bluuebunny/crossref_metadata_2025_split huggingface dataset:
Dectin-1 pathway activation is important to Cryptococcus neoformans killing (67.10)
Authors: Bocca Anamelia , Coelho Carolina , Casadevall Arturo 
Published: January 2023

Abstract
Cryptococcus neoformans (Cn) is an encapsulated yeast that causes life-threatening meningoencephalitis in immunocompromised patients. The infectious propagules are inhaled into the host’s lug and interact with alveolar macrophages. An adequate pattern of macrophage activation is crucial to the outcome of the infection. However, it has been very difficult to demonstrate macrophage fungicidal activity in vitro. The main goal of this work was to determine if differential activation of macrophages by the dectin-1 pathway could increase Cn killing and improve host survival. Peritoneal macrophages were stimulated with zymozan and co-cultured ex vivo with opsonized Cn (H99) to allow phagocytosis. Our results showed that after zymozan stimulation of macrophages, fungal killing was increased. Stimulation with zymosan was more effective in fungal killing than stimulation with depleted-zymosan. Blockade of dectin-1 receptor reverted fungal killing to control levels only in macrophages stimulated with depleted zymozan. The ROS production was lower than in control groups. There was also a higher acidification of endosomes in zymozan-stimulated groups. Taken together, the data suggests that dectin-1 pathway activation by zymozan contributes to Cn killing. However, for the interaction between encapsulated C. neoformans cells and macrophages dectin-1 stimulation may be inadequate because the polysaccharide capsule blocks access to cell wall structures that trigger the dectin-1 receptor.
Peptidoglycan recognition protein 3 (Pglyrp3) is associated with intestinal mucosal homeostasis and protection against colitis (67.12)
Authors: Jing Xuefang , Dziarksi Roman , Gupta Dipika 
Published: January 2023

Abstract
Peptidoglycan recognition protein 3 (Pglyrp3) is a bactericidal protein expressed in the epithelial cells of tongue, esophagus, stomach and intestine. Pglyrp3-deficient mice compared to wild type (WT) mice have increased sensitivity to dextran sodium sulfate (DSS)-induced colitis. The increased colitis is characterized by loss of epithelial cells, severe hyperplasia of the lamina propria and ulcers. The aim of this study was to determine whether Pglyrp3 plays a role in maintaining intestinal epithelial integrity by regulating proliferation and apoptosis of epithelial cells. We report that Pglyrp3-deficient mice treated with DSS have significantly higher TUNEL positive cells, increased Annexin V staining and higher levels of cleaved caspase 3 in the epithelial cells of the colon compared to WT mice. The number of bromodeoxyuridine (BrdU) positive cells, which indicates proliferating cells, is significantly lower in Pglyrp3-deficient mice compared to WT mice. Serum levels of FITC-dextran are significantly higher in DSS-treated Pglyrp3-deficient compared to WT mice, which indicates an increased loss of epithelial lining and loss of barrier function in Pglyrp3-deficient mice. Our results indicate that Pglyrp3 is important in maintaining the epithelial lining of the colon and loss of this protein results in increased apoptosis, decreased proliferation and increased loss of barrier function, which are important contributing factors to increased colitis in Pglyrp3-deficient mice.
Inflammatory macrophages in dengue virus infection pyroptosis, infectivity, and enhancement of endothelial permeability (67.5)
Authors: Hsieh Shie-Liang , Wu Ming-Fang , Chen Szu-Ting 
Published: January 2023

