bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting TIGIT to modulate immunity and disease during experimental malaria
Authors: Graham Amy C , Obeng-Adjei Nyamekye , Guthmiller Jenna J , Zander Ryan A , Wohlfert Elizabeth A , Crompton Peter D , Butler Noah S 
Published: January 2023

Abstract
Plasmodium infections and the disease malaria remain global health emergencies. CD4 T cells are essential for coordinating protective immunity against Plasmodium infection and promoting parasite clearance, yet long-lived immunity is rarely acquired. We have linked immune failures during human and experimental Plasmodium infection to the expression of immuno-regulatory networks that impair CD4 T cell activity. Here we show the immuno-inhibitory molecule, TIGIT, is highly expressed by parasite-specific CD4 T cells during human and experimental Plasmodium infection, but not experimental Toxoplasma gondii infection. Strikingly, the bulk (&gt;90%) of TIGIT+ parasite-specific CD4 T cells are T-bet+ Th1 effectors, not Foxp3+ T regulatory cells. Moreover, sustained expression of TIGIT is associated with CD4 T cell-expression of IL-10 and is regulated by systemic inflammation, not persistent antigen or chronic T cell stimulation. Preliminary studies using TIGIT-specific agonistic and antagonistic reagents support the biological relevance of sustained TIGIT expression during Plasmodium infection. Current studies are focused on genetic manipulation of TIGIT to dissect the CD4 T cell subset-intrinsic roles of TIGIT during malaria. Collectively, our data support that TIGIT represents an additional host factor that can be targeted to improve immunity against Plasmodium infection and limit disease severity.
Carbonic anhydrase enzymes regulate mast cell-mediated immunity to Trichinella spiralis.
Authors: Siracusa Mark C , Henry Everett K , Sy Chandler B , Inclan-Rico Juan M. 
Published: January 2023

Abstract
Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the detrimental inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cell populations contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. Here we identify that carbonic anhydrase (Car) enzymes are upregulated in type 2-asscoaited progenitor cells and demonstrate that Car enzyme inhibition was sufficient to prevent murine mast cell development, type 2 cytokine-mediated inflammation and protective immunity to Trichinella spiralis. Moreover, we show that Car enzyme inhibition was also sufficient to prevent intestinal mast cell responses in a murine model of food allergy-like disease. Finally, we performed translational studies and demonstrated that Car enzymes can be targeted with an FDA-approved inhibitor to prevent human mast cell development. Collectively these studies identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that FDA-approved Car enzyme inhibitors may possess additional off-label therapeutic potential that can be employed to treat mast cell-mediated inflammation.
Defining the correlates of protective immunity mediated by Ly6C+CD44+CD62L−CD4+ T effector (TEFF) cells against Leishmania major infection: implications for vaccination against intra-phagosomal pathogens
Authors: Hohman Leah S , Carneiro Matheus BH , Peters Nathan C 
Published: January 2023

Abstract
The protozoan Leishmania parasite is a human obligate intra-cellular pathogen and the causative agent of leishmaniasis, a chronic neglected tropical disease of existing and growing global importance. Despite considerable effort a human vaccine does not exist. In the C57Bl/6 mouse model of naturally acquired protective immunity, chronic primary infection maintains short-lived Ly6C+ TEFF cells that mediate protective immunity against secondary challenge. These cells, not memory cells or cells derived from memory cells following challenge, emulate the rapid IFN-g response associated with protective immunity against natural infected sand fly challenge. Defining the mechanisms by which these cells mediate their protective effect will be essential for informing future vaccine design. To elucidate the importance of the rapidity of the Ly6C-mediated response as a protective correlate, the influence of these cells on innate immune cells, and ultimately their capacity to facilitate the priming and activation of Leishmania-specific naïve cells, we devised an adoptive transfer system in which Ly6C+ TEFF cells from chronic mice are transferred into recipient mice at the time of infection or 4 days following infection, just prior to the initiation of parasite replication. Disease progression was followed for 3 weeks and the activation of phagocytes, antigen-presenting cell function, and IFN-g production by both adoptively transferred and recipient populations was analyzed. Our observations are likely to enhance our understanding of the correlates of protective immunity beyond the simple generation of IFN-g producing memory cells, a strategy that has so far failed to generate an effective human vaccine.
Immunomodulation by Leishmania-derived surface oligosaccharides promotes pro-inflammatory cytokine secretion and reduces L. major parasite load
Authors: Grinnage-Pulley Tara , Roychoudhury Rajarshi , Schaut Robert , Osanya Alex , Martinez Pedro , Gibson-Corley Katherine , Toepp Angela , Lamb Ian , Pohl Nicola , Petersen Christine A 
Published: January 2023

