bluuebunny/crossref_metadata_2025_split huggingface dataset:
Identification of antigen-specific antibody responses associated with upper genital tract pathology in mice infected with Chlamydia muridarum (166.3)
Authors: Zeng Hao , Zou Quanming , Zhong Guangming 
Published: January 2023

Abstract
Urogenital infection with C. trachomatis in some women can lead to upper genital tract pathologies such as hydrosalpinx, potentially affecting fertility. In the current study, 27 of 40 mice intravaginally infected with C. muridarum developed visible hydrosalpinges in the oviduct while the remaining 13 did not although all infected mice displayed a similar infection time course. Antisera from the 40 mice recognized 130 out of 257 C. muridarum proteins as antigens and 17 as immunodominant antigens. Importantly, the 27 mice with hydrosalpinx preferentially recognized two C. muridarum proteins (TC0582 & TC0912; thus, designated as pathology-associated antigens) while the 13 mice with no hydrosalpinx preferentially recognized 10 proteins designated as non-pathology antigens. The preferential recognition was validated by absorption and independently confirmed in Western blot. A fragment of TC0912 was found to improve the differentiation of hydrosalpinx from non-hydrosalpinx mice. TC0582 is a highly conserved ATP synthase and it may contribute to chlamydial pathogenesis via similar mechanisms hypothesized for the highly conserved HSP60. Thus, we have identified chlamydial antigens and epitopes that are associated with either susceptibility or resistance to upper genital tract pathology, which will help us to further understand chlamydial pathogenesis and develop anti-Chlamydia subunit vaccines.
C1q engages leukocyte-associated inhibitory receptor (LAIR)-1 and inhibits monocyte-derived dendritic cell differentiation (167.1)
Authors: Son Myoungsun , Santiago-Schwarz Frances , Diamond Betty 
Published: January 2023

Abstract
Leukocyte-associated inhibitory receptor (LAIR)-1 is a collagen receptor. Cross-linking of LAIR-1 suppresses the differentiation of dendritic cells (DCs). We found that C1q, which is known to have an inhibitory role in the differentiation of DCs, maintained the expression of LAIR-1 in cells transitioning between monocytes and DCs. Since C1q contains a collagen-like tail, we hypothesized that a C1q/LAIR-1 interaction leads to DC lineage arrest. In order to assess interactions between C1q and LAIR-1, we explored three models. First, HEK293T cells were transfected with a plasmid encoding LAIR-1. Labeled C1q associated with LAIR-1 expressing cells in a dose specific manner; this binding was inhibited by soluble LAIR-2, which exhibits the same collagen binding capacity as LAIR-1. Second, THP-1 cells, a LAIR-1hi human monocytic leukemia cell line, exhibited a high degree of binding to C1q which was also blocked by sLAIR-2. Third, in primary human monocytes, sLAIR-2 blocked the effects of C1q on monocyte-derived DC differentiation. We confirmed a direct interaction between C1q and LAIR-1 by dot blot analysis. Moreover, LAIR-1 was phosphorylated in a C1q-dependent manner in primary monocytes, demonstrating that C1q is an inducer of LAIR-1/ITIM-specific phosphorylation. Collectively, these data indicate that C1q functions as a natural ligand for LAIR-1. These findings provide novel insights into how C1q may prevent unwarranted immune responses.
RNA splicing regulates the temporal order of TNF-induced gene expression (167.5)
Authors: Hao Shengli , Baltimore David 
Published: January 2023

Abstract
When cells are induced to express inflammatory genes by treatment with TNF the mRNAs for the induced genes appear in three distinct waves, defining gene Groups I, II and III or early, intermediate and late genes. To examine the basis for these different kinetic classes, we developed a PCR-based procedure to distinguish pre-mRNA synthesis from mRNA synthesis. It showed that the three Groups initiate transcription virtually simultaneously but that delays in splicing characterize Groups II and III. We examined the elongation times and polyadenylation timing, concluding that pre-mRNA synthesis is coordinate but splicing differences directly regulate the timing of mRNA production. Coupled to previous measurements of the half-life of mRNAs, the kinetic parameters can be combined in a general mathematical model of pre-mRNA conversion to mRNA that reproduces the experimental kinetics without recourse to differences in transcription.This model could be a generally relevant description of sequential transcriptional events in response to inducers.
19S ATPase subunits of the 26S proteasome play critical roles in transcription elongation. (167.7)
Authors: Greer Susanna , Maganti Nagini , Thakkar Meghna , Truax Agnieszka 
Published: January 2023

