bluuebunny/crossref_metadata_2025_split huggingface dataset:
CCR5-mediated recruitment of NK cells to the kidney is a critical step for host defense to systemic Candida albicans infection
Authors: Kang Sang W. , Tran Vuvi G. , Nguyen Nu Z. N. , Lee Saerom , Kim Juyang , Kim Hye J. , Lee Jong S. , Cho Hong R. , Kwon Byungsuk 
Published: January 2023

Abstract
CCR5 regulates the trafficking of various immune cells to the site of infection. Expression of CCR5 and its ligands were rapidly increased in the kidney after systemic Candida albicans infection and infected CCR5−/− mice showed increased mortality and morbidity, indicating that CCR5 contributes to an effective defense mechanism against systemic C. albicans infection. The susceptibility of CCR5−/− mice to C. ablicans infection was due to their impaired capacity of fungal clearance, which in turn resulted in exacerbated renal inflammation and damage. CCR5-mediated recruitment of NK cells to the kidney in response to C. albicans infection was necessary for the anti-microbial activity of neutrophils, the main fungicidal effector cells. Mechanistically, C. albicans rapidly induced expression of IL-23 and IL-15 by CD11b+CD11c+ dendritic cells (DCs) and Ly6C+ monocytes, respectively. IL-23 and IL-15 in turn augmented the fungicidal activity of neutrophils through GM-CSF production by NK cells. As GM-CSF potentiated production of IL-23 and IL-5 in response to C. albicans, a positive feedback loop formed between NK cells and DCs or Ly6C+ monocytes seemed to function as a central amplification point for host defense. Taken together, our results suggest that CCR5-mediated recruitment of NK cells to the site of fungal replication is a critical step that underlies innate resistance to systemic C. albicans infection.
Eosinophils in tick transmitted ehrlichial infection
Authors: Saito Tais B , Walker David H 
Published: January 2023

Abstract
Vector-borne diseases pose significant global health concerns with tick-borne disease doubling over the past 13 years. Tick-borne ehrlichiosis are life-threatening diseases that affect humans and animals. Many studies have been focused on the pathogenesis of these infections; however not much is known about in vivo immune responses to tick transmitted ehrlichiosis. With our model of a human pathogen Ehrlichia (EML) transmitted by ticks, we observed intense changes at the site of infection that persisted for several days. Lethal infection suggests an involvement of vascular dysfunction in disease pathogenesis. Therefore, the goal of this study was to evaluate the granulocyte response to tick transmission, primarily eosinophils. Skin site of the arthropod attachment showed intense infiltration of granulocytes, extending through dermal and subcutaneous tissue. The predominant cells contained eosinophilic granules and were surrounded by other poly and mono-nuclear cells. Also, we further identified increased cellular signaling associated with granulocyte recruitment and vascular dysfunction. The progression of disease was also characterized by increased eosinophils in the blood and immune mediators (e.g. IL-1β) in serum, indicative of proliferation, chemotaxis, and activation of these cells. A needle infection model demonstrated that granulocytes were implicated in immunopathology, bacterial replication, over-production of cytokines/chemokines. We believe that tick transmitted ehrlichiosis induces eosinophilic inflammation that result in release of an arsenal of mediators that regulate inflammation and vascular permeability and could be involved in the establishment of infection and/or disease development.
Demonstration of TLR response in O. mykiss by the bacterial 23S rRNA motif
Authors: Head Kelly , Kobayashi Koichi S , Criscitiello Michael F , Vijayan Saptha 
Published: January 2023

Abstract
The innate immune system is designed to recognize conserved pathogenic sequences known as pathogen-associated molecular patterns (PAMPs), and it is through the modification of these PAMPs that pathogens can subvert innate immune mechanisms. The target of this study is a conserved motif in the bacterial 23S rRNA, which demonstrates a reduced ability to mutate due to lethality to the organism from degraded ribosomal function. The detection of this motif through the pattern recognition receptor (PRR) TLR13 was demonstrated to elicit an immune response across eight animal phyla and Protistan amoeba phyla through this receptor or its orthologs. In teleost fish, the representative model rainbow trout (Oncorhynchus mykiss) was used to study 23S rRNA recognition by TLR22 and TLR13 initiation of an immune response.
mTORC1-mediated macrophage polarization into M1 Contributes to Ehrlichia-induced sepsis
Authors: El Andaloussi Abdeljabar , Haloul Mohamed Abdalla , Kader Muhamuda , Tominello Tyler , Wells Jakob Z. , Ismail Nahed 
Published: January 2023

