Ouyang Yong , Liu Zhe , Walker Bruce D , Baltimore David 
Published: January 2023

Abstract
Virtually all HIV-infected patients progress to AIDS if not treated. A group of patients, called Elite Controllers (ECs), can suppress HIV infection without treatment. This ability of ECs is, in part, due to potent CD8+ T cell (CTL) responses against HIV epitopes presented by human leukocyte antigen (HLA) molecules. In this study, we focused on CTL responses restricted to HLA-B27, an allele that is enriched in ECs, but is not sufficient for protective ability. In HLA-B27+ ECs or non-controllers (NCs), immunodominant CTL responses specific to the KK10 epitope in Gag are found. Previous studies have shown that unlike NCs, B27-KK10-specific CTLs from ECs are efficient at eliminating HIV-infected or KK10-peptide pulsed cells. As the potency of CTLs can be modulated by their T cell receptor (TCR), we hypothesized that B27-KK10-specific TCRs play a significant role in suppressing HIV in ECs. Therefore, we cloned B27-KK10-specific TCRs from ECs or NCs, expressed them in primary T cells, and tested their cytotoxicity. We incubated TCR-transduced T cells with either HIV-infected or KK10-peptide pulsed target cells and measured target cell lysis. Unexpectedly, EC-TCRs were not significantly different than NC-TCRs in their cytotoxicity. We then tested the ability of these cells to suppress HIV in humanized mice and found no significant difference between EC- and NC-TCRs. We are currently investigating various aspects of these TCRs such as cross-reactivity to variants of KK10. The result that TCRs from ECs and non-controllers do not recapitulate the phenotype of CTLs is intriguing and warrants further studies to uncover the mechanism of immunologic control of HIV. Our studies also have implications in immunotherapy and vaccine approaches for HIV.
MCMV-specific salivary gland CD8+ TRM cells are formed independently of viral infection of the salivary gland, CD4+ T cell help or CXCR3, but can be transiently boosted by restimulation.
Authors: Dantas Sofia Caldeira , Smith Corinne , Quinn Michael , Snyder Christopher M. 
Published: January 2023

Abstract
The salivary gland is a mucosal site of cytomegalovirus (CMV) replication, persistence, latency and shedding. Using the murine (M)CMV model, we found that MCMV-specific CD8+ T cells localized to the salivary gland within 7 days of infection and adopted a tissue-resident memory (TRM) phenotype by day 14. This timing correlates with viral replication in the salivary gland leading us to hypothesize that viral infection promoted TRM development. However, we found that MCMV-specific TRM developed normally in the salivary gland regardless of the route of infection or the presence of replicating virus. Despite the induction of the chemokines CXCL9 and CXCL10 by salivary gland infection, MCMV-specific TRM developed independently of the chemokine receptor CXCR3 on CD8+ T cells. In fact, salivary gland TRM formed even when activated T cells were transferred into MCMV-naive mice. Moreover, CD8+ TRM were formed independently of CD4+ T cells, which control of MCMV in the salivary gland. These data suggest that T cell activation programs T cells to migrate to the salivary gland, irrespective of local infection or inflammation. Interestingly, the overall numbers of salivary gland TRM were remarkably consistent in these experiments, which could suggest that space was limited in the salivary gland for TRM cells. We found that we could markedly boost the numbers of MCMV-specific TRM by restimulating circulating T cells with a peptide delivered I.V.. However the numbers of salivary gland TRM were only elevated transiently and declined to normal levels over time. Together, these data suggest that salivary gland TRM are formed readily upon antigen stimulation, but that maintenance of TRM in the salivary gland is subject to homeostatic limitations.
Biological Activities of IL-15 superagonist - IL-15 Mutein:IL-15RaFc complex following Intravenous or Subcutaneous Administration
Authors: Liu Bai , Kong Lin , Jones Monica , Noel Terra , Han Kaiping , Rhode Peter R , Jeng Emily K , Cai Weibo , Wong Hing C 
Published: January 2023