Abstract
Major histocompatibility class II molecules are cell surface glycoproteins that present extracellular peptides to CD4+ T cells and initiate adaptive immune responses. MHC II molecules are inducibly expressed in response to interferon gamma and are tightly regulated at the level of transcription by a master regulator, the class II transactivator, CIITA. We have recently shown that the 26S proteasome, itself a master regulator of proteins, regulates transcription initiation at interferon gamma inducible CIITApIV and MHC II genes in a degradation independent manner. The 26S proteasome consists of two major subunits, a 19S regulatory particle and a 20S proteolytic core. The 19S contains six ATPases which associate with MHC II and CIITA promoters and play important roles in transcription initiation by recruiting critical histone modifying enzymes. To determine if the 19S ATPases function in transcription elongation, 19S ATPase binding and activity in CIITApIV coding regions was analyzed. ChIP assays indicate significant binding of 19S ATPases in CIITA coding regions, and knockdown of 19S ATPases results in significant decreases in RNA pol II binding throughout CIITApIV coding regions. Further, knockdown of 19S ATPases has minimal impact on the expression of short CIITApIV transcripts but significant negative impact on long transcript expression, indicating roles for 19S ATPases in RNA pol II processivity at CIITApIV and likely other inducible mammalian genes.
Macrophage migration inhibitory factor enhances dengue virus replication through autophagy formation and ROS generation (168.10)
Authors: Chuang Yung Chun , Yeh Trai Ming 
Published: January 2023

Abstract
Macrophage migration inhibitory factor (MIF) is a proinflammatory cytokine which has been identified as a risk factor in dengue virus (DENV) infection. Previous study showed MIF deficient mice exhibit lower virus titer than wild type mice during DENV infection. However, the mechanism is still unknown. Herein, we first examined whether MIF interfere DENV replication in vitro. By using flow cytometry assay, we found both MIF inhibitor ISO-1 or MIF knock down could reduce DENV replication in Huh 7 cells. Moreover, we found that reactive oxygen species (ROS) of Huh 7 cells induced by DENV infection were also decreased in the presence of ISO-1. ROS is an inducer of autophagy which has been showed to be involved in DENV replication. Thus, we hypothesize MIF facilitate DENV replication through ROS generation and autophagy formation. We found ISO-1, MIF knock down, or ROS scavenger N-acetyl-L-cysteine (NAC) could reduce autophagy during DENV infection by western blotting analysis. The LC3 punctae formation was also reduced in MIF knock down Huh 7 cells during DENV infection. Taken together, blocking of MIF by its inhibitor or antibody may not only prevent inflammation but also viral replication during DENV infection.
Toll-like receptor 2 is required for complete protection against lethal HSV-1 encephalitis in a murine lip scarification model (168.25)
Authors: Kollias Christina , Jennings Stephen 
Published: January 2023

Abstract
Herpes simplex virus type 1 (HSV-1) is a ubiquitous human pathogen capable of causing fatal encephalitis in rare instances. The immediate recognition of the virus by pattern recognition receptors at the infection site is crucial for establishing an antiviral state and limiting nervous system involvement. The importance of TLR3 and TLR9 in the type I interferon-dependent protection against HSV disease has been well documented, however, the role of TLR2 is less clear. This study aims to define the function of TLR2 in a natural infection model of mucocutaneous HSV-1 disease. TLR2 is expressed on the cell surface of various cell types, and ligation leads to an NF-B-dependent inflammatory response. Here we demonstrate that Tlr2-/- mice are significantly more susceptible to HSV-1 disease than WT controls. Whereas Tlr2-/- mice have indistinguishable levels of infectious virus at the inoculation site, the deficient animals display faster nervous system invasion and elevated viral loads in the trigeminal ganglia, brainstem, and brain, indicating that TLR2-expressing cells in the nervous system aid in controlling HSV-1 replication and spread. Mortality from HSV-1 CNS infection is the result of virus-mediated cytotoxicity in combination with the ensuing neuroinflammatory response. We are currently assessing the magnitude and kinetics of CNS inflammation as well as the activation and infiltration of immune cells to the CNS in order to delineate the mechanism of TLR2 protection.
LPS enhances HIV-1-induced maturation and programmed death ligand-1 expression on human plasmacytoid dendritic cells (168.27)
Authors: Patel Meher , Fitzgerald-Bocarsly Patricia , Dai Jihong 
Published: January 2023