Abstract
Macrophages heterogeneity that undergo dynamic changes in phenotype and function as well as reprograming of immune response to multiple intracellular bacterial infections is an important key to understand the host responses to infection. Ehrlichia is an obligate Gram-negative intracellular bacterium that cause potentially fatal human monocytotropic ehrlichiosis (HME). We utilized murine models of mild and fatal ehrlichiosis caused by Ehrlichia muris and Ixodes Ovatus Ehrlichia (IOE), respectively, to evaluate the macrophages polarization to inflammatory (M1) and regenerative (M2). Our data show that in vivo and in vitro infections of macrophages with IOE significantly polarize macrophages towards M1, while EM infection enhances M2 polarization. M1 polarization of macrophages in IOE-infected mice was associated with recruitment and/or expansion of granzyme B+ neutrophils, NK cells, IL-17+ NKT cells, and IL-17+ CD4 Th17 cells compared to EM infection. We previously identified mTORC1 (mammalian target of rapamycin complex-1), a negative regulator of autophagy and the key mediator for immunopathology during IOE infection. We found that M1 polarization in the livers of IOE-infected mice is dependent on mTORC1 activation. Blockade of mTORC1 activation with rapamycin decreased frequency of Th17, and enhanced autophagy, which in turn decreased inflammation as well as the pathogenic immune response during lethal IOE infection. Together, these data reveal a key role of mTORC1 in M1 polarization of macrophages, which likely promotes Ehrlichia-induced sepsis. Understanding the dynamic changes of macrophage polarization and how it affects immune responses to infection is crucial for development novel therapeutic strategies.
Identification and characterization of Escherichia coli genes associated with grazing resistance to the social amoeba Dictyostelium discoideum
Authors: Snyder Michelle , Perez-Vazquez Marta , Johnson De’sha , Rasko David A. 
Published: January 2023

Abstract
Pathogenic Escherichia coli strains remain a significant health challenge, particularly in developing countries. The social amoeba, Dictyostelium discoideum, which phagocytizes bacteria for nutritional purposes, serves as a host model for several pathogenic bacteria, including E. coli. Here we have characterized the interactions of D. discoideum with 35 representative E. coli strains, and found that strains sensitive and resistant to D. discoideum grazing were found in each E. coli pathotype. Whole genome phylogenomic analysis revealed that grazing resistance is distributed among the phylotypes, although resistant strains are enriched in the B2 phylogenomic group. Comparative genomic analysis identified genes more prevalent among strains resistant to D. discoideum grazing, including genes associated with adhesion, carbohydrate modification, iron transport, signaling and metabolism. Interestingly, the gipA (growth in Peyer’s Patches) gene, which has been found associated with microbiota in patients with Crohn’s disease, was widely present in E. coli strains resistant for D. discoideum grazing. We are currently working to characterize the role that E. coli genes that have been found associated with grazing-resistance might play in resistance to phagocytosis by D. discoideum, through creation and analysis of E. coli strains manipulated for expression of the identified genes. Such characterization is aimed at providing insight into potentially novel E. coli virulence factors.
12/15-lipoxygenase supports inflammatory cytokine production and PMN recruitment during invasive aspergillosis
Authors: Mackel Joseph J , Jones MaryJane , Steele Chad 
Published: January 2023