Abstract
ALT-803 is a fusion protein complex consisting of IL-15N72D superagonist and a dimeric IL-15 receptor alpha (IL-15Rα) sushi domain IgG1 Fc fusion protein. When administered to mice, ALT-803 is capable of inducing NK and CD8+ T cell proliferation and activation, as well as potent antitumor responses. ALT-803 is currently in clinical studies using an intravenous (iv) route of administration. We were interested in exploring treatment regimens using subcutaneous (sc) administration of ALT-803 as an alternative to iv administration in order to lessen the adverse side effects that were observed. In this study, we compared the pharmacokinetics, immunostimulation, and anti-tumor efficacy of iv and sc administration of ALT-803 in C57BL/6 mice. We found the half-life of ALT-803 to be 7.5 hrs for iv administration vs. 7.7 hrs for sc. The maximal detected serum concentration of ALT-803 was 495 ng/ml at 16 hr time point following sc administration or 3926 ng/ml at 0.5 hr time point following iv administration. Similar bio-distribution of radio-labeled ALT-803 in mice was observed using quantitative PET-scan studies. We also demonstrated that ALT-803 administered iv or sc induced comparable proliferation of CD8+ T cells and NK cells and similarly activated immune cells which resulted in the reduction of tumor burden. A toxicity study of mice receiving multiple injections of ALT-803 for 4 weeks by iv or sc administration revealed that comparable immune system-related changes were observed and ALT-803 was well tolerated. The gradual absorbance into blood stream and lower maximal blood level of ALT-803 in sc injected mice, along with similar antitumor efficacy supports the use of ALT-803 by sc administration in patients with metastatic malignancies.
IL-2 functionalized hydroxyethylstarch nanocapsules for targeting of human T cells with different IL-2 receptor affinities in vitro and in vivo
Authors: Domogalla Matthias Philipp , Wurm Frederik Robert , Mailänder Volker , Landfester Katharina , Steinbrink Kerstin 
Published: January 2023

Abstract
Cell type specific delivery of drugs by use of nanocapsules (NC) is a promising approach for induction of efficient anti-tumor immunotherapies. Here, we report the generation of IL-2 functionalized NC (HES-IL-2) to target CD25+ (IL-2 receptor α chain) T cells. In flow cytometry experiments HES-IL-2 exhibited an enhanced uptake by human CD25+ T cells compared to control capsules. The observed uptake was CD25 specific as CD25high T cells displayed a significantly enhanced NC incorporation compared to CD25− T cells with negligible internalization. In addition blocking of the IL-2 receptor dependent binding by an anti CD25 mAb significantly reduced the HES-IL-2 uptake by human CD25+ T cells. Furthermore, comparing and competitive studies of naïve CD25−, activated CD25+ and regulatory CD25high human T cells revealed a low incorporation of HES-IL-2 in naïve and a moderate and high uptake, respectively in activated or regulatory T cells. Additionally, in order to preferentially address different T cell populations by means of various IL-2 receptor affinities, we generated HES-IL-2 with distinct reduced amounts of IL-2 on their surface. Intriguingly, in contrast to naïve CD25− and activated CD25+ T cells, in which the NC uptake was clearly IL-2 dose-dependent we did not observe any differences when HES-IL-2 with a twofold and tenfold decreased amount of IL-2 were used for studies with regulatory CD25high T cell, indicating a high IL-2 sensitivity of regulatory T cells for a specific targeting. In addition, in vivo studies in human T cell reconstituted RAG2−/−γc−/− mice exhibited a significantly enhanced uptake of HES-D-IL-2 by CD25+ T cells. In summary, we generated IL-2 functionalized NC for targeting of human CD4+CD25+ T cells in vitro and in vivo.
Mkp-1 deficiency strengthens immune defense against fungal infection
Authors: Liu Yusen , Crowell Sara A. , Tang Juan , Kim Victoria Y. , Nelin Leif D. , Zhang Jian 
Published: January 2023