Abstract
Elevated plasma levels of lipopolysaccharide (LPS) resulting from disruption of gut mucosal integrity during HIV infection has been implicated as a major factor contributing to immune activation that is a hallmark of HIV infection. The negative costimulatory molecule, Programmed Death-1 (PD-1), and its ligand, Programmed Death Ligand -1(PD-L1), negatively regulate the function of exhausted CD8 T cells in chronic HIV-1 infection leading to suppression of specific anti-viral T cell responses. In HIV-infected individuals, increased PD-L1 expression on APCs correlates directly with viral load, indicating a potential effect of the virus on PD-L1 expression. Since the mechanisms of PD-L1 up-regulation in these settings are not understood, we investigated how PD-L1 expression is regulated in plasmacytoid dendritic cells (pDC). We also investigated the influence of LPS on virally stimulated pDC maturation and PD-L1 expression. By kinetic studies, we observed that LPS enhanced HIV-1 induced PD-L1, CD40 and CD83 expression on pDC, and that PD-L1 expression was up-regulated on matured pDC. IFN-α expression preceded PD-L1 expression on pDC following HIV-1 stimulation, but IFN-a by itself only modestly increased PD-L1 expression, indicating that up-regulation of PD-L1 on pDC was specifically a primary response to HIV stimulation. Together, these results suggest that pDC adopt a tolerogenic phenotype following maturation during HIV-1 infection and LPS helps mediate this process.
Modeling childhood resistance to influenza mortality in mice (169.14)
Authors: Suber Freeman , Kobzik Lester 
Published: January 2023

Abstract
In the 1918 influenza pandemic, infected children between ages 5-14 had low mortality. To study the mechanisms for childhood resistance to disease mortality, we created a murine model of mortality difference from influenza (flu) in pre-pubertal (Pre-P) vs. post-pubertal (P) mice (onset is day 28). We compared mortality rates in C57BL/6 (Pre-P) and (P) mice infected with the same viral dose (1 HAU of A/PR/8/34). We also used gonad-intact and gonadectomized (Gx) mice that received hormone replacement to test the effect of sex steroids on morbidity and mortality during flu infection. Mortality was lower in Pre-P mice (22% for infections started on postnatal day 25 (P25), 16% at P26) when compared to P mice (71% at P28, n &gt; 18, p&lt;0.05). Data were similar for both sexes. In the sex steroid-ablated Gx mice, mortality was also lower (23 % vs. 64%, 28% vs. 50% for the castrated vs. sham-castrated, and ovariectomized (Ox) vs. sham-Ox mice, respectively). Gx female mice treated with estrogen (E) replacement (i.p. (E), 10ug/100ul) showed an increase in mortality (28% in Ova+vehicle (V) vs. 71%, 66% and 80% respectively, for the Ova+E, sham-Ova+V and sham-Ova+E mice, p=0.057). Histopathology showed severe lung injury with hyaline membranes in all E-intact, however, this pathology was absent in (V)-treated Gx mice. The model will be useful for further studies of how sex hormones, e.g. (E), and other host factors may contribute to mortality after influenza infection.
The IL-10-/- mouse as a model of chronic Lyme arthritis. (169.16)
Authors: Sonderegger F. Lynn , Ma Ying , Weis John , Weis Janis 
Published: January 2023

Abstract
IL-10 suppresses the development of arthritis in Borrelia burgdorferi infected mice. Infected IL-10-/- mice were previously found to have a robust and sustained interferon-inducible response in joint tissue, and elevated IFN-γ in sera. Treatment of IL-10-/- mice with anti-IFN-γ reduced arthritis severity and suppressed interferon-inducible transcripts to wild type levels, thereby linking dysregulation of IFN-γ to disease in the IL-10-/- mouse. Arthritis in IL-10 deficient mice was associated with elevated numbers of NK cell, NKT cell, α/β T cell, and macrophage infiltration of the infected joint. FACS lineage sorting revealed NK cells and CD4+ T cells as sources of IFN-γ in the joint tissue of IL-10-/- mice. These findings suggest the presence of a positive feedback loop in the joint tissue of infected IL-10-/- mice, where production of inflammatory chemokines, infiltration of IFN-γ producing cells, and additional production of inflammatory cytokines result in arthritis. This mechanism of arthritis is in contrast to that seen in C3H mice, where arthritis development is linked to transient production of Type I interferon, and develops independently of IFN-γ. Due to the sustained interferon response driven by NK cells and T cells, we propose the IL-10-/- mouse as a potential model to study the prolonged symptoms observed in some human Lyme disease patients.
Salmonella enterica Typhimurium evasion of caspase-1 dependent flagellin recognition promotes mucosal injury and systemic dissemination (169.4)
Authors: Lai Marvin , Quarles Ellen , Lopez-Yglesias Americo , Zhao Xiaodan , Smith Kelly 
Published: January 2023

