bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mycolic acid nanoparticle vaccination leads to antigen persistence and unique differentiation of mycobacterial lipid antigen-specific T cells
Authors: Morgun Eva , Zhu Jennifer , Bobbala Sharan , Aguilar Melissa Salinas , Wang Junzhong , Conner Kathleen , Cao Liang , Seshadri Chetan , Scott Evan A , Wang Chyung-Ru 
Published: January 2023

Abstract
Tuberculosis remains a serious global epidemic and with the rise of multi-drug resistant strains, an efficacious vaccine solution is imperative. Vaccines currently being developed for Mtb utilize protein antigens, which target MHC-restricted conventional T cells, overlooking the potential of Mycobacterium tuberculosis (Mtb) lipid antigens such as mycolic acid (MA), a key lipid found in Mtb cell wall. Mycobacterial lipids are presented by group 1 CD1 molecules (CD1a, b, c) to cognate T cells. Group 1 CD1-restricted T cells can be identified in patients with TB and have been shown to provide protection in Mtb infection. Using biocontinuous nanospheres (BCNs), a type of self-assembled nanostructure able to load both hydrophobic and hydrophilic molecules, we have created a vaccine containing MA. We found that MA BCN is able to effectively activate CD1b-restricted MA-specific T cells in vitro and in vivo. Interestingly, we discovered that MA persists within lung alveolar macrophages for at least 6 weeks after intratracheal vaccination with MA BCN. Antigen archiving was in part due to the encapsulation of MA within BCN. Nanoparticle vaccinations carrying lipid antigens may thus lead to persistent depots of antigen that could offer long-lasting immune response and protection.
Supported by grants from NIH (5R01AI145345-03, 1F30AI157314-01, 5T32GM008152-35)
Duration of peripheral blood cellular immune responses induced in dogs in response to a modified live attenuated vaccine for Ehrlichia chaffeensis
Authors: McGill Jodi L , Madesh Swetha , Hove Paidashe , Ganta Roman R 
Published: January 2023

Abstract
Ehrlichia chaffeensis (ECH) is an obligate intracellular gram-negative bacterium and a frequent cause of severe and fatal tick-borne infection in people in North America. The canine is a common incidental host and a useful model for vaccine development and assessing immune responses to ECH infection. We recently established mutagenesis methods for ECH and demonstrated that immunization of dogs with an ECH mutant with a functional disruption in the ECH_0660 gene protected the vertebrate host from both tick-transmitted and intravenous wildtype ECH challenge when given 4 weeks after immunization. In the current study, we evaluated the duration of immunity offered by the ECH_0660 gene mutant live attenuated vaccine (MLAV) against wildtype infection challenge. Groups of 12 dogs were immunized with the ECH MLAV and then challenged 2, 4, 8 and 12 months later via tick-transmitted or blood-transmitted infection with wildtype ECH. Animals were monitored for 4 weeks after challenge and then sacrificed for evaluation of tissue pathology and bacterial burden. Immunization with the MLAV induced ECH-specific T cell responses, detectable by ELISPOT for IFNγ; and differentiation of IFNγ- and/or TNFα-producing ECH-specific T effector memory CD4 T cells (CD45RAneg CD45RO+ CD62Lneg). Antigen-specific recall responses were detectable in the peripheral blood of most (27/32) vaccinated dogs for 4 months after immunization, but only in 5/24 of the dogs after 8 months. This result suggests that a single MLAV vaccination induces cellular immune responses and differentiation of memory helper T cells. Future work will investigate the correlations between cellular immunity, humoral responses and bacterial load.
Supported by grants from NIH (R01 AI152418)
Resident CD8+ T-cells drive dysplastic repair of aged lungs following viral pneumonia
Authors: Narasimhan Harish , Goplen Nicholas P , Cheon In Su , Sun Jie 
Published: January 2023

