bluuebunny/crossref_metadata_2025_split huggingface dataset:
Just in Time Teaching (JiTT) Strategies: From Implementation to Student Buy-in
Authors: Brown Deborah M , Brazeal Kathleen R. , Couch Brian A. 
Published: January 2023

Abstract
The Vision and Change in Undergraduate Biology Education calls for a transformation in instructional practices toward a more student-centered learning environment. Students in immunology courses can benefit from these strategies and one such approach, known as Just-in-Time Teaching (JiTT), is an inquiry based, active learning tactic that has been shown to enhance student retention of complex concepts. Prior to class, students read assignments and answer specific conceptual questions that involve linking new material or ideas with previously learned concepts. Importantly, an open-ended, reflective question is also asked about what students found most interesting, confusing, or difficult about the assignment. JiTT assignments have a positive impact on learning by allowing students to prepare ahead and use real life applications to better understand the material. Accordingly, the most successful JiTT assignments are questions based on the Case Studies in Immunology, 7th edition (Raif Geha and Luigi Notarangelo), that indicate which concepts are being discussed for each case. Overall, the JiTT approach has been well-received for upper level Immunology students. Results from formative assessment surveys generated by discipline based educational researchers (DBER) in our department in 2017 and 2018 indicate that most students understand the value of JiTT to enhance their learning, however, some students believe that assessments should always come after lecture, not before. Students agree that JiTT questions give them feedback on what material is important and what they still need to learn. Utilizing these surveys will help improve the messaging, learning intentions and overall student buy-in for future iterations of the course.
Post-traumatic pulmonary infection: the innate immune response protects the lung at the expense of the healing cutaneous wound
Authors: Crane Meredith , Xu Yun , Monaghan Sean F. , Hall Benjamin M. , Tran Holly L. , Henry William L , Albina Jorge E. , Jamieson Amanda M. 
Published: January 2023

Abstract
Hospitalized trauma patients have an increased risk of pulmonary infection. The acute response to injury, which relies on the coordinated activity of recruited leukocytes, may affect the early, innate immune-mediated control of lung infection. We hypothesized that a cutaneous wound would inhibit the ability of innate leukocytes to respond to a subsequent pulmonary bacterial infection. To address this, we developed a murine model of post-injury pneumonia. Mice were wounded by the dorsal subcutaneous implantation of polyvinyl alcohol sponges, which models the acute stages of wound repair, and a cohort was infected intranasally with the opportunistic bacterium Klebsiella oxytoca. For comparison, a control group was only infected. Wounding did not alter the early control of lung bacterial infection, the infiltration of innate leukocytes into the infected lung, or cytokine and chemokine levels in the bronchoalveolar lavage fluid. In contrast, pulmonary infection suppressed wound healing, caused decreased monocyte and neutrophil trafficking and lower cytokine and chemokine concentrations in the wound. Exogenous delivery of CCL2 and CXCL1 to the wound increased the number of neutrophils and accelerated healing. However, this led to increased pulmonary bacterial burden, highlighting the balance of cellular responses required to protect the lung. These data suggest that the innate immune system prioritizes the protection of one site above the other when faced with competing inflammatory insults. Here, early control of lung infection took priority over the healing wound. This work aims to elucidate mechanisms by which the innate immune system responds to multiple insults, which may be broadly applicable to inflammatory conditions.
Role of pulmonary innate immune memory leukocytes in the repeated respiratory infection of Influenza A virus
Authors: li nan 
Published: January 2023

Abstract
In recent years, innate immune memory and inflammation have become the frontier hot research fields in the host anti-infection field, especially in the respiratory infection of respirovirus, such as the influenza A virus. However, the fundamental and important scientific issues in the field of innate immune memory and inflammation remains poorly understood, such as the mechanism of pathogen-host interaction under acute and chronic infection in the infected upper respiratory track and lower respiratory track, and the way by which innate immune cells ( dendritic cells, monocytes/macrophages, NK cells, etc. ) acquire immune memory. Platelet chemokines CXCL4/5 play roles in mouse respiratory infection of bacteria or influenza A virus and also have regulatory effects on immune/inflammatory response in the infected lungs. Here studies on exploring the function and molecular mechanism of CXCL4/5 in inflammatory memory under IAV primary and repeat infection were conducted using CXCL4/5 knockout mice and wild-type mice by means of FACS, ATAC-seq, immunohistochemistry, mass cytometry and viral quantification. Data revealed that NK cells, NKT cells and macrophages have different inflammatory memory functions in repeated infection, and can be rapidly activated to play the function of anti-virus infection to protect the body. This memory function is due to epigenetic modification of genetic chromosome of the above leukocytes. Our results indicate that influenza-induced innate immune memory of NKT cells and macrophages play critical roles in anti-influenza repeat infections.
HIV infection associated oxidation of innate immune proteins in the human lung mucosa alters the host response to Mycobacterium tuberculosis infection
Authors: Akhter Anwari , Olmo-Fontánez Angélica , Moliva Juan , Azad Abul , Kelley Holden , Scordo Julia , Gavrilin Mikhail , Wewers Mark , Torrelles Jordi 
Published: January 2023