Abstract
Lipophosphoglycans (LPG) of Leishmania spp. are known to alter innate immune responses and be critical for parasite binding to the vector gut wall. LPG displays various oligosaccharides capping the terminal and branch apexes. However, it is unknown how these capping oligosaccharides serve as immunomodulators in the absence of a conjugated protein. Several oligosaccharides including dimannose and trimannose, were synthesized and covalently linked to latex beads to study their effect in a Leishmania infection model. In vitro incubation of activated J774 or bone marrow derived macrophages with di- and tri-mannose resulted in differential modulation of IL-12p40, a key cytokine to control intracellular pathogens by driving a Th1 response. Co-inoculation of trimannose and L. major into the footpad of C57BL/6 mice increased IL-12p40 and IFN-γ production 48 hours post-infection, a significantly Th1 skewed response. Noticeably at 14 days post-infection, L. major infected, trimannose treated mice had significantly decreased lesion size and decreased parasite load compared to infected untreated, controls. Cytokines from draining lymph node supernatants measured via Luminex at 14 days post infection showed decreased IL-12p40 and IL-10 secretion and increased IFN-γ in the co-inoculated mice. In vitro, the effects of trimannose were mediated by macrophage TLR and mannose receptors as well as T cell proliferation. Leishmania-derived trimannose represents a novel immunomodulator that provides early Th1 skewed cytokine production to control parasite load and alter the course of infection.
Exogenous induction of type I IFN protects mice from Cryptococcus neoformans and Cryptococcus gattii infections by distinct CD4+ T cell and CD8+ T cell-mediated mechanisms.
Authors: Davis Michael J , Sionov Edward , Mayer-Barber Katrin D. , Barber Daniel L , Chang Yun C. , Kwon-Chung Kyung J. 
Published: January 2023

Abstract

Rational
Cryptococcus neoformans (Cn) causes deadly mycosis in AIDS patients whereas the Vancouver outbreak strain of Cryptococcus gattii (Cg) mostly infects otherwise healthy individuals but not AIDS patients even where the strains are equally prevalent in the environment. As HIV infection induces type I IFN (t1I) we hypothesized that exogenously induced t1I would differentially affect infections by Cn and Cg.

Results
Cn or Cg infected mice were dosed with poly(I:C)LC (PIC) to induce t1I. PIC-treated mice were protected from Cn and Cg infection-mediated death with reduced fungal burdens. Both Cn and Cg infection produced a non-protective immune response dominated by Th2 cell recruitment, M2/DC2 polarization and eosinophilia. PIC-treatment reversed the Th2 polarization toward increased Th1/17 cells, M1/DC1 polarization and reduced eosinophilia. PIC also induced activation of CD8 T cells in both Cg and Cn infected mice. Cg-infected CD8 cell-deficient mice were not protected by PIC treatment while PIC protection was intact in Cn-infected CD8 cell-deficient mice. In contrast, PIC protection was intact in Cg-infected CD4 cell-deficient mice while Cn-infected CD4 cell-deficient mice were not protected by PIC treatment.

Conclusions
These data show that t1I induction protects mice from Cn and Cg however protection was mediated by distinct immune mechanisms. PIC-mediated protection from Cn requires CD4 but not CD8 cells while PIC-mediated protection from Cg requires CD8 but not CD4 cells. Notably, Cn but not Cg was able to grow in CD4-deficient t1I-induced mice, which somewhat resemble the immunological condition of AIDS patients, suggesting a novel explanation for the observed AIDS patient tropism of these cryptococcal species.
Loss of efficacy of the antifungal caspofungin is mediated by increased chitin exposure and concomitant eosinophilia in invasive pulmonary aspergillosis
Authors: Amarsaikhan Nansalmaa , Tsoggerel Angar , Sands Ethan M , Templeton Steven P 
Published: January 2023