Abstract
Global studies have established age as the most critical risk factor in determining morbidity and mortality following respiratory viral infections such as influenza and SARS-CoV2. Previous studies from our group identified non-resolving inflammation in aged lungs post influenza infection, primarily driven by the persistence of tissue resident memory (Trm) CD8 T-cells. We also observed sustained impaired lung function in aged COVID19 convalescents, which negatively correlated with levels of pulmonary CD8 Trm cells. While critical for acute antiviral responses, we have demonstrated that this population is pathologic rather than protective following viral clearance during aging, evidenced by improved outcomes upon its depletion.
Upon severe lung damage during viral infection, epithelial progenitor cells characterized by cytokeratin 5 (Krt5) expression are mobilized for repair. However, these cells are known to be incapable of differentiating into functional ATI and ATII cells, instead persisting as dysplastic epithelial scars, a process known to be exacerbated with age. Thus, in addition to mortality during acute infection, aged individuals also experience adverse long-term outcomes due to dysfunctional repair of the lung.
We identified that Krt5 cysts typically associate with CD8 Trm cells, suggesting potential immune-epithelial crosstalk. Furthermore, upon depletion of pulmonary CD8 Trm cells, we observed a reduction in Krt5 cysts, increased ATI and ATII levels, and improved lung function. Hence, we hypothesize that the interactions between CD8 Trm cells and Krt5 cysts are responsible for sub-optimal repair and aim to manipulate this crosstalk to promote functional repair of the aged lung following viral pneumonia.
Supported by grants from NIH - AI147394, AG047156, and AG069264 and Mayo Clinic CBD Research Fund
Restriction of viral replication, rather than T cell immunopathology, drives lethality in MNV CR6-infected STAT1-deficient mice
Authors: Sharon Andrew J , Filyk Heather A , Fonseca Nicolette M , Simister Rachel L , Filler Renata B , Yuen Wallace , Hardman Blair K , Robinson Hannah G , Seo Jung Hee , Rocha-Pereira Joana , Welch Ian , Neyts Johan , Wilen Craig B , Crowe Sean A , Osborne Lisa C 
Published: January 2023

Abstract
Recent evidence indicates that viral components of the microbiota can contribute to intestinal homeostasis and protection from local inflammatory or infectious insults. However, host-derived mechanisms that regulate the virome remain largely unknown. Here, we used colonization of C57BL6/J mice with the model commensal murine norovirus (MNV CR6) to interrogate host-directed mechanisms of viral regulation, and show that STAT1 is a central coordinator of both viral replication and antiviral T cell responses. In STAT1-sufficient mice MNV CR6 is asymptomatic and restricted to the colon, despite the persistence of high viral loads. However, in the absence of STAT1 viral replication is disseminated and observed in key innate and adaptive immune populations.
STAT1-deficient mice develop dysregulated inflammatory CD8+ and CD4+ T cell responses, which coincide with weight loss and severe necrosis of the spleen and liver. Despite these altered T cell responses which resemble those that mediate lethal immunopathology following other model viral infections of STAT1-deficient mice, depletion of adaptive immune cells and their associated effector functions had no effect on CR6-induced disease. In contrast, therapeutic administration of an antiviral compound limited viral replication, preventing viral-induced tissue damage and death despite ongoing inflammatory antiviral T cell responses. Collectively, our data show that STAT1 restricts MNV CR6 replication within the intestinal mucosa. Unlike other model viral infections, CR6 induces disease in STAT1-deficient mice via uncontrolled viral replication rather than the concomitant development of dysregulated antiviral T cell responses.
Research in the Osborne lab is supported by the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research, the Canada Research Chair program and scholarships from the University of British Columbia.
Tetramerization of STAT5 promotes autoimmune-mediated neuroinflammation
Authors: Monaghan Kelly Lynn , Aesoph Drake , Ammer Amanda G , Zheng Wen , Rahimpour Shokofeh , Farris Breanne Y , Spinner Camille A , Li Peng , Lin Jian-Xin , Yu Zu-Xi , Lazarevic Vanja , Hu Gangqing , Leonard Warren J , Wan Edwin C K 
Published: January 2023