Abstract
Salmonella enterica Typhimurium is a flagellated bacterium and one of the leading causes of gastroenteritis in humans. Bacterial flagellin is critical for motility and also a prime target of the innate immune system. Innate immune recognition of flagellin is mediated by two independent innate immune pathways, TLR5 and Naip5-Naip6/NlrC4/Caspase-1. The functional significance of each of the two independent flagellin recognition systems in innate immunity to Salmonella infection is modest, and we hypothesized that this was due to efficient modulation of flagellin expression in vivo to evade innate immune detection. Salmonella deficient in the anti-sigma factor flgM overexpress flagellin, are attenuated in vivo, and this attenuation is dependent on flagellin expression. In this study, we used flgM- Salmonella to determine if flagellin recognition by the innate immune system was responsible for the attenuation of flgM- S. typhimurium, and to dissect the contribution of each flagellin recognition pathway to bacterial clearance, inflammation and infection. Our results indicate that Salmonella evasion of caspase-1 dependent flagellin recognition is critical for establishing systemic infection and inducing intestinal inflammation and injury during intestinal infection. In contrast, TLR5 paradoxically promotes bacterial colonization in the cecum, but does not influence systemic infection, and plays a modest role in intestinal inflammation.
Inflammation-resolving mediator resolvin E1 inhibits osteoclast fusion. (169.6)
Authors: Zhu Min , Van Dyke Thomas , Gyurko Robert 
Published: January 2023

Abstract
Resolution of inflammation is an active, highly coordinated process leading to the return of tissues to homeostasis. The ω-3 polyunsaturated fatty acid derivative RvE1 is a proresolving receptor agonist that has been demonstrated to protect from inflammatory bone loss by inhibiting osteoclast formation and bone resorption. It is unclear whether the actions of RvE1 in inflammatory bone disease are indirect through modulation of inflammation or the direct action of RvE1 on bone cells. Investigation of the direct impact of RvE1 treatment on the specific stages of osteoclast maturation in vitro revealed that RvE1 targets late stages of osteoclast maturation. Time-lapse vital microscopy revealed that RvE1 inhibits migration and fusion of osteoclast precursors. Western blot analysis revealed that RvE1 specifically down-regulates the pivotal osteoclast fusion protein DC-STAMP (dendritic cell specific transmembrane protein) through the leukotriene receptor BLT-1. RvE1 does not change NFATc1 induction or nuclear translocation; however, NFATc1 binding to the DC-STAMP promoter was inhibited by RvE1 treatment. The data suggest that RvE1 inhibits the binding of the transcription factor NFATc1 to the promoter of osteoclast fusion protein DC-STAMP, leading to DC-STAMP down-regulation and attenuation of osteoclast fusion. Our observations establish a dual role for inflammation resolution in innate immunity as well as bone preservation through the direct regulation of bone cell function.
Memory Treg cells regulate the immune response to influenza virus infection (170.10)
Authors: Brincks Erik , Roberts Alan , Cookenham Tres , Sell Stewart , Blackman Marcia , Kohlmeier Jacob , Woodland David 
Published: January 2023

Abstract
Regulatory CD4+FoxP3+ T cells (Treg) are key regulators of inflammation and control the magnitude of cellular immune responses to viral infections. However, little is known about Treg regulation of recall responses to previously-encountered pathogens. Here we investigated the influence of Treg on recall responses to influenza virus infection. Utilizing influenza NP311-325/I-Ab Class II tetramers, we tracked the antigen (Ag)-specific Treg during primary and secondary influenza virus infections in C57BL/6 mice. Ag-specific Treg accumulated in the lung-draining lymph node and lung parenchyma during secondary virus infection with accelerated kinetics relative to primary influenza infection, suggesting the existence of a “memory” Treg pool. These Treg contributed to the control of in vivo responses to secondary influenza infection by limiting the magnitude of the Ag-specific memory CD8+ T cell recall response and by contributing to the control of pulmonary inflammation as well as airway chemokine/cytokine expression. In vitro studies verified that memory Treg cells can effectively control the proliferation of memory CD8+ T cells in an Ag-specific fashion, and that this regulatory function was MHC class II dependent. Together, these data demonstrate a previously unappreciated role for Treg in shaping the cellular immune response to secondary influenza virus challenges and need to be considered during vaccine development.
Spred-2 negatively regulates influenza A virus (H1N1)-induced pneumonia (170.11)
Authors: Ito Toshihiro , Yoshimura Akihiko , Matsukawa Akihiro 
Published: January 2023

