bluuebunny/crossref_metadata_2025_split huggingface dataset:
A comparative survey of Gopherus polyphemus hemoparasites in four different South Florida habitats
Authors: Cooney Brian Thomas , Elhassani Dana , Frazier Evelyn , Caruso Joseph 
Published: January 2023

Abstract
The gopher tortoise (Gopherus polyphemus) is a keystone species, for its burrows house more than 300 species of animals. Habitat destruction and its consequent fragmentation have led to a decline in populations within southeastern ranges of the United States. Haemogregarina (intracellular protozoan parasites) have previously been identified in the blood of gopher tortoises. High levels of blood parasitaemia have shown to be a potential indication of stress resulting from overcrowding. The goals of this study are: (1) to characterize hemoparasite species through the use of Polymerase Chain Reaction (PCR) from tortoise blood samples and the ticks attached to tortoises and (2) to determine if free ranging gopher tortoises that live in poorly maintained habitats exhibit higher prevalence and parasitaemia levels within their blood when compared to tortoises inhabiting better maintained sites with prescribed fires. Research goals will be examined at four sites: Blazing Star Preserve (BSP), Pine Jog Preserve (PJP), Florida Atlantic University Preserve (FAUP), and Johnathan Dickinson State Park (JDSP), to determine both hemoparasite prevalence and parasitaemia levels. PJP and JDSP are sites currently practicing fire management and herbicides, whereas FAUP utilizes mechanical and chemical management while BSP is not managed. We hypothesize that parasitaemia will be higher in poorly managed sites as a result of crowding, when compared to well managed sites. This study will benefit current conservation and management practices for gopher tortoises in South Florida and help provide a baseline study for reptile hemoparasites.
Comparative analysis of expression profiles of cytokines in Riemerella anatipestifer infection in ducks and chickens highlights the role of IL-17A in bacterial susceptibility
Authors: Kim Woohyun , Lillehoj Hyun S , Fernandez Cherry P , Min Wongi 
Published: January 2023

Abstract
Riemerella anatipestifer (R. anatipestifer) cause severe infection in ducks at up to 75% mortality, but corresponding infection in chickens is comparatively mild. In order to understand differences in susceptibility, both species infected with R. anatipestifer, then analyzed mortality, bacterial burden and expression profiles of cytokines in infected birds. As expected, ducks exhibited increased susceptibility to R. anatipestifer infection compared to chickens, as determined by mortality rate and bacterial burden. Interestingly, comparative expression analysis of immune- related genes in R. anatipestifer-infected tissues and -stimulated splenic lymphocytes obtained from both species revealed that IL-17A is strongly associated with Riemerella infection in only ducks. Moreover, marked expression of IL-6 which is associated with Th17 cell differentiation, but not TGF-β, was identified in infected tissues from ducks, but not those from chickens. Furthermore, treatment with 3,3′-diindolylmethane (DIM) and berberine (BBR) in ducks ameliorated the detrimental effects of R. anatipestifer infection, as determined by decreases in mortality rate and bacterial burden, as well as downregulation of IL-17A and IL-6 mRNA expression. Taken together, these results suggest that upregulation of IL-17A influenced susceptibility to R. anatipestifer infection and that anti-IL-17A agents could prove to be promising therapies for alleviating Riemerella infection.
Immunomodulation of Host Immunity by Bacteriodes fragillis Polysaccharide A (PSA) Prevents Viral Encephalitis
Authors: Chandran Ramakrishna , Liu Hiutung , Mazmanian Sarkis K , Cantin Edouard 
Published: January 2023

Abstract
A major impact of commensal microbiota on many aspects of host physiology including regulation of host immunity extends beyond the gut to remote sites, including the brain. Studies in mouse models have shown that the commensal Bacteroides fragilis and its capsular PSA can prevent various inflammatory disorders including colitis, experimental autoimmune encephalomyelitis and asthma. However, little is known about the interaction of gut bacteria and their products with the immune system during viral infection. We assessed the immunomodulatory potential of PSA in a murine model of herpes simplex virus (HSV) encephalitis (HSE). Fatal HSE results from inflammation of the brain in susceptible 129 strain of mice due to uncontrolled invasion by Ly6Chigh inflammatory monocytes (IM) and neutrophils. Naïve 129 mice pretreated with PSA or PBS were then given a 1-week course of the anti-viral drug acyclovir (ACV) from day 4-post HSV infection to simulate a clinical setting. PSA, but not PBS-treated mice survived with dramatically reduced brain inflammation including fewer degranulating IM and altered cytokine and chemokine profiles. Mesenteric lymph node cellularity was increased and IL-10 secreting ICOS+ CD73+ CD4+ T cells and CD73+ CD8+ T cells were induced by PSA treatment. Importantly, IL-10 deficient and Rag knockout mice were not protected, suggesting T/B cells derived IL-10 as the protective mechanism. Interestingly, B cells were required for PSA mediated protection. We infer that the microbiota augment immunity to HSV using pathways distinct from those required for protection in chronic autoimmunity models, and that probiotics in combination with antivirals might act synergistically to limit HSV induced inflammatory diseases.
Human microglia cells participate in inflammatory responses, viral reproduction and transmission in Japanese encephalitis virus infection
Authors: Lannes Nils , Neuhaus Viviane , Kharoubi-Hess Solange , Walch Michael , Summerfield Artur , Filgueira Luis 
Published: January 2023