Abstract
Recently significant interest has focused on the composite recognition of fungal molecular patterns that program innate and adaptive immunity to the human fungal pathogen Aspergillus fumigatus. We observed that decreased relative levels of cell wall β-glucan to chitin in A. fumigatus strains correlated with increased airway eosinophil recruitment associated with decreased fungal clearance by type 2 immune responses in invasive pulmonary aspergillosis. Furthermore, an increase in surface chitin exposure driven by growth and germination in the presence of the anti-fungal, β-glucan targeting drug caspofungin resulted in increased airway eosinophilia upon aspiration of A. fumigatus conidia. More importantly, in a model of invasive aspergillosis, we observed a decrease in fungal clearance upon caspofungin treatment that was reversed in eosinophil-deficient mice. Eosinophil recruitment was partially dependent on γδ T cells, and our preliminary results show a similar increase in caspofungin mediated clearance in γδ-T cell-deficient mice. Our results provide a novel mechanism that may explain the widely reported paradoxical loss of efficacy in response to caspofungin, and we are currently working to define the relationship between drug treatment, eosinophil activation, and fungal burden in clinical samples.
Dual roles of scavenger receptor MARCO in innate versus adaptive immune responses during Cryptococcus neoformans infection
Authors: XU JINTAO , Flaczyk Adam , Eastman Alison J , Neal Lori , Zhao Guolei , Malachowski Antoni , Akolkar Jay , Osterholzer John J , Olszewski Michal A 
Published: January 2023

Abstract
Resistance to the opportunistic fungal pathogen Cryptococcus neoformans (Cn) is associated with development of Th1/Th17 immune bias while a Th2 immune response results in increased susceptibility. Macrophage Receptor with Collagenous Structure (MARCO) is important for recognition of some pathogens and subsequent activation and polarization of the immune responses by DC and macrophages, however, its role during Cn infection remains unknown.
Here we found that in spite of diminished early (innate) control of Cn in the infected lungs, Cn-infected MARCO−/− mice showed improved fungal clearance during the adaptive phase (wk 5) compared to MARCO+/+ mice. MARCO−/− mice showed: 1) improved accumulation of exudate macrophages and CD11b+ DC and their improved activation phenotype (CD80+, CD86+ and MHCIIhigh); 2) increased intracellular IFN-γ and IL-17 production by pulmonary CD4+ and CD8+ T cells; 3) decreased IL-4, IL-5, IL-10 and increased IFN-γ and IL-17 production by splenocytes treated with Cn antigen; 5) diminished systemic level of IgE. Interestingly, in spite of improved clearance, MARCO−/− mice showed decreased frequency of lung resident CD44highCD62LlowCD69+ CD103+CD11a+CCR7− effector memory T cells. We conclude that while important for the innate control of Cn in the lungs, MARCO can be exploited by Cn to interfere with immune polarization leading to an altered, non-protective efferent immune bias, which outweighs potentially beneficial effects of MARCO.
Th17 cells are more protective than Th1 cells against the intracellular parasite Trypanosoma cruzi.
Authors: Cai Catherine Wen , Blase Jennifer R. , Eickhoff Christopher S. , Hoft Daniel F. 
Published: January 2023

Abstract
Th1 cells are considered the major CD4+T helper subset responsible for the control of intracellular pathogens, including Trypanosoma cruzi, the protozoan parasite of Chagas disease. Th17 cells are known for their involvement in autoimmunity and the defense against some extracellular organisms, but are generally not believed to have a significant function during intracellular infections.
In contrast, we show that Th17 cells are highly protective against the intracellular pathogen T. cruzi. We reconstituted RAG KO mice lacking endogenous T cells with polyclonal CD8+ T cells and parasite-specific Th1 or Th17 cells, generated from novel T cell receptor transgenic mice recently developed by us. After adoptive cell transfer, recipients were infected with a normally lethal dose of T. cruzi. Th17 cells impressively protected 100% of mice from mortality long-term, while Th1 cells protected only 38%.
Transfer of Th17 cells alone failed to protect, implicating helper effects on CD8+ T cells as the basic mechanism of Th17-mediated intracellular immunity. We confirmed this using in vitro assays, and discovered that Th17 cells help activate CD8+ T cells through IL-21 secretion, indicating a protective mechanism surprisingly independent of the main Th17 cytokine IL-17A. In vivo, co-transfer of IL-21R knock-out CD8+ T cells with Th17 cells failed to protect mice, confirming the importance of IL-21 signaling.
In summary, our data define an important new role for Th17 cells in the defense against a major intracellular human pathogen and define novel mechanisms of Th17 cell effects. This work increases our understanding of the protective immune interactions in T. cruzi infection, and more broadly, illuminates the growing diversity of Th17 cell roles.
Oxygen metabolism regulates macrophage susceptibility to Trypanosoma cruzi.
Authors: Koo Sue , Garg Nisha Jain 
Published: January 2023