Abstract
Tuberculosis (TB) is the leading killer of people with HIV infection. Limited studies have considered HIV infection associated changes to the soluble components of the innate immune system in the alveolar lining fluid (ALF) as a contributing factor to increased susceptibility to pulmonary infections. We hypothesize that altered function of soluble innate immune components in human ALF of HIV infected subjects, drives susceptibility to primary M.tb infection. Here, we analyzed levels and functions of various soluble innate immune molecules present in human ALF from both healthy and HIV infected subjects. We also examined the effects of ALF components from HIV positive subjects on M.tb infection of human macrophages in vitro. Our results indicate an increased oxidation of innate proteins within ALF from HIV positive subjects not treated with anti-retroviral therapy (ART). We also found that complement components and some Th1 and Th2 cytokines/chemokines significantly differed between ALF from HIV positive and healthy subjects. Moreover, we found a deficiency of binding of surfactant protein-D to M.tb in ALF from HIV positive subjects, suggesting a defective innate immune function in the lung with HIV infection. Macrophages infected with M.tb exposed to ALF from HIV positive subjects without ART were less capable of controlling the infection. Our studies provide new information on how HIV infection could modify lung mucosal innate immune responses, thereby impacting M.tb infection and potentially other pulmonary diseases in the HIV infected population without ART treatment. Our data suggest that M.tb may benefit from the declining host innate defense function of the lung mucosa during HIV infection.
Age and HIV perturb the TB Immunity in Regulatory and Cytotoxic Subpopulations of NKT cells
Authors: Nishiguchi Tomoki , Mtetwa Godwin , Kay Alexander , Maphalala Gugu , Mace Emily , Mandalakas Anna M , DiNardo Andrew R 
Published: January 2023

Abstract
In the pre-antibiotic era, ~20% of Tuberculosis (TB) patients overcame the disease without therapy, implying host immunity can sometimes control disease. The risk of disease progression is higher among HIV-infected individuals and children, therefore we evaluate how HIV and age alter the balance of cytotoxic versus immune regulatory NKT immune phenotype in individuals with TB and latent Mycobacterium tuberculosis infection (LTBi). We evaluated the NKT immune response from 49 individuals with TB (25 HIV-infected) and 48 with asymptomatic LTBi (14 HIV-infected). Using flow cytometry based multi-dimensional immune profiling, we analyzed the expression level of previously described determinants of NKT cytotoxicity (CD3dim) and immune regulatory (CD3bright) phenotype and function. CD3bright NKT cell population was correlated with age during children TB (p = 0.002). This cell type had increased in adults with TB (p = 0.034), but not in children. Also, high level of perforin producing CD3bright NKT cells had increased in adults with TB compare to adults with LTBi (p = 0.004). On the other hand, CD3dim NKT cell had no age correlation nor difference between TB and LTBi participants. While HIV-infected LTBi individuals had decreased perforin production in CD3dim NKT cells (p = 0.012). CD3bright and CD3dim NKT sub-populations previously reported influence regulatory versus cytotoxic function. We demonstrate that age and HIV status of participants have effected to regulatory and cytotoxic function, respectively. This suggested that these two factors have different mechanisms, decreasing perforin high producing CD3bright NKT cells and decreasing perforin production in CD3dim NKT, which promote TB disease progression.
Ketogenic diet activates protective γδ T cell responses against influenza virus infection
Authors: Goldberg Emily Lauren , Molony Ryan , Sidorov Sviatoslav , Kudo Eriko , Dixit Vishwa Deep , Iwasaki Akiko 
Published: January 2023