Abstract
Japanese encephalitis virus (JEV) is a neurotropic flavivirus and a major cause of mortality and morbidity in humans. JEV-infected patients exhibit strong inflammation of the brain and an accumulation of viral particles in the hypothalamus and hippocampus. Microglial cells (MG) are the brain-resident macrophages and are proposed to serve as reservoir for JEV. Using primary human MG and a model of human monocyte-derived MG, this study explores the influence of JEV on chemokine ligands/receptors of human MG and the role of MG in viral replication and transmission to susceptible cells. To achieve this work, the attenuated inactivated JEV as used in vaccines and two live JEV strains were employed. JEV induced morphological changes of human microglia, consistent with an activated state. Upon exposure to live JEV, human microglia adopted an inflammatory state characterized by increased levels of CCL2, CXCL9 and CXCL10. Furthermore, both inactivated and live treated human microglia transiently up-regulated the fraktalkine receptor CX3CR1 in a dose dependent manner. Interestingly, JEV vaccine but not live JEV remarkably enhanced levels of MHCII expression on MG. Importantly, human microglia supported JEV replication. Although JEV-derived microglia was not infectious in supernatants, virus particles were highly infectious if preserved inside the cells. Indeed, human microglia contributes to viral transmission in cell-cell conditions. In conclusion, JEV-infected cells express higher levels of CX3CR1, a relevant chemokine receptor involved in cell migration and inflammation in the central nervous system. In long term infection, human microglia may be a source of neuronal infection and sustain JEV brain pathogenesis.
HIV and HIV Tat inhibit LPS-induced IL-23 production in human macrophages by distinct intracellular signaling pathways
Authors: Kumar Ashok , Gajnayaka Niranjala , Angel Jonathan 
Published: January 2023

Abstract
Monocyte-derived macrophages (MDMs) from HIV-infected patients and MDMs infected in vitro with HIV manifest inhibition of IL-12. Whether HIV infection or HIV accessory proteins such as tat, impact production of IL-23, a member of IL-12 family cytokines, in macrophages remains unknown. Our results show that in-vitro HIV infection, intracellular HIV-tat and HIV tat peptides inhibit LPS-induced IL-23 production in MDMs suggesting impairment of TLR-4 signalling.
To study the mechanism governing HIV- and HIV-tat-mediated inhibition of LPS-induced IL-23 production, we first established that p38 mitogen-activated protein kinase (MAPK), the phosphoinositide-3-kinase (PI3K), and SRC homology region 2 domain-containing tyrosine phosphatase-1 (SHP-1) positively regulated whereas c-Jun N-terminal kinase (JNK) MAPK negatively regulated LPS-induced IL-23 production in MDMs.
HIV-Tat downregulated TNF-receptor associated factor (TRAF)-6 and inhibitor of apoptosis-1 (cIAP-1) and caused decreased phosphorylation of downstream PI3K, and p38 MAPKs. In contrast, HIV-tat-mediated inhibition of JNK MAPK negatively regulated IL-23 production. However, SHP-1 and Src kinases were not inhibited by HIV-Tat and hence were not implicated in tat-mediated inhibition of LPS-induced IL-23 production.
In contrast to HIV-Tat, in vitro HIV infection of MDM inhibited LPS-induced IL-23 production via inhibition of p38 MAPK activation. Overall, HIV and HIV-Tat regulate LPS-induced IL-23 production in human macrophages via distinct mechanisms: HIV-Tat through the inhibition of cIAP-1-TRAF-6, and subsequent inhibition of PI3K and p38 and JNK MAPKs whereas HIV through the inhibition of p38 MAPK activation.
Dengue virus-elicited tryptase breaks tight junctions to induce endothelial permeability
Authors: Rathore Abhay P.S. , Syenina Ayesa , Gubler Duane , St. John Ashley L. 
Published: January 2023