Abstract
Macrophages (Mϕ) are the major source of inflammatory cytokines during dengue virus (DV) infection It has been shown that macrophage differentiation under macrophage-colony stimulating factor (M-CSF) (denoted as M-Macrophage) is regarded as M2-like Mϕ, while GM-CSF-derived macrophage (denoted as GM-Mϕ) is regarded as M1-like Mϕ, or inflammatory macrophages. Compared to M-Mϕ, we found that GM-Mϕ is more susceptible to DV infection, and release higher amounts of proinflammatory cytokines and infectious viral particles when incubated with DV alone or DV-Ab immune complex. In addition, GM-Mϕ releases higher amounts of IL-1and IL-18 and is susceptible to DV-induced pyropsis. Moreover, culture supernatant from DV-infected GM-Mϕ causes more severe endothelial cell permeability change than that of M-Mϕ. It is interesting to note the differential expression of innate immunity receptors, including C-type lectin CLEC5A, were found between GM-Mϕ and M-Mϕ, and anti-CLEC5A mAb is able to inhibit the release of IL-1 and IL-18, capase I activation, and pyropsis in DV-infected GM-Mϕ and M-Mϕ.
Cyclophilin A restricts rotavirus infection by enhancing type 1 interferon response in infected epithelial cells (68.1)
Authors: Li Jintao , He Haiyang , Wu Yuzhang 
Published: January 2023

Abstract
Rotavirus (RV) infection is the main cause of acute dehydrating diarrhea in infants and young children below 5 years old worldwide. RV infection causes a global shutoff of host protein synthesis, however, previous studies have revealed that RV infection can also lead to the upregulation of host proteins, which could play crucial roles in RV infection. Using proteomic methods, we found that Cyclophilin A (CYPA), a peptidyl-prolyl cis-trans isomerase (PPIase), was upregulated in MA104 cells infected by human rotavirus (HRV). Following infection, CYPA was recruited to the viroplasm where it interacted with HRV structural protein VP2, to inhibit viral protein expressions, thus producing a repressive effect on HRV replication, which was dependent on its PPIase activity. We further show that CYPA was required for host type-1 interferon (IFN-I) response to HRV infection, and this effect was independent on its PPIase activity but dependent on JNK signaling pathway. Furthermore, we found that the expression of CYPA in enterocytes correlates to the period when BALB/c mice become resistannt to RV infection-induced diarrhea. Together, our data identify CYPA as a new host restrictive factor that confers protection against rotavirus infection.
A heterozygous S32I mutation in IκBα that causes EDID results in defective development of lymphoid organs and impaired B cell function (68.13)
Authors: Mooster Jana , Le Bras Severine , Manis John , Geha Raif 
Published: January 2023

Abstract
Autosomal ectodermal dysplasia with immunodeficiency (EDID) is caused by mutations in the inhibitor of NFκB α (IκBα), which is phosphorylated and degraded in response to several immune signaling pathways. We generated a mouse model of EDID by replacing one IκBα allele with a non-phosphorylatable IκBα, which resulted in decreased NFκB signaling. These mice have dysmorphic hair and teeth, as well as decreased serum immunoglobulins, and a severe decrease in their specific antibody response to T-dependent and T-independent antigens. The mice lack lymph nodes (LNs) and Peyers patches (PPs), and have a disrupted splenic architecture, with no marginal zone and fail to develop germinal centers (GCs). T cell function is intact but B cell function is deficient in vitro. Rag2 bone marrow chimeras formed proper lymphoid organs and had normal cutaneous hapten sensitivity but did not produce specific antibodies. This mouse model shows that autosomal EDID results in failure to develop LNs and PPs, disorganized splenic architecture, failure to develop GGs and an intrinsic B cell defect.
Repression of the H3K4 demethylase Jarid1b leads to activation of RSV-infected dendritic cells (68.18)
Authors: Ptaschinski Catherine , Mukherjee Sumanta , Petersen Bryan , Moore Martin , Kunkel Steven , Lukacs Nicholas 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is a common pathogen in children, with nearly all children being infected before the age of 2. Severe infection requiring hospitalization has been linked to the development of asthma later in life due to an improper Th2 skewing of the immune response. Dendritic cells (DCs) are key cells involved in presenting antigen to T cells and polarizing the T cell response. It has been reported that RSV interferes with the initiation of the adaptive immune response by inhibiting the production of type I interferons (IFN), including IFNβ, thus leading to a Th2 environment in the lungs. The mechanism by which this occurs is not fully understood. Epigenetic modulation of gene transcription has been shown to be important in regulating inflammatory pathways. We found that bone marrow derived DCs (BMDCs) infected with the RSV clinical isolate A2001/2-20 upregulated expression of Jarid1b, an H3K4 demethylase. Jarid1b has been described as a transcriptional repressor in cancer cells. We therefore hypothesized that Jarid1b plays a role in suppressing inflammatory genes in RSV infected DCs. We used siRNA to downregulate Jarid1b in BMDCs. Loss of Jarid1b led to a 10-fold increase in IFNβ compared to cells transfected with non-specific siRNA, as well as an increase in IL-6 and TNF-α. DC phenotype was unaffected as determined by flow cytometry. Investigations into the role that Jarid1b-induced DC regulation has in directing the T cell response are ongoing.
Recombinant modification of surfactant protein D (SP-D) increases neutralizing and opsonizing activity for influenza virus (68.19)
Authors: Hartshorn Kevan , Seaton Barbara , White Mitchell , McCormack Francis , Crouch Erika 
Published: January 2023