Abstract
Fungal infections are a serious threat to people with a compromised immune system. The initiation of an immune response toward fungal pathogens relies on the recognition of fungal molecular patterns through pathways mediated by TLRs and C-type lectin receptors. Activation of these pathways converges on both NF-κB and MAPKs to initiate cytokine and chemokine production, leading to recruitment of inflammatory/phagocytic leukocytes and pathogen elimination. Mkp-1 is a negative regulator of the innate inflammatory response triggered by pathogen recognition, acting to attenuating cytokine production by deactivating p38 and JNK. To understand the role of Mkp-1 in immune defense against fungal pathogens, we assessed the effects of Mkp-1 deficiency on the immune response to C. albicans, the most common fungal pathogen. Contrary to our previous observation with bacterial pathogens such as E. coli or bacterial products such as LPS, Mkp1−/− mice were protected from infection with a lethal dose of C. albicans, which correlates with lower kidney fungal burdens. In response to C. albicans challenge, Mkp1−/− mice produced greater TNF-α. Interestingly, in response to heat-killed C. albicans yeasts and hyphae Mkp-1−/− macrophages also produced significantly greater amounts of TNF-α and had markedly higher p38 and JNK activities than did wildtype macrophages. TNF-α production in both wildtype and Mkp1−/− macrophages in response to heat-killed C. albicans (both yeast and hypha forms) was attenuated by the specific inhibitors of MEK1, JNK, and p38 as well as Syk. Taken together, our results suggest that during fungal infection Mkp-1 acts to restrain the production of cytokines and thus hamper the immune response against fungal infections.
Cytotoxic T lymphocytes in channel catfish, Ictalurus punctatus, can express an inhibitory immunoglobulin-binding receptor
Authors: Spencer David A , Bengtén Eva , Nayak Deepak K , Wilson Melanie 
Published: January 2023

Abstract
Surface immunoglobulin (Ig)-binding receptors, i.e. Fc receptors (FcRs), are well characterized in mammals and play both activating and inhibitory roles in immune cell responses, however how they function in teleosts is less well understood. Here we report an inhibitory IgM-binding receptor on catfish cytotoxic T lymphocytes (CTL). Briefly, flow cytometric analysis revealed a morphologically defined subset of clonal CTL that can express a surface IgM-binding receptor. Chromium release and cell membrane labeling assays reveal that cells within this subset are unable to kill allogeneic target cells. After activation with alloantigen, however, these CTL downregulate the IgM-binding receptor, replicate, and efficiently kill target cells. Importantly, cross-linking the IgMbinding receptor with anti-catfish IgM mAb resulted in cell cycle arrest in the G1/G0 phase with fewer cells transitioning to the cytotoxic effector morphology. Co-immunoprecipitation of surface-biotinylated CTL with anti-catfish IgM identified putative receptor components of 38, 52, and 75 kDa. To identify the protein(s), these gel bands are being analyzed by LC-MS/MS, and Ig-binding of candidate proteins will be examined using transfected insect cells. Overall, this Ig-binding receptor is expressed on &gt;95% of cells in CTL cultures that can no longer be activated to kill target cells. Thus the presence of this receptor may provide a marker for functionally exhausted catfish CTL.
Impaired T cell immunity in the elderly via N-glycosylation
Authors: Hayama Ken L , Khachikyan Khachik , Mkhikian Haik , Li Carey F , Zhou Raymond W , Klaus Suzi , Ly Kim M , Gong Andrew D , Raffatellu Manuela , Demetriou Michael 
Published: January 2023

Abstract
Aging is associated with a decline in immune function, increasing the frequency and severity of infection in the elderly. We have previously shown that Asparagine (N) – linked protein glycosylation is a critical negative regulator of T cell immunity in both mice and humans. Here we report N-glycan branching in T cells increases with age, leading to T cell hypo-activity and increased susceptibility to infection. Reducing N-glycan branching rejuvenates T cell activation, proliferation and pro-inflammatory TH17 over anti-inflammatory Treg differentiation in aged T cells. Susceptibility of aged mice to Salmonellae typhimurium invasion/dissemination was reduced by lowering N-glycan branching. A critical metabolic precursor of N-glycosylation and branching is N-acetylglucosamine (GlcNAc), a common amino sugar that is part of the regular human diet. GlcNAc is endogenous to human serum, increases with age and correlates with N-glycan branching in T cells. T cell specific deletion of N-acetylglucosamine kinase, thereby blocking salvage of GlcNAc into N-glycans, reduces branching in aged T cells and rejuvenates T cell activation. Collectively, our results suggest that age-dependent increases in N-glycan branching, via increased supply of GlcNAc, impairs T cell immunity in the elderly. Therapeutic inhibition of N-glycan branching may provide a novel mechanism to rejuvenate T cell responses and reduce infection risk in the elderly.