Abstract
Signal transducers and activators of transcription 5 A and B (STAT5A & B) play a critical role in mediating cellular responses following cytokine stimulation. STAT5 proteins critically signal via the formation of dimers through SH2 domain interactions. However, tetramerization of STAT5 through dimer interactions in the N-domain, has key biological roles. STAT5 tetramers control the suppressive function of regulatory T cells (Tregs), the expansion of CD8+ T cells, and the terminal differentiation of NK cells. However, the role of STAT5 tetramerization in autoimmune-mediated neuroinflammation has not been investigated. Using the STAT5 tetramer-deficient Stat5a-Stat5b N-domain double knock-in (DKI) mouse strain, in which dimer function is preserved, we found that STAT5 tetramers promote the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a murine model of multiple sclerosis. The mild EAE phenotype observed in DKI mice correlates with impaired extravasation of pathogenic Th17 cells and interactions between Th17 cells and monocyte-derived cells (MDCs) in the meninges. We further demonstrated that STAT5 tetramerization mediated by GM-CSF signaling, a key EAE-associated cytokine, regulates the production of the chemokine CCL17 by MDCs. Importantly, CCL17 can partially restore the pathogenicity of DKI Th17 cells, and this is dependent on the activity of the integrin VLA-4. Thus, our study reveals a novel GM-CSF-STAT5 tetramer-CCL17 pathway in MDCs that promotes autoimmune-mediated neuroinflammation.
This work was supported by NIH grant P20 GM109098 and WVU Institutional Funds to E.C.K.W.; Praespero Innovation Award Program to E.C.K.W. and V.L.; NIH grants P20 GM103434 and U54 GM104942 to G.H.; the Intramural Research Program of the National Heart, Lung, and Blood Institute, NIH to W.J.L.; the Intramural Research Program of the National Cancer Institute, NIH to V.L. NIH grants S10 OD016165, U57 GM104942, P30 GM103488, and P20 GM103434 to the WVU Flow Cytometry & Single Cell Core Facility. NIH grants U54 GM104942, P20 GM103434 and P20 GM121299 to the WVU and Marshall University Genomics Cores. Funds from WVU Cancer Institute, WVU HSC Office of Research and Graduate Education, and NIH grants P20 RR016440, P30 GM103488, P20 GM121322, U54 GM104942, and P20 GM103434 to the WVU Microscope Imaging Facility. K.L.M. was supported through The American Association of Immunologists Careers in Immunology Fellowship Program.
Investigating immune responses to Harmful Algal Bloom cyanotoxins in protection of human health and the environment
Authors: Augustine Swinburne A J , Robillard Michelle Catherine , De la Cruz Armah 
Published: January 2023

Abstract
Harmful algal blooms (HABs) are a major environmental and public health concern globally that impact multiple essential areas including agriculture, drinking water, and recreational water. Although harmful blooms are caused by other organisms, those from cyanobacteria are the most common freshwater pollutant. Cyanobacteria produce secondary metabolites including cyanotoxins that pollute drinking and recreational waters and produce metabolites and cell components that can contribute to skin irritation. The aim of this study is to elucidate the specific mechanisms that lead to inflammation and irritation caused by exposure to these toxins. Multiplexing technology afforded the ability to investigate a variety of human cytokines and chemokines, and soluble receptors to measure immune responses in a single sample. 3D human tissue cultures were exposed to a variety of different toxins found in HABs. These samples were then examined using Luminex™ xMAP technology to look at 38 different cytokines/chemokines and 14 soluble receptors in each sample. We observed the expression of several cytokines/chemokines that regulate the inflammatory process in endothelial and epithelial cells and play a role in the recruitment of neutrophils to the site of inflammation. This could contribute to the rashes or skin irritation commonly reported by patients exposed to HABs. Additional observations and analyses are needed to identify the specific immune response pathways activated during exposure to these toxins. These findings could lead to a better understand of human exposure to cyanotoxins and more appropriate and effective treatment modalities for patients who exhibit rashes or skin irritations after being exposed to these blooms.
This work is supported by the United States Environmental Protection Agency.
Early life adversity programs a hyperactive mast cell phenotype and induces long-lasting changes in the mast cell transcriptome
Authors: LeMon Janelle , Maradiaga Nidia , Moeser Adam James 
Published: January 2023

Abstract
Early life adversity (ELA) induces long-lasting chronic low-grade immune activation and increases the risk for inflammatory and metabolic disorders later in life. Our previous studies demonstrated that mast cells (MCs) which are well-established orchestrators of immune responses and as effector cells of the stress response exhibit heightened reactivity to later life stressors. Here, we used a murine model of ELA (neonatal maternal separation + early weaning; NMSEW) to determine the long-lasting programming effects of ELA on MC phenotype and function. Bone marrow-derived mast cells (BMMCs) from adult female NMSEW mice exhibited greater IgE-mediated histamine release and LPS- and IL33-induced cytokines release, compared with normally handled (NH) control mice. RNA sequencing of BMMCs from adult NH and NMSEW female mice, followed by gene pathway analysis using Ingenuity Pathway Analysis, revealed significant alterations in gene expression associated with cell migration and trafficking, glycolysis and TCA cycle regulation, lipid and cholesterol synthesis, and toll like receptor signaling. Ongoing experiments aim to characterize the long-lasting metabolic alterations induced by NMSEW through functional assays and protein expression analysis. Understanding how ELA programs MCs could identify the cellular mechanisms driving persistent MC hyper-activation and related risk for inflammatory diseases.
Supported by grants from NIH/NICHD (R01 HD072968), NIH/NIAID (R01 AI152268), and USDA (USDA-NIFA 2019-67015-29483).
Atopic dermatitis patients have increased numbers of FcɛRIα and IgE double positive monocytes and plasmacytoid dendritic cells in peripheral blood mononuclear cells
Authors: Bin Lianghua , Richers Brittany , Leung Donald Y M 
Published: January 2023