Abstract
Influenza A virus (IAV) infection-associated morbidity and mortality are a key global healthcare concern, necessitating the identification of novel therapies capable of reducing the severity of IAV infections. In this study, we show that the consumption of a low-carbohydrate, high-fat ketogenic diet (KD) protects mice from lethal IAV infection and disease. KD feeding resulted in an expansion of γδ T cells in the lung that improved barrier functions, thereby enhancing anti-viral resistance. Expansion of these protective γδ T cells required metabolic adaptation to a ketogenic diet, as neither feeding mice a high-fat high-carbohydrate diet nor providing chemical ketone body substrate that bypasses hepatic ketogenesis protected against infection. Therefore, KD mediated immune-metabolic integration represents a viable avenue towards preventing or alleviating influenza disease.
Gamma Herpesvirus manipulates HVEM regulated IL-1β pathway to evade immune responses
Authors: Lin Wai W , Chapell Elizabeth , Brar Gurpreet , Wu Ting-Ting , Sun Ren , Baaten Bas , Ware Carl F. 
Published: January 2023

Abstract
The herpes virus entry mediator (HVEM) a member of the TNFR superfamily, is a key immunoregulator with both proinflammatory and inhibitory signaling functions. Both α and β-herpes viruses exploit HVEM to establish persistent infections, however little is known about whether the oncogenic γ-herpesviruses modulate HVEM. Here, we investigate the role of HVEM in a mouse model of γ-herpesvirus (MHV68) infection. Control C57BL/6 and HVEM-deficient (Tnfrsf14−/−) mice were intranasally infected with MHV68. We found that virus replication in the lungs of Tnfrsf14−/− mice increased significantly indicating HVEM expression is required to control MHV68 infection. We found that alveolar macrophages were drastically reduced in Tnfrsf14−/− mice compared to C57/BL6 controls suggesting their survival requires HVEM signaling. Importantly, we showed that IL-1β levels in the lungs of MHV68 infected Tnfrsf14−/−mice were significantly higher than C57BL/6 controls. Bone marrow-derived macrophage from Tnfrsf14−/− showed that HVEM is necessary to prevent IL-1β production in response to inflammasome activator. Antibodies that block IL-1R or IL-1β drastically increased the viral load in the lungs suggested that IL-1β is necessary to control viral replication. Taken together, our results highlight the role for HVEM in innate immune response evasion of MHV68 that could involve the inflammasome.
Inflammasome-mediated sensing of multi-component pore-forming toxins
Authors: Man Si Ming 
Published: January 2023

Abstract
Host recognition of microbial components is essential in mediating activation of an effective immune response that drives clearance of the pathogen. Cytosolic innate immune sensors and the inflammasome can recognize both intracellular and extracellular pathogens. Here, we identified a bacterial factor secreted by the extracellular bacterial pathogen Bacillus cereus which engages activation of the inflammasome without entering the host cytoplasm. The identity of the secreted factor is a multi-component enterotoxin called hemolysin BL (HBL) that is highly conserved amongst B. cereus strains. The three subunits of HBL bind to the cell membrane in a single and linear order, forming a lytic pore inducing efflux of potassium, activation of caspase-1, secretion of IL-1β and IL-18, and cell death. Further, HBL-producing B. cereus induces rapid inflammasome-mediated mortality in the host within 24 hr. Pharmacological inhibition of the NLRP3 inflammasome using MCC950 efficiently prevented B. cereus-induced lethality. Overall, our results reveal that cytosolic sensing of a membrane-bound multi-subunit toxin via the inflammasome is central to the innate immune recognition of B. cereus infection. Therapeutic modulation of innate immune sensing pathways can lead to enhanced host protection against deadly bacterial infections.
Conditional disruption of Hematopoietic protein-1 in mice reveals an essential role for Hem-1 in myeloid cell functions
Authors: Suwankitwat Nutthakarn , Park Heon , Iwata Terri , Libby Stephen , Liggitt Denny , Iritani Brian M 
Published: January 2023