Abstract
Human SP-D inhibits seasonal, but not pandemic, influenza A virus (IAV). We modified key residues in the carbohydrate recognition domain (CRD) of SP-D to increase antiviral activity. Isolated neck and CRD (NCRD) preparations of SP-D were used. The NCRD of wild type human SP-D did not inhibit IAV (although the full length molecule does). We reported that the substitutions D325A and R343V in the NCRD markedly increase anti-IAV activity in vitro and in vivo. We now report similar activity of a double mutant containing D325S and R343V changes. These double mutants (called D325A+R343V or D325S+R343V) also inhibit pandemic IAV strains. Crystals of D325A+R343V show distinct interactions with viral glycans. D325A+R343V causes marked viral aggregation and increase in IAV uptake by neutrophils and monocytes while wild type SP-D NCRD does not. D325A+R343V inhibits viral protein synthesis in monocytes and suppresses IAV induced tumor necrosis factor (TNF) production. Surprisingly, the wild type human SP-D NCRD also suppresses IAV-induced TNF production without altering viral replication in monocytes. Hence, modification of residues surrounding the lectin site of SP-D markedly increases viral neutralizing and aggregating activity and also broadens the spectrum of inhibited strains. Inhibition of IAV-induced TNF production by monocytes is at least in part mediated by a direct effect on these cells independent of viral neutralization.
Transcriptional factor E2A regulates the differentiation of Th17 cells (69.10)
Authors: Nakatsukasa Hiroko , Maruyama Takashi , Chen Wanjun 
Published: January 2023

Abstract
The molecular mechanisms that direct transcription of the gene encoding the transcription factor RORγt, a master regulator of Th17 cells, remain ill-defined. We previously showed that transcription factor E2A is enriched at the Foxp3 promoter and regulates the differentiation of regulatory T cells in response to TGF-β. Since TGF-β is also required to generate Th17 cells, we hypothesized that E2A might also be involved in the differentiation of Th17 cells. We utilized Id3 deficient mice, as Id3 is reported to inhibit E2A binding to DNA, and found that Id3 deficient mice had a much greater frequency and absolute number of Th17 cells in the lamina propria and Peyer’s patches. In vitro study showed that Id3 deficient CD4(+)CD25(-) naïve T cells showed greater differentiation into Th17 cells in response to TGF-β1 plus IL-6. Treatment with TGF-β1 substantially enriched E2A at the Rorc promoter in naïve CD4(+) T cells. In addition, E2A knockdown by siRNA resulted much less Rorc transcription and IL-17 production in CD4(+) T cells stimulated with TGF-β1 plus IL-6. These data suggest that E2A plays an important role in promoting the RORγt expression through enrichment to Rorc promoter and the consequent Th17 differentiation. We plan to investigate how IL-6-mediated signaling pathway is integrated with E2A-mediated Rorc activation in directing IL-17 production in CD4(+) T cells.
How does the age-dependent loss of central tolerance relate to the regulation of ectopic gene expression? (69.6)
Authors: Michel Chloe , Kyewski Bruno 
Published: January 2023