Abstract
Antigen presenting cells including monocytes and dendritic cells have been reported to express cell surface high-affinity IgE receptor (FcɛRI) and binds to IgE. However, the frequencies of these cells in human peripheral blood mononuclear cells (PBMCs) are ambiguous, and the biological function of these cells in human remains to be characterized. In this study, we investigated the frequencies of cell surface expression of FcɛRIα and cell surface bound IgE in PBMCs isolated from normal human controls (NC) and atopic dermatitis (AD) patients using multicolor flow cytometry methods. While the frequencies of FcɛRIα+ single positive cells have no significant differences between NC and AD, we found that the frequencies of FcɛRIα and surface-bound IgE double positive cells (FcɛRIα+ IgE+) in human PBMCs are significantly increased in AD patients (mean ±SD: 2.52% ± 1.33%) compared to NC (mean ±SD: 1.26% ± 0.79%) (p=0.003). In addition, the frequencies of FcɛRIα+ IgE+ cells are positively correlated with serum IgE levels (Spearman analysis: r=0.67, p&lt;0.0001). The FcεRIα+ IgE+ cells in both NC and AD subjects are comprised of monocytes, conventional DCs (cDCs) and plasmacytoid DCs (pDCs). While the numbers of FcεRIα+ IgE+ cDCs have no significant difference between NC and AD, FcɛRIα+ IgE+ monocytes and pDCs are significantly increased in AD patients compared to NC subjects. Collectively, our study identified a distinct FcɛRIα+ IgE+ cell population in human PBMCs, and this population is increased in AD. Further investigation is warranted to characterize the biological significance of this particular cell population in normal humans and AD patients.
Supported by grants from Genentech (ML41620)
Obesity Inhibits Innate Immune Functions During Pseudomonas aeruginosa Pneumonia
Authors: Huizinga Gabrielle P , Warheit-Niemi Helen I , Gallagher Katherine , Moore Bethany B , Singer Kanakadurga 
Published: January 2023

Abstract
Obesity is a major global public health concern. Worldwide, 39% of the population is overweight and 13% of the population is obese. Obesity contributes to many diseases, such as heart disease, stroke, some cancers, and notably, type 2 diabetes (T2D). Although T2D itself is a non-communicable disease, many patients with diabetes are more susceptible to microbial infections and exhibit a higher burden of disease. Although obese animals have an increased production of myeloid cells, previous work from our labs has shown that a failure to heal diabetic wounds corresponds to elevated levels of prostaglandin E2 (PGE2) in the inflammatory macrophages that are recruited to the wound. Furthermore, past studies from our lab have demonstrated that PGE2 signaling can impair the innate immune functions of macrophages. Therefore, we hypothesized that diabetic obese mice would be more susceptible to a respiratory Pseudomonas aeruginosa strain PA01 infection due to impaired function of lung resident and recruited macrophages. Preliminary studies demonstrate that obese diabetic mice do have an increased P. aeruginosa burden in the lung 24 hours after infection. Additionally, we have determined that naïve obese diabetic mice have an increase in lung neutrophils compared to lean mice, however, after infection with P. aeruginosa, these mice have a trend of decreased neutrophil recruitment. Additionally, functional assays show that macrophages and neutrophils from obese diabetic mice have a defect in killing P. aeruginosa. These observations suggest that obese diabetic mice have not only a defect in innate immune cell recruitment, but also a defect in innate immune cell function during bacterial pneumonia.
Supported by grants from NIH (T32 AI007528-21)
Innate type 2 immunity controls hair follicle commensalism by Demodex mites
Authors: Ricardo-Gonzalez Roberto R , Kotas Maya E , O’Leary Claire , Tenvooren Iliana , Marquez Diana , Singh Katelyn , Damsky William , Liao Chang , Schroeder Andrew , Cohen Jarish , Fassett Marlys S , Lee Jinwoo , Daniel Scott G , Bittinger Kyle , Diaz Roberto Efrain , Fraser James , Ansel Karl Mark , Spitzer Matthew , Liang Hong-Erh , Locksley Richard M 
Published: January 2023