Abstract
Eicosanoids are a family of inflammatory lipid mediators produced via the metabolism of arachidonic acid by a network of biosynthetic enzymes. We and others have recently shown that pathways within this network, specifically the cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX) pathways, participate in induction of protective immune responses during invasive aspergillosis (IA). Based on the high degree of cooperation and interconnection within the eicosanoid network, we hypothesized that a third core enzyme, 12/15-lipoxygenase (12/15-LOX), also may support innate antifungal responses. We report here that mice deficient in the gene encoding 12/15-LOX, Alox15, exhibit decreased survival and increased fungal burden in a model of IA. These defects were associated with decreased PMN numbers in the lung and decreased levels of PMN chemokines (CXCL1, CXCL2, CCL3) in Alox15−/− mice, while fungal killing by PMNs in vitro was unaffected. Alox15−/− mice produced lower levels of the inflammatory cytokines IL-17A, IL-22, IL-1α and IL-6 during infection. iNKT cells, which we have reported to be a major cell source of IL-22 during IA, were present in decreased numbers in Alox15−/− mice. This reduction was associated with lower levels of IL-7, a cytokine we have recently shown to be required for optimal numbers of iNKT cells during IA. Decreased IL-22 levels were further associated with decreased levels of IL-23. Together, these data indicate that 12/15-LOX is a critical player in induction of multiple aspects of the innate immune response to A. fumigatus.
Role of the protein CagA from Helicobacter pylori in the modifications of the human B lymphocyte cytoskeleton
Authors: Cervantes Rodrigo , Piedra-Quintero Zayda , Sandoval-Montes Claudia , Amieva Manuel , Torres-López Javier , Santos-Argumedo Leopoldo , Maravillas-Montero José Luis 
Published: January 2023

Abstract
The cytotoxin-associated gen A (CagA) is an oncogenic virulence factor of Helicobacter pylori that is related with the development of gastric cancer and gastric MALToma: a B cell non-Hodgkin’s lymphoma.
CagA has an important role in the development of cancer due to its promiscuous interaction with different signaling-mediators. The association of CagA with cytoskeleton regulators generates an effect that gives invasive characteristics to epithelial cells, thus explaining the evolution to late stages of the gastric carcinoma. Although the translocation of CagA has been demonstrated in B lymphocytes, its impact on MALToma development and its effects over B cell cytoskeleton have not been characterized.
Human Raji B cells were transiently transfected to express an EGFP-tagged CagA fusion protein. In culture, these cells displayed altered morphological and adhesion properties when compared with control cells. Fibronectin induced-spreading and adhesion assays were performed to assess the changes observed. The transfected cells exhibited atypical size and shape descriptors, determined by analyses of confocal microscopy images. Concomitantly, the adhesion of CagA+ Raji cells was observed reduced. These phenotypes could be explained by the diminished basal levels of ezrin that we detect in the CagA+ cells, determined by Western blot, that contrast with a high expression of this actin-regulatory molecule in Raji control cells.
Taken together, our results show that the expression of CagA produces important changes in B cell morphology as well as cell adhesion due to alteration in actin cytoskeleton regulation; changes that could explain an invasive and aggressive B lymphocyte profile.
Lymphotoxin β receptor: A crucial role in Toxoplasma gondii infection
Authors: Wichert Anne , Sorg Ursula , Degrandi Daniel , Pfeffer Klaus 
Published: January 2023

Abstract
After infection with the obligate intracellular protozoan parasite Toxoplasma gondii (T. gondii) the production of cytokines (especially Interferon γ (IFNγ)) induces potent cell autonomous effector mechanisms which can control the pathogen. Lymphotoxin β receptor (LTβR) mediated signalling plays an important role in the efficient initiation of innate and adaptive host responses to a variety of pathogens.
Therefore, the immune response to T. gondii infection was analyzed in vivo and in vitro in LTβR deficient (LTβR−/−) and wildtype mice (WT) mice. Compared to WT mice, LTβR−/− mice showed an increased parasite burden and a markedly increased mortality in the acute phase of T. gondii infection. FACS analysis revealed that while these mice are generally able to generate T. gondii specific CD8+ T cells this does not seem sufficient for clearing the infection. Tissue and serum of LTβR−/− mice revealed deregulated cytokine expression patterns and production, particularly regarding interferons and interleukins. Since IFNγ mediated upregulation of murine guanylate-binding proteins (mGBPs) is essential for parasite clearance, expression and localization of mGBPs was evaluated. In vivo, delayed/reduced up-regulation of mGBPs expression was observed, whereas initial in vitro experiments in LTβR−/− fibroblasts demonstrated that mGBPs can be upregulated after IFNγ treatment and are able to localize at the parasitophorous vacuole.
These data suggest that defects in cytokine signalling, especially IFNγ deregulation, may contribute to the decreased survival rates of LTβR−/− mice in T. gondii infection. New insights into the pathology of T. gondii could provide new therapeutic strategies for the treatment of human toxoplasmosis.
Effect of Sodium Butyrate Supplementation on the Gut Microbiome during Colorectal Cancer
Authors: Alrafas Haider Rasheed Daham , Busbee Brandon P. , Nagarkatti Prakash , Nagarkatti Mitzi 
Published: January 2023