Abstract
Hematopoietic protein1 (Hem-1) is a hematopoietic cell-specific subunit of WAVE (WASP-family verprolin homologous protein) complex, which acts downstream immune receptors (including BCR, TCR, TLR, and cytokine receptors) to stimulate filamentous actin (F-actin) polymerization. Inactivating mutations in NCKAP1L, the gene encoding Hem-1, have been recently associated with Primary Immunodeficiency Disease in humans (unpublished), and high NCKAP1L expression has been associated with a poor prognosis in Chronic Lymphocytic Leukemia. Using constitutive Hem-1 null mice, we previously published that Hem-1 is critical for normal lymphopoiesis and innate immunity. However, the cell autonomous functions of Hem-1 in individual immune cell types remain an enigma. The objective of this study was to define the cell autonomous roles of Hem-1 in myeloid cells. We created conditional Nckap1lfl/flmice, which were bred to LyzMCre mice to delete Hem-1 specifically in myeloid cells. We found that neutrophils from myeloid cell specific Hem-1 null mice exhibited defective F-actin polymerization and impaired migration in response to the chemoattractant fMLP. Hem-1 deficient macrophages were unable to efficiently phagocytose live bacteria. Myeloid specific Hem-1 null mice were much more susceptible to influenza virus (H1N1/PR8) infection based on significantly increased body weight loss, increased peribronchial inflammation, reduced alveolar macrophage number, and increased pro-inflammatory cytokines in bronchiolar lavage fluid. Collectively, our results reveal previously uncharacterized cell autonomous roles for Hem-1 in primary myeloid cells, and suggest that Hem-1 is critically important for effective anti-viral immunity.
Syk-dependent Glycolytic Reprogramming in Dendritic Cells Regulates IL-1-beta Production to Fungal-assoicated Ligands in a TLR-independent Manner
Authors: Amiel Eyal , Thwe Phyu M. , Fritz Daniel , Snyder Julia 
Published: January 2023

Abstract
Dendritic cells (DCs) activated via TLR ligation experience metabolic reprogramming, in which the cells are heavily dependent on glucose and glycolysis for the synthesis of molecular building blocks essential for maturation, cytokine production, and the ability to stimulate T cells. Although the TLR-driven metabolic reprogramming events are well documented, fungal-mediated metabolic regulation via C-type Lectin Receptors such as Dectin-1 is not clearly understood. Here, we show that activation of DCs with fungal-associated ligands induces acute glycolytic reprogramming that supports the production of IL-1b via inflammasome activation. This acute glycolytic induction to fungal-associated ligands is depending on Syk signaling in a TLR-independent manner, suggesting now that different classes of innate immune receptors functionally induce conserved metabolic responses to support immune cell activation. These studies provide new insight into the complexities of metabolic regulation of DCs immune effector function regarding cellular activation associated with protection against fungal microbes.
Role of NLRC5 and IRF1 in the induction of MHC class I
Authors: Vijayan Saptha , Meissner Torsten B. , Lee Kyoung-Hee , Liu Yuen-Joyce , Downs Isaac , Sidiq Tabasum , Zhang Chi , van den Elsen Peter J. , Kobayashi Koichi S. 
Published: January 2023

Abstract
MHC class I and MHC class II plays a major role in adaptive immune responses through activation of CD8+ T cells or CD4+ T cells respectively, by presenting intracellular or extracellular antigens. The MHC class I transactivator (CITA), NLRC5 was recently identified as a key transcriptional regulator of MHC class I and related genes. Although promoters of both MHC class I and class II genes share similar cis-regulatory elements, the specificity of NLRC5 to MHC class I gene transactivation remains unclear. To delineate the specificity of NLRC5 in NLRC5-dependent MHC classs I transactivation, we performed co-immunoprecipitation with different deletion mutants of IRF1. The results were further confirmed in mice lacking Irf1 and Nlrc5. We found that the transcription factor IRF1 associates with NLRC5, enabling efficient transactivation of MHC class I and related genes. Double deficiency of Irf1 and Nlrc5 resulted in the severe reduction of MHC class I and related gene expression in vitro and in vivo. Therefore, IRF1 is a key component that determine the specificity of NLRC5-dependent MHC class I gene transactivation, and their involvement in the CITA enhanceosome is critical for MHC class I-dependent immune responses. Further studies on the interaction of IRF1 and NLRC5 would shed light on the potential therapeutic intervention on the MHC class I related diseases such as auto-immune disorders, cancer immunity and in organ transplantation
TLR-2, TLR-3 and TLR-4 agonists induce synthesis of IFN-γ in human M1 but not in M2a, M2b and M2c macrophages through the activation of S6K1-S6 pathwayγ
Authors: Kumar Ashok , Iqbal Salma , Mukerjee Ananda , Gajnayaka Niranjala , Ahmad Faria , Crawley Angela 
Published: January 2023