Abstract
Aging is accompanied by an increased susceptibility to autoimmune diseases and a heightened cancer incidence. It has been suspected that age-related T cell-mediated autoimmunity is causally connected to the involution of the thymus. Thymic involution is characterised by a reduction of T cell output to the periphery. While it is well established that the heterogeneous thymic stroma is essential for T cell development, our knowledge of stromal cell function in aging is still limited. Here we report how aging affects: (i) the composition of the epithelial compartment in relation to other thymic cell types; (ii) the promiscuous expression of self-antigens in the medullary thymic epithelial cells (mTECs). Our results show that among mTECs, the mature subset decreased more rapidly with age than the immature subset. The expression of self-antigens per cell was not significantly different in old as compared to young animals, a finding compatible with their rapid turnover. Since the tolerance process is limited by available niches provided by mTECs, the efficacy of this process will also depend on the ratio of thymocytes to mTECs. Interestingly the number of single-positive thymocytes vs. mature mTECs was already increased 2 fold in 12 month-old animals when compared to their young counterparts. These findings document age-related changes in the thymic microenvironment, which collectively are conducive to subvert central tolerance induction.
Tim3/Galectin-9 interactions regulate innate and adaptive immunity to Mycobacterium tuberculosis (70.6)
Authors: Jayaraman Pushpa , Sada-Ovalle Isabel , Anderson Ana , Kuchroo Vijay , Behar Sam 
Published: January 2023

Abstract
In vivo control of Mycobacterium tuberculosis (Mtb) reflects the balance between host-immunity and bacterial evasion strategies. Effector TH1 cells that mediate protective immunity by depriving the bacterium of its intracellular niche are regulated in many ways to prevent over-exuberant inflammation. Although Tim3 is generally recognized to down regulate TH1 responses and mediate T cell exhaustion, we recently described that its interaction with Galectin-9 (Gal9) expressed by Mtb infected macrophages (Mϕ) stimulates IL-1β secretion, which is essential for host resistance to Mtb. IL-1β signaling is both necessary for Tim3 mediated Mtb control and sufficient to directly kill Mtb in murine and human Mϕ. The molecular mechanism by which IL-1β restricts bacterial growth is not known. We report that IL-1β kills Mtb through the recruitment of other antimicrobial effector molecules. IL-1β directly augments TNF signaling through increased TNF secretion and TNFR cell surface expression. Furthermore, Tim3/Gal9 and IL-1β activates the executioner caspase-3. Thus, Tim3/Gal9, via IL-1β and downstream TNF production lead to apoptosis and restriction of intracellular Mtb growth. We propose that Tim3/Gal9 interaction acts as a bidirectional molecular rheostat that activates pathways to clear intracellular pathogens in innate immune cells while fine-tuning termination of TH1 responses to prevent immunopathology.
Host resistance to a gastrointestinal parasite regulated by a SNP modulating SMAD3 binding to a TGFβ-regulated transcriptional enhancer of Mina, encoding an immunoregulatory member of the Jmjc protein family (70.9)
Authors: Bix Mark , Lian Shangli , Pillai Meenu 
Published: January 2023

Abstract
In a hunt for Th2-bias regulatory loci in mice, we have used interval-specific congenic mapping to positionally clone a gene called Mina, encoding an immunoregulatory member of the JmjC protein family. Th2-bias is a genetic trait defined as the propensity of naïve T helper cells to develop in vitro under neutral conditions into T helper 2 (Th2) effector cells. Th2 cells play a critical role in host protection from multicellular parasites such as intestinal helminths and when disregulated contribute to allergic diseases such as asthma. The Th2-bias trait is known to vary across different inbred mouse strains and correlates inversely with the relative abundance of intracellular Mina protein. Adding further support for a causal link between Mina protein level and Th2-bias, Mina was shown to act as a dose-dependent transcriptional corepressor of the gene encoding interleukin-4 (IL4), a key regulator of Th2 development. We have now identified a SNP that explains differential Mina expression level in high and low Th2-biased strains such as BALB/c and C57BL/6. Most interestingly, this SNP acts by modulating SMAD3 binding to a TGFβ-regulated intronic Mina enhancer. We are currently tying this into its physiological role in pulmonary inflammation and intestinal helminth infection using Mina conditional KO mice, which exhibit dramatic phenotypes in both models.
Role of Regulatory T cells and TGF-β in an Experimental Model of Psoriasis in mice (71.8)
Authors: Zanvit Peter , Chen Wanjun 
Published: January 2023