Abstract
Macrophage activation rely on the metabolism which supports the generation of compounds crucial for proper cell function. Aerobic metabolism is dependent on mitochondrial oxidative phosphorylation, and is essential for the activation of immunomodulatory macrophages (M2). Conversely, mitochondria-independent, anaerobic metabolism provides substrates to produce anti-microbial mediators by pro-inflammatory macrophages (M1). Reactive oxygen species (ROS) and nitric oxide (NO) are key M1 molecules for host defense against intracellular parasites, including the etiologic agent of Chagas disease, Trypanosoma cruzi. In this study, we report deficient production of ROS and NO by macrophages infected with T. cruzi (H2DCFDA, Amplex Red and Griess assays), and show that mitochondrial gene expression (qPCR) and function (Seahorse Extracellular Flux Analyzer) are in concordance with the M2 phenotype and macrophage susceptibility to T. cruzi infection. These findings indicate the possibility of manipulating oxygen metabolism to improve the pro-inflammatory function and pathogen clearance by macrophages.
Short-chain fatty acids induce effector T helper cells and cause inflammatory responses in the renal system.
Authors: Park Jeongho , Goergen Craig , HogenEsch Harm , Kim Chang H 
Published: January 2023

Abstract
Short-chain fatty acids (SCFAs) are major products of gut microbial fermentation and profoundly affect host health and disease. SCFAs generate IL-10+ regulatory T cells, which may promote immune tolerance. SCFAs can also induce Th1 and Th17 cells during active immune responses and, therefore, have the potential to induce inflammatory responses. However, the potential function of SCFAs in induction of tissue inflammation has not been documented to date. We investigated, in depth, the impact of elevated SCFA levels on T cells and tissue inflammation in mice. Orally administered SCFAs induced effector (Th1 and Th17) and regulatory T cells in ureter and kidney tissues, and induced T-cell mediated ureteritis leading to kidney hydronephrosis (hereafter called C2RD). Kidney hydronephrosis in C2RD was caused by ureteral obstruction, which was, in turn, induced by SCFA-induced inflammation in the ureteropelvic junction (UPJ) and proximal ureter. Oral administration of all major SCFAs, such as acetate, propionate, and butyrate, induced the disease. We found that C2RD development is dependent on mTOR activation, T cell-derived inflammatory cytokines such as IFNg and IL-17, and gut microbiota. In a manner similar to many types of chronic renal diseases in humans, young or male animals were more susceptible than old or female animals respectively. However, SCFA receptor (GPR41 or GPR43) deficiency did not affect C2RD development. Our study provide evidence for the first time that SCFAs can cause dysregulated T cell responses and tissue inflammation in a specific organ in the body. We believe that our results have significant ramifications in therapeutic applications of SCFAs.
Deep phenotypic profiling of small clinical samples through MultiSpectral Imaging Cytometry (MuSIC) in nanowell arrays
Authors: Gierahn Todd M , Yalcin Ayca , Loginov Denis , Love J. Christopher 
Published: January 2023

Abstract
Many disease relevant immune processes occur within tissues, making them challenging to monitor clinically using standard blood based assays. Comprehensive phenotyping of the scarce cells acquired directly from tissue samples is limited by inefficiencies in sample handling and data collection inherent in current flow-based profiling methods. To overcome this barrier, we developed Multi-Spectral Imaging Cytometry (MuSIC), a method that combines an array of sub-nanoliter wells (nanowells) for efficient cell capture with multi-spectral imaging to resolve up to 16 fluorescent markers on ~103–105 cells. Importantly, the cells remain viable for further functional characterization, enabling linkage of deep cell surface phenotypes with functional activity. Using MuSIC in combination with a single-cell protein secretion assay, we were able to identify unique T cell populations present in human cervical biopsies. MuSIC provides an effective and accessible means to acquire deep phenotypic profiles of leukocytes from small clinical samples.
Digital Vivarium™ Platform Enables Automated Drug Efficacy Assessment Correlated with Pathology in Rheumatoid Arthritis
Authors: Schaevitz Laura , Cha Paulyn , Ford Daniel , Heath Kyle , Jadzinsky Pablo , Lim Maria , Robertson Timothy 
Published: January 2023