Abstract
IFN-γ, a pro-inflammatory cytokine produced primarily by T cells and NK cells, activates macrophages and engage mechanisms to control pathogens. Although murine macrophages have been shown to produce IFN-γ, very little is known about IFN-γ production by normal human macrophages and their subsets. Herein, we show that priming of human monocyte-derived macrophages (MDM-M0) with IL-12 and IL-18 or IFN-γ alone leads to IFN-γ production in M1 macrophages that is significantly enhanced transcriptionally as well as at the protein level following stimulation with Toll-like receptors (TLR)-2, TLR-3 or TLR-4 agonists in contrast to the M0, M2a, M2b and M2c macrophages. The macrophage derived IFN-γ is biologically active and can activate macrophages in an autocrine manner. To determine the signalling pathway responsible for TLR-4-induced IFN-γ production in M1 macrophages, our results show that TLR-4-induced IFN-γ production is regulated by mTORC-1/2, PI3K, p38 and JNK MAPKs and S6Kinase-S6 pathway. The S6K1-S6 pathway plays a crucial role in TLR-induced IFN-γ production in M1 macrophages as IFN-γ-induced S6 phsophorylation (Ser 235/236) was inhibited by the inhibitors specific for PI3K, p38-MAPK and JNK MAPK, and mTORC-1/2 suggesting that S6K1-S6 pathway plays a critical role in TLR-4 induced IFN-γ production in human M1 macrophages.
Ikaros zinc finger transcription factors as novel regulators of STAT factor activity
Authors: Read Kaitlin , Sreekumar Bharath , Powell Michael Duane , Jones Devin , Oestreich Kenneth J 
Published: January 2023

Abstract
Cytokine signaling is important for the differentiation and function of a number of cell types, including lymphocyte populations. One mechanism by which cytokine signals are propagated is via phosphorylation-mediated activation of Signal Transducer and Activator of Transcription (STAT) factors, which directly regulate cell type-specific gene programs. We recently identified novel regulatory modules composed of STAT and Ikaros Zinc Finger (IkZF) transcription factors in CD4+ T cell populations. Specifically, we found that IkZF/STAT modules composed of Aiolos/STAT3 and Eos/STAT5 directly activate genes associated with T follicular helper (TFH) and T helper 1 (TH1) gene programs, respectively. Here, we extend these findings and show that IkZF factor expression correlates with STAT activation, suggesting that IkZF proteins may regulate STAT factor activity in CD4+ T cells. We find that overexpression of Aiolos, but not the IkZF factors Ikaros and Eos, results in increased STAT3 activation. Conversely, overexpression of Eos, but not Ikaros or Aiolos, results in increased activation of STAT5. Importantly, when we performed these studies using IkZF protein mutants incapable of interacting with STAT factors, the observed increase in STAT factor phosphorylation was lost. We also find that in CD4+ T cells, Eos deficiency correlates with reduced STAT5 activation, while Aiolos-deficient cells display reduced STAT3 activation. Finally, we observe differential IkZF factor expression across CD4+ T cell subsets. When coupled with known differences in STAT factor activation, these findings suggest that IkZF/STAT regulatory modules may broadly regulate T helper cell differentiation.
Single cell profiling reveals unique stages of NK cell development
Authors: Beaulieu Aimee M 
Published: January 2023

Abstract
Natural killer (NK) cells are potent cytotoxic lymphocytes that provide critical host defense against pathogens and malignancy. Current understanding of the molecular and cellular events that define the stage-wise progression of NK cell development is limited. Here, we use single-cell RNA sequencing (scRNA-seq) to identify unique stages of NK cell development. Our data reveal previously unappreciated heterogeneity within the progenitor and immature NK cell compartments. Notably, we find that these compartments are comprised of several unique subpopulations that express distinct transcriptional and epigenetic factors, intracellular signaling molecules, metabolic enzymes, and cell cycle regulators. Collectively, our data provide important insights into the molecular events that underlie NK cell development, and have the potential to inform NK cell-based therapies aimed at treating cancer and infectious disease in humans.