Abstract
Influenza A (H1N1) viral infections have been identified as the etiologic agents for historic pandemics, and contribute to the annual mortality associated with acute viral pneumonia. Many studies have elucidated the functions of H1N1-viral proteins of this negative-strand RNA virus have been well elucidated. However, the virus-induced intracellular signaling events remain unknown. The Raf/MEK/ERK cascade is the prototype of mitogen-activated protein (MAP) kinase cascades and has an important role in cell growth, differentiation, and survival. The Sprouty-related Ena/VASP homology 1-domain-containing protein (Spred) has recently been identified as a negative regulator of Raf-dependent ERK activation. Here, we demonstrate that Spred-2-knockout (KO) mice led to higher mortality with greater virus load compared with wild-type (WT) mice during influenza A (H1N1) viral infection. In addition, Spred-2 KO mice showed more severe pneumonia with higher mRNA levels of Type-I IFNs (IFN-α and IFN-β) and pro-inflammatory cytokines (TNF-α and IL-6). Moreover, administration of MEK-inhibitor, U0126, improved mortality with lower viral load with lower mRNA levels of Type-I IFNs and pro-inflammatory cytokines. Together, the results of this study show that Spred-2 negatively regulates anti-viral immunity during H1N1 infection. We propose that Spred-2 might be a novel therapeutic target for controlling the immune response against influenza H1N1 virus infection.
Respiratory Syncytial Virus infection in mice reduces spatial learning capacity and long term potentiation. (170.16)
Authors: Espinoza Janyra , Cortes Claudia , Valenzuela Javier , Sandoval Rodrigo , Gómez Roberto , Céspedes Pablo , Pancetti Floria , Riedel Claudia , Kalergis Alexis 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is the major cause of bronchiolitis and pneumonia in children, the elderly and immune-compromised individuals causing significant health burden worldwide. Clinical reports have shown that infants infected with RSV suffer CNS disorders like seizures; central apnea, lethargy, feeding or swallowing difficulties, abnormalities of tone or strabismus, abnormalities of the cerebrospinal fluid (CSF) and encephalopathy . Whether these CNS disorders result from either RSV replication or immune system reactivity at nervous tissue is still unknown. In this context, clarifying RSV entry, localization and spread on CNS will seed insights on RSV neuropathology. Preliminary evidences have shown the presence of viral RNA and anti-RSV antibodies in the cerebrospinal fluid of infected host. We show by Immunofluorescence analysis the presence of RSV proteins and by RT-PCR the nucleocapsid transcripts in mice infected with RSV. After one month that the RSV infection has cleared out, these mice showed reduced capacity for spatial learning and long-term potentiation in response to theta-burst stimulation to the Schaffer collateral pathway in the area of CA1 of the hippocampus Ammon’s horn stratum radiatum. These are the first evidences that support that RSV infection can alter brain function.
Galectin-3 promotes HIV-1 budding through association with Alix and Gag-p6 (170.25)
Authors: Chen Huan-Yuan , Wang Sheng-Fan , Tsao Ching-Han , Hsu Daniel , Liu Fu-Tong 
Published: January 2023

Abstract
Galectin-3 (Gal3), a β-galactoside-binding lectin, has been reported to regulate the functions of a number of immune cell types. We demonstrated that Gal3 is translocated to the immunological synapse in T cells upon T cell receptors engagement and associated with ALG-2-interacting protein X (Alix). Alix is known to coordinate with endosomal sorting complex required for transport (ESCRT) to promote HIV-1 virion release through binding to the HIV-1 Gag-P6 protein. We hypothesized that Gal3 plays a role in HIV-1 viral budding. Co-transfection of Gal3 and HIV-1 plasmids in HEK293T cells indicate that endogenous Gal3 facilitates HIV-1 budding. This effect was inhibited by knocking down Gal3 expression by shRNA. Immunoblotting of trypsin-treated virions and immuno-electron microscopy indicate that Gal3 is mainly located inside the HIV-1 virions. Immunofluorescent staining and coimmunoprecipitation (Co-IP) suggest that Gal3, Alix, and Gag-p6 are colocalized in HIV-1-infected cells. Notably, Gal3 expression was found to promote the association between Alix and Gag-p6 as demonstrated by Co-IP. Co-transfection of Gal3 and HIV-1 plasmids in Alix knocked-down cells indicate that promotion of HIV-1 budding by Gal3 is mediated through Alix. Finally, knocking down Gal3 expression in primary CD4+ T cells resulted in a significant decrease of HIV-1 titer. Our results indicate that endogenous Gal3 facilitates the HIV-1 virus budding through stabilizing the association between Alix and Gag-p6.