Abstract
Dengue virus (DENV) is a mosquito-borne virus that causes a characteristic pathology in humans involving dysregulation of the vascular system. In some patients with dengue hemorrhagic fever (DHF), vascular pathology can become severe, resulting in extensive microvascular permeability and plasma leakage into tissues and organs. The predominant view in the field is that vascular leakage during infection is the result of immune pathology that is induced by cytokines and other de novo transcribed vasoactive factors released from infected cells. Recent evidence has shown that mast cells (MCs), which are granulated immune cells that line blood vessels and regulate vascular function, are able to detect DENV particles in vivo and promote vascular leakage, however the molecular mechanism of this vascular leakage is unknown. Here, we identified the pre-stored MC protease, tryptase, to be a product that promotes endothelial cell permeability during DENV infection, through inducing breakdown of tight junctions. Tryptase alone, injected in mice at concentrations equivalent to those found in the serum of human DHF patients, is able to promote substantial vascular leakage. This study provides a new molecular mechanism by which DENV can induce vascular pathology in vivo.
Synaptogyrin-2 Promotes Replication and Immune Evasion of A Novel Tick-borne Bunyavirus through Interacting with Viral Nonstructural Protein NSs
Authors: Xing Zheng , Sun Qiyu , Qi Xian , Wu Xiaodong , Liang Mifang , Li Chuan , Cardona Carol J 
Published: January 2023

Abstract
Synaptogyrin-2 is a non-neuronal member of the synaptogyrin family involved in synaptic vesicle biogenesis and trafficking. Little has been known about the function of synaptogyrin-2. Severe Fever with Thrombocytopenia Syndrome (SFTS) is an emerging infectious disease characterized by high fever, thrombocytopenia, and leukocytopenia with a high fatality and caused by a novel tick-borne phlebovirus in the family Bunyaviridae. Our previous studies have shown that viral nonstructural protein NSs formed inclusion bodies (IBs) which are involved in viral immune evasion as well as in viral RNA replication. In this report, we sought to elucidate the mechanism how NSs formed the IBs, a lipid droplet-based structure confirmed by NSs co-localization with perilipin A and ADRP. We identified synaptogyrin-2 to be highly upregulated in response to SFTS bunyavirus (SFTSV) infection through a high throughput screening and be a promoter of viral replication. We demonstrated that synaptogyrin-2 interacted with NSs and was translocated into the IBs, which were reconstructed from lipid droplets into large structures in infection. Viral RNA replication decreased and infectious virus titers were lowered significantly when synaptogyrin-2 was silenced in specific shRNA-expressing cells, which was in parallel to the reduced number of the large IBs restructured from regular lipid droplets and increased antiviral interferon induction. We hypothesize that synaptogyrin-2 is essential to promoting the formation of the IBs, to be virus factories for viral RNA replication and immune evasion through its interaction with NSs. The findings unveiled the function of synaptogyrin-2 as an enhancer in viral infection.
Distinct upstream role of type I IFN signaling in hematopoietic stem cell-derived and epithelial resident cells for concerted recruitment of Ly-6Chi monocytes and NK cells via CCL2-CCL3 cascade
Authors: Eo Seong Kug , Kim Jin Hyoung , Patil Ajit , Choi Jin Young , Kim Seong Bum , Uyangaa Erdenebileg 
Published: January 2023

Abstract
Type I interferon (IFN-I)-dependent orchestrated mobilization of innate cells in inflamed tissues is believed to play a critical role in controlling replication and CNS-invasion of herpes simplex virus (HSV). However, the crucial regulators and cell populations that are affected by IFN-I to establish the early environment of innate cells in HSV-infected mucosal tissues are largely unknown. Here, we found that IFN-I signaling promoted the differentiation of CCL2-producing Ly-6Chi monocytes and IFN-g/granzyme B-producing NK cells, whereas deficiency of IFN-I signaling induced Ly-6Clo monocytes producing CXCL1 and CXCL2. More interestingly, recruitment of Ly-6Chi monocytes preceded that of NK cells with the levels peaked at 24 h post-infection in IFN-I–dependent manner, which was kinetically associated with the CCL2-CCL3 cascade response. Early Ly-6Chi monocyte recruitment was governed by CCL2 produced from hematopoietic stem cell (HSC)-derived leukocytes, whereas NK cell recruitment predominantly depended on CC chemokines produced by resident epithelial cells. Also, IFN-I signaling in HSC-derived leukocytes appeared to suppress Ly-6Ghi neutrophil recruitment to ameliorate immunopathology. Finally, tissue resident CD11bhiF4/80hi macrophages and CD11chiEpCAM+dendritic cells appeared to produce initial CCL2 for migration-based self-amplification of early infiltrated Ly-6Chi monocytes upon stimulation by IFN-I produced from infected epithelial cells. Ultimately, these results decipher a detailed IFN-I–dependent pathway that establishes orchestrated mobilization of Ly-6Chi monocytes and NK cells through CCL2-CCL3 cascade response of HSC-derived leukocytes and epithelium-resident cells.
Calcitonin gene related protein antiviral role in LP-BM5 infection of astrocytes and microglia
Authors: Grlickova-Duzevik Eliza , Chiem Daniel , Vaughn James , Cao Ling 
Published: January 2023