Abstract
Colorectal Cancer(CRC) is most common cancer of gastrointestinal tract. In the current study, we investigated the effects of sodium butyrate (BUT) on azoxymethane-dextran sodium sulfate (AOM-DSS)-induced CRC murine model. The data shows that supplementation with BUT reduces overall CRC severity. Endoscopic and histopathological evaluation showed BUT decreased colonic tissue damage and tumor growth. In addition, BUT was able to decrease myeloid-derived suppressor cells (MDSCs) in the blood and BUT was able to altered T cells populations which included significant increases in Tregs and IL-10 producing T cells while decreasing Th1 and Th17 cells. To investigate alterations in the gut microbiome we performed 16S rRNA sequencing of cecal flushes and validated significant findings. The data showed AOM-DSS administration led to significant decreases in bacterial species Ruminococcus gnavus and Akkermansia muciniphila, however, mice that were treated with BUT showed a reversal in these gut microbial alterations. We quantified short chain fatty acids (SCFA). AOM-DSS administration led to a significant decrease in i-butyric and n-butyric acids, but mice supplemented with BUT restored these SCFA levels significantly. Lastly, we examined in vivo and in vitro expression of histone deacetylases (HDACs) after supplementing BUT. Results showed that BUT was able to decrease Class I (HDAC I) and class II (HDACII) in both in vivo and in vitro studies which correlated with a significant increase in Tregs. Collectively, these data showed that BUT can ameliorate CRC by preventing cancer-associated gut microbial dysbiosis through increase in i-butyric and n-butyric acids level which leads to an anti-inflammatory response by suppressing HDACs.
Cytokine mediated control of microbiota and inflammation in atherosclerosis
Authors: Koltsova Ekaterina , Peshkova Iuliia , Dzutsev Amiran , Aghayaev Turan , Hazen Stanley , Trinchieri Giorgio , Fatkhullina Aliia 
Published: January 2023

Abstract
Atherosclerosis is lipid-driven, chronic inflammatory disease of the arterial wall. While commensal microbiota is involved in the distal regulation of systemic immune responses, how this distant connection influences the development of atherosclerosis and what are the underlying mechanisms remains largely unknown. In a mouse model of atherosclerosis, we found that disease was augmented when expression of the otherwise inflammatory cytokine IL23 was ablated. IL23 and its immediate downstream target IL22 restrict atherosclerosis by preventing outgrowth of microbiota, as inactivation of IL23/IL22 signaling led to dysbiosis and expansion of bacteria with pro-atherogenic properties, due to defective production of antimicrobial peptides in the intestine. These pro-atherogenic bacteria contributed to elevated serum levels of several pro-atherogenic metabolites, which in turn induced osteopontin (OPN) expression by subsets of myeloid cells including aortic macrophages. Microbiota transfer from IL23 deficient mice accelerated atherosclerosis, while microbial depletion or IL22 administration reduced aortic osteopontin expression and ameliorated the disease. Overall, our work uncovers the innate inflammatory IL23-IL22 cytokine signaling axis as a key regulator of atherosclerosis that controls diet-induced expansion of pro-atherogenic microbiota, and argues for informed usage of cytokine blockers with regard to cardiovascular side effects driven by microbiota and inflammation
The role of oral pathobionts in the pathogenesis of gastrointestinal inflammation
Authors: Kamada Nobuhiko 
Published: January 2023