Abstract
Current methods for evaluating new therapeutics in rodent disease models and improving understanding of disease mechanisms are frequently labor-intensive and require the same technician to perform key measurements for consistency. To address these limitations, we established a novel Digital Vivarium™ platform, which monitors subjects continuously for disease and health-related endpoints, without human interaction, to evaluate drug efficacy. As a proof of principal, we validated automated disease scoring in a standard model of arthritis with an algorithm that captures salient motion metrics during the animals’ active period to compute an arthritis score. This Digital Arthritis Index™ score reproducibly correlated to disease pathology and was better at detecting mild disease pathology as compared to joint swelling across standard-of-care compounds including Methotrexate, Etanercept, and Dexamethasone. Additional health endpoints, include breathing rate, overall activity, and circadian rhythms, are also monitored continuously and stored in auditable electronic and videographic records. The platform was then used to screen 9 re- purposed drugs at appropriate dose ranges for efficacy. Study-specific disease and health endpoints are available real-time remotely over the internet to enable rapid decisions. Our results demonstrate a low-touch digital platform that will pave new ways for more rapid, reproducible, drug discovery and evaluation, not only for RA, but also more broadly in other autoimmune diseases such as MS and Lupus, as well as outside of immunology such as cancer, CNS and toxicology.
Ubiquitin ligases and immune response: Quantitative analysis of their substrates and drug discovery
Authors: Lu Xiaolong , Rapp Matthew , Corson Joy , Strickler James 
Published: January 2023

Abstract
Protein ubiquitylation has emerged as a key regulatory mechanism of innate and adaptive immune systems. In particular, Cbl-b (Casitas B-lineage lymphoma proto-oncogene b), a RING finger E3-ubiquitin ligase primarily expressed in immune cells, acts as an intracellular checkpoint and a master negative regulator of both CTLs and NK cells. As such, Cbl-b is a novel target for developing small molecule cancer immunotherapy agents. Nedd4-family E3 ligases including Itch are known to negatively regulate inflammatory immune responses by suppressing both TH2 and TH17 differentiation and cytokine production. Modulators of Itch are expected to have anti-inflammatory properties. In addition, deubiquitylases such as USP7 and USP4 are implicated in modulating immune responses. Thus, several ubiquitin pathway enzymes have emerged as therapeutic targets for a variety of immune disorders. Therapeutic modulation of these ubiquitin pathway enzymes is expected to alter the ubiquitylation of their substrate proteins and documentation of such changes is critical to establish mechanism of action in the cell and develop physiological screens for target validation and drug discovery. Current methods to study polyubiquitin on substrates are cumbersome, inefficient, and low throughput. Here we describe a powerful technology that allows selective and quantitative analysis of polyubiquitylated proteins in high throughput format in the cell. Validation is provided using small molecule modulators of E3 ligase and deubiquitylase enzymes. This technology allows detection of changes in highly dynamic poly-ubiquitylated substrates, thus elucidating the role of these enzymes in the cell and the mechanism of action of drug molecules.
Estrogen induces multiple regulatory B cell subtypes and promotes M2 microglia and neuroprotection during experimental autoimmune encephalomyelitis
Authors: Zhang Jun , Benedek Gil , Bodhankar Sheetal , Vandenbark Arthur A , Offner Halina 
Published: January 2023

Abstract
Sex hormones promote potent immunoregulatory effects on autoimmune diseases, including multiple sclerosis (MS). Our previous studies demonstrated a critical role for regulatory B cells in mediating estrogen (17β-estradiol, E2)-mediated protection against experimental autoimmune encephalomyelitis (EAE), a mouse model for MS, leading to elevated numbers of IL-10 secreting CD1dhiCD5+B regulatory cells (Bregs) in wild type mice. The current study evaluated estrogen effects on regulatory B cells and resident CNS microglia during EAE and demonstrates for the first time an E2-dependent induction of multiple regulatory B cell markers indicative of IL-10 dependent as well as IFN-γ dependent pathways. Moreover, although E2 pretreatment of female EAE mice inhibited the infiltration of pro-inflammatory immune cells into the CNS compared with sham pretreated mice, it enhanced the frequency of regulatory B cells and M2 microglia in the CNS. Our study suggests that estrogen has a broad effect on the development of regulatory B cells during EAE, which in turn could promote neuroprotection in the CNS.