Abstract
Demodex mites are obligate commensal parasites of hair follicles (HF) in mammals. Normally asymptomatic, inflammatory outgrowth of mites can accompany malnutrition, immune dysfunction and aging, but mechanisms restricting Demodex outgrowth and pathogenesis are not defined. Here, we show that control over mite HF colonization of mice requires ILC2s, IL-13, and its receptor IL-4Ra, but not IL-4 or the adaptive immune system. Epithelial HF-associated ILC2s elaborate IL-13 that attenuates HF and epithelial cell proliferation at anagen onset; in their absence, Demodex colonization leads to increased epithelial proliferation and replacement of gene programs for repair by aberrant inflammatory programs leading to loss of barrier function and premature HF exhaustion over time. Humans with rhinophymatous acne rosacea, a nasal inflammatory condition associated with a high burden of Demodex, had increased HF inflammatory cells with decreased type 2 cytokines, consistent with the inverse relationship seen in mice. Our studies uncover a critical role for skin ILC2s and IL-13, which comprise an immune checkpoint necessary to sustain cutaneous integrity and restrict pathologic infestation by colonizing HF mites.
This work was supported by the National Institutes of Health (AR007175 to R.R.R.G. and M.S.F, AR075880 to R.R.R.G, HL140868 to M.E.K., DK121476 to C.E.O., AI159229 to W.D., AR074556 to M.S.F., AI026918 and HL107202 to R.M.L.), Dermatology Foundation (R.R.R.G., M.S.F.), A.P. Giannini Foundation (R.R.R.G, M.E.K.), Robert Wood Johnson Foundation (R.R.R.G.), Howard Hughes Medical Institute (R.M.L.), University of California Tobacco-Related Disease Research Program (T29IP0554 to J.S.F.), and the Sandler Asthma Basic Research Center at the University of California San Francisco. R.E. Díaz was supported by NSF GRFP (#1650113). R.E. Díaz is a Howard Hughes Medical Institute Gilliam Fellow (#GT11377).
The role of IL-1a during early-stage Pseudomonas aeruginosa infection of the corneas
Authors: Ratitong Bridget , Marshall Michaela , Dragan Morgan , Anunciado Charissa , Pearlman Eric 
Published: January 2023

Abstract
Pseudomonas aeruginosa is an important cause of dermal, pulmonary and ocular disease. Our studies have focused on P. aeruginosa infections of the cornea as a major cause of blinding microbial infections. The infection leads to an influx of innate immune cells with neutrophils making up to 90% of recruited cells during early stages. We previously reported that the proinflammatory cytokines IL-1a and IL-1b were elevated during infection. Infected Il1b−/− mice developed more severe corneal disease that is associated with impaired bacterial killing as a result of defective neutrophil recruitment to the corneas. We also reported that neutrophils are an important source of IL-1b and IL-1a.
To examine the role of IL-1a in Pseudomonas aeruginosa keratitis, we inoculated corneas of C57BL/6 (WT), Il1a−/−, Il1b−/− and Il1a−/−Il1b−/− (DKO) mice with 5×10^4 ExoS expressing P. aeruginosa (PAO1 strain). We identified neutrophils and monocytes as the main producers of IL-1a which peaked at 24 hours post infection (hpi). Depletion of neutrophils or monocytes led to more severe corneal disease and higher bacterial burden. Il1b−/− and DKO mice have significantly higher bacterial burden that was consistent with impaired neutrophil and monocyte recruitment to the corneas. Surprisingly, Il1a−/− mice had the opposite phenotype with significantly less bacteria than WT mice. There were no significant differences in neutrophil recruitment. However, we hypothesize that Il1a−/− neutrophils have enhanced antimicrobial functions that resulted in more effective bacterial killing which we are addressed by RNA sequencing of neutrophils isolated from WT or Il1a−/− corneas.
Supported by grants (EP) RO1: EY18612 and (BR) F31: EY032312-01