Abstract
Mounting evidence suggests that gut microbiota contributes to the pathogenesis of inflammatory bowel disease (IBD). However, the identity of disease-associated pathobionts is unknown. Recent studies showed that patients with IBD are colonized by atypical bacterial members, particularly those residing in the oral cavity (e.g., Enterobacteriaceae, Pasteurellaceae, Fusobacteriaceae, and Veillonellaceae). Given that patients with IBD often accompanied by oral inflammation and/or oral dysbiosis, it is conceivable that oral disease (inflammation, dysbiosis) may in turn impact on the development of intestinal pathology. In this study, we demonstrate that periodontal inflammation exacerbates colitis in mice. Periodontitis in mice was induced by insertion of the oral ligature. Colitis was induced by the administration of dextran sulfate sodium (DSS). Mice with periodontitis developed more severe DSS-induced colitis compared to those without periodontitis. During periodontitis, Enterobacteriaceae were expanded in the oral cavity. Amassed Enterobacteriaceae of oral origin were then ingested and ectopically colonized the colon. Gut colonization by the oral Enterobacteriaceae elicits the activation of the inflammasome and promotes inflammation. Taken together, inflammation in the oral mucosa may foster the abnormal expansion of oral pathobionts whose ectopic gut colonization aggravates IBD.
Toll-like Receptor 2/IL-1β signaling is required for sensing and responding to a commensal bacterium at the ocular surface
Authors: Zhu Wenjie , St. Leger Anthony , Almaghrabi Fatimah , Xu Xiaoyan , Caspi Rachel 
Published: January 2023

Abstract
Conjunctiva-associated lymphoid tissue (CALT) resembles a conventional mucosal immune tissue, and harbors a variety of immune cells. CALT is exposed to diverse microorganisms that come in contact with the ocular surface. Previously, we demonstrated that colonization of the ocular mucosa with the commensal bacterium, Corynebacterium mastitidis (C. mast), results in increased resistance of the ocular surface to infectious fungal and bacterial pathogens. Further, we showed that this effect is due to IL-17 produced by Vγ4+γδ T cells that respond to C. mast in an IL-1-dependent fashion. In this study, we show that the toll-like receptor 2 (TLR2) and IL-1β are important for IL-17 production, activation and proliferation of Vg4+ γδ T cells. Using in vivo and in vitro approaches, we show that cells of TLR2 KO mice have reduced production of IL-1β in response to C. mast. These mice also fail to recruit Vg4+γδ T cells and neutrophils to the conjunctiva. We interpret these data to mean that TLR2 is required for sensing this commensal on the conjunctiva and its draining lymph nodes to activate the inflammasome and consequent IL-1 production, which in turn drives the IL-17 response. Our data highlight the importance and the role of the innate receptor TLR2 in the generation of the ocular mucosal immune response and in maintenance of the homeostatic γδ T cell response at the ocular surface.
Gut antibody deficiency in CD19−/− mice results in a spontaneous Celiac-Like sprue
Authors: Mohammed Ahmed Dawood , Kubinak Jason L. 
Published: January 2023

Abstract
Primary immunodeficiencies are heritable disorders of the immune response that most commonly manifest as an inability to generate immunoglobulin A (IgA). Despite its prevalence, IgA deficiency is considered a benign form of antibody deficiency due to a lack of easily observed clinical symptoms. CD19 is an important co-receptor that facilitates B cell receptor signaling and B cell development into antibody-secreting plasma cells. CD19 deficiency is a known genetic risk factor for the development of common variable immunodeficiency (CVID). Here, we utilize the CD19−/− mouse model to quantify the role of IgA deficiency on gut homeostasis. Our results indicate that CD19−/− mice develop a severe gut IgA deficiency associated with aberrant anti-commensal IgA responses that result in the outgrowth of anaerobic bacteria in the gut. More importantly, anaerobic expansion results in intestinal malabsorption under steady-state conditions. Intestinal malabsorption is associated with defects in normal hepatobiliary circulation, vitamin deficiency, and dyslipidemia. Additionally, results from histological analysis and RNAseq experiments indicate that CD19−/− mice develop intestinal epithelial cell (IEL) lymphocytosis mediated by CD8aa+TCRgd lymphocytes. Finally, CD19−/− mice, while deficient in anti-gliadin antibody (AGA) production compared to WT mice, demonstrate a significantly stronger relationship between serum AGA titers and total serum IgG and IgA production compared to WT animals and have significantly elevated ileal expression of tissue transglutaminase 2. Collectively, we believe that we have identified a novel mouse model of sero-negative celiac disease that will be of great value to the celiac research community.