Abstract
CGRP (calcitonin gene related protein) is a neuropeptide expressed by primary sensory neurons upon infection. LP-BM5 retrovirus infection induces profound immunodeficiency in B6 mice and has been used as a murine model of HIV infection. Previously, we showed that LP-BM5 induced increased CGRP expression in the spinal cords of infected mice. In vitro studies indicated a microglia dependent, CGRP-induced reduction of LP-BM5 viral loads in primary mixed glial cells. To further delineate CGRP’s effects on glial cells, we treated specific murine cell lines (C8D1A astrocyte cell line and C8B4 microglia cell line) with LP-BM5 and CGRP. We found that LP-BM5 was capable of infecting both microglia and astrocytes individually and PCR detection for selected CGRP receptor components indicated the presence of CGRP receptor in both cell lines. CGRP’s antiviral effect was observed in both astrocytes and microglia, however a lower dose of CGRP was required for microglia. Western blot analysis suggested differential changes in CGRP downstream signaling pathways in astrocyte vs. microglia upon CGRP treatment. In addition, type I interferons known for their antiviral properties were elevated in astrocytes following CGRP treatment. We propose that CGRP mediated signaling pathways may mediate type I interferon production thus further promote antiviral responses.
The JAK/STAT signaling cascades of multiple cytokines are dysregulated during West Nile virus infection.
Authors: Roby Justin Alexander , Keller Brian C , Ramos Hilario J , Diamond Michael S , Gale Michael J 
Published: January 2023

Abstract
The neurotropic arthropod-borne flavivirus West Nile virus (WNV) is responsible for sporadic outbreaks of fever and encephalitis in infected humans, with an almost global distribution of circulating strains. During WNV infection in mammals Interferon-α/β (IFN-α/β) drives signaling through JAK/STAT pathways to enhance the expression of antiviral genes with an overall protective effect against WNV infection. However, WNV strains have been demonstrated to be able to antagonize IFN-α/β signaling within infected cells, interrupting this JAK/STAT cascade and promoting viral replication. We hypothesized that JAK/STAT signaling downstream of multiple cytokines would be broadly inhibited in WNV infected cells as a consequence of viral replication. To assess the degree of cytokine signaling in infected cells, A549 and PMA-differentiated THP-1 cells were infected with WNV for 24 hr prior to acute course treatment with various cytokines. We reveal that STAT3 and STAT5 phosphorylation, in addition to STAT1 and STAT2, is blocked in WNV-infected cells in response to IFN-β. Remarkably, JAK/STAT signaling cascades downstream of IFN-γ, IFN-λ3, IL-4, and IL-6 are also similarly dysregulated upon WNV infection, suggesting that global JAK/STAT signaling may be inhibited independent of the identity of the cytokine receptor. The breadth and mechanisms of the WNV-imposed JAK/STAT signaling blockade will be presented.
IL-27 suppresses CD4 and CD8 T cell cytotoxicity and viral control during cytomegalovirus infection
Authors: Wehrens Ellen J , Wong Kurt , Gupta Ankan , Benedict Chris , Zuniga Elina 
Published: January 2023

Abstract
Cytomegalovirus (CMV) is a large DNA β-herpes virus that infects the majority of humans and is endemic in wild mice. CMV establishes life-long latency with sporadic reactivation, and both primary infection and reactivation can cause serious disease in patients with compromised or naïve immunity. Horizontal CMV transmission commonly occurs through prolonged replication in the salivary gland (SG). In mice, CD4 T cells are absolutely required to curtail SG persistence, whereas CD8 T cells control acute systemic infection. Both CD4 and CD8 CMV-specific T cells from infected individuals display a strong cytotoxic phenotype and are able to kill target cells ex vivo. However, the immune factors that promote or regulate differentiation of these cytotoxic T cells remain largely unclear. Here we show that the pleiotropic cytokine IL-27 plays a key role in regulating CMV-specific T cell responses. Infection of mice deficient for the IL-27 receptor a subunit (Il27ra−/−) with mouse CMV (MCMV), resulted in enhanced expression of KLRG1 by both CD4 and CD8 T cells, a marker associated with terminal differentiation and cytotoxicity. Consistently, MCMV-specific CD4 and CD8 T cells from Il27ra−/− mice showed increased expression of both granzyme A and FasL. Importantly, this enhanced cytotoxic phenotype correlated with improved control of MCMV persistence in the SG. Taken together, our data reveal an unexpected and novel role for IL-27 in restricting T cell cytotoxicity and control of MCMV persistence, and suggest that targeting IL-27 has the potential to limit disease caused by persistent viral infection.
Interferon-stimulated gene LY6E enhances entry of diverse RNA viruses
Authors: Mar Katrina Bockying , Eitson Jennifer , Schoggins John 
Published: January 2023

Abstract
The type I interferon (IFN) response is the primary cellular defense mechanism against viruses. IFN protects against viral infection by activating the expression of hundreds of interferon-stimulated genes (ISGs), some of which have potent antiviral effector activity. Our recent screening efforts to identify novel antiviral ISGs unexpectedly uncovered a small subset of genes that enhanced viral infectivity. The goals of this project are to characterize the mechanism of LY6E, an ISG that enhanced unrelated viruses from multiple families. Here we show that ectopic expression of LY6E enhances cellular infection by a subset of enveloped RNA viruses from diverse families, including yellow fever virus, influenza A virus, vesicular stomatitis virus, and O’nyong’nyong virus. The enhancement phenotype is dependent on cell lineage, with the strongest effects seen in fibroblast and monocytic cell lines. Ablation of endogenous LY6E by CRISPR/Cas9 reduces but does not abrogate viral infectivity, indicating that LY6E is important for optimal infection. Loss of LY6E does not alter antiviral protection by IFN, suggesting that the enhancing effects may be direct. Mechanistic studies reveal that LY6E enhances infectivity at an early step in the viral life cycle, after viral binding but prior to the establishment of replication. Visualization of single-cell infections by ImageStream confirms that LY6E enhances viral entry. We conclude that LY6E enhances viral uptake at the population level, which may be important for initiation of the cell-mediated antiviral immune response. Understanding the mechanism and significance of LY6E to the antiviral interferon response may aid in the development of novel antiviral therapeutics.
Exploring a possible role for the MHC Class II accessory molecule H2-O in the development of experimental autoimmune encephalomyelitis
Authors: Welsh Robin A , Song Nianbin , Kim Aeryon , Poluektov Yuri , Sadegh-Nasseri Scheherazade 
Published: January 2023

Abstract
HLA-DO (DO), or H2-O in mice, is a non-classical, non-polymorphic MHC Class II accessory molecule. Expressed primarily in the thymic medulla and B cells, little is known about its physiological role in vivo. To gain insight of what role DO might have in CD4 T cell selection, our laboratory has previously used in vitro biochemical experiments to show that DO binds peptide-receptive DR1 and enhances binding of DM-insensitive peptides to the HLA-DR1 molecule, while inhibiting the binding of DM-sensitive peptides. These observations led us to hypothesize that in vivo, DO might serve to optimize presentation of immunodominant epitopes in the thymic medulla; thereby ensuring proper negative selection in the thymus. Lack of DO then could lead to faulty negative selection and a larger precursor pool of autoreactive CD4 T cells in the periphery. To test this hypothesis, we utilized H2-O knock-out (KO) mice and the well characterized autoimmune murine model of experimental autoimmune encephalomyelitis (EAE). We found that H2-O KO mice have a faster onset of EAE when compared to C57BL/6 wild-type mice. The rapid onset of the disease correlates with the recovery of larger numbers of MOG tetramer specific CD4 T cells from the CNS of H2-O KO mice at all stages of disease. A comparison of MOG tetramer specific CD4 T cell precursors in naïve H2-O KO and H2-O WT mice demonstrated larger numbers of MOG specific CD4 T cells in H2-O KO mice. Our data suggests that loss of DO correlates with an increase in the number of autoreactive MOG CD4 in KO mice likely due to faulty negative selection.