Abstract
Psoriasis is inflammatory disease with active interactions between the immune system and the skin, which affects approximately 2% of the world’s population and attacks about 10 million people in North America. The pathogenesis of this disease is not completely understood. Regulatory T cells (Tregs) are typically considered to be inhibitors of autoimmune responses, but the role of Tregs in pathogenesis of psoriasis remains largely unclear. Previous works have suggested that overexpression of transforming growth factor beta (TGF-β) is involved in severe skin inflammation similar to psoriasis, but the molecular mechanism by which TGF-β functions in this autoimmune disease remains to be determined. By utilizing an experimentally induced model of psoriasis using Imiquimod (TLR7/8 ligand and potent immune activator), we observed that topical aplication of Imiquimod can induce psoriasis through the IL-23/IL-17 axis in mice. We also found that TGF-β signaling and frequency of Tregs are decreased in this model of psoriasis. To further understand the molecular mechanism of TGF-β in psoriasis we have created transgenic mouse model K14.TGF-β1glo that overexpress TGF-β in epidermal keratinocytes. We are actively investigating the interplay between TGF-β and Treg cells in skin in the pathogenesis of psoriasis.
The E3 ubiquitin ligase Smurf2 suppresses c-myc expression and B cell lymphoma in mice (74.4)
Authors: Gerstein Rachel , Ramkumar Charusheila , Kong Yahui , Cui Hang , Hao Suyang , Jones Stephen , Zhang Hong 
Published: January 2023

Abstract
The NCI estimates in 2012 there will be 70,130 new cases and 18,940 deaths from non-Hodgkin’s lymphoma (NHL) in the US. Diffuse large B-cell lymphoma (DLBCL) is the most common NHL. This aggressive B-cell lymphoma is heterogeneous, with significant variation in response to treatment. Gene expression profiling identifies biologically distinct subtypes of DLBCL, which correlate with both response to treatment and survival. This suggests the critical importance of sub-type-specific targets in the diagnosis and treatment of DLBCL. The E3 ubiquitin ligase Smurf2 induces senescence in human cells, suggesting it is a tumor suppressor. We discovered that ~30% of mice deficient in Smurf2 develop NHLs with a post-germinal center phenotype resembling human DLBCL. B cells from healthy Smurf2-deficient mice exhibit enhanced proliferation and elevated expression of the oncogene c-myc. We find that Smurf2 mediates ubiquitination of a key transcription factor, which, when stabilized in Smurf2-deficient cells increases c-myc expression. This Smurf2-c-Myc axis represents a novel mechanism by which Smurf2 suppresses cell proliferation and lymphomagenesis. Analysis of gene expression databases reveals a significant decrease in Smurf2 expression in human DLBCL compared to normal B cells. Importantly, low level Smurf2 expression correlates with inferior overall survival in DLBCL patients. These data suggest that Smurf2 is a novel target in the diagnosis and potential treatment of human DLBCL.
No neurorestorative effect of IVIg in a mouse model of Parkinson Disease (75.6)
Authors: St-Amour Isabelle , Bousquet Mélanie , Paré Isabelle , Drouin-Ouellet Janelle , Bazin Renée , Calon Frederic 
Published: January 2023

Abstract
Immunotherapies have been proposed as a therapeutic strategy for the treatment of Parkinson disease (PD). Intravenous immunoglobulin preparation (IVIg) is used for the treatment of immunodeficiency and autoimmune diseases. Here, we investigated the effect of IVIg treatment on the dopaminergic (DAergic) nigrostriatal system after MPTP-induced denervation in mice. Mice received 4 MPTP injections (15 mg/Kg) at 2-hour intervals followed by a 14 days treatment with IVIg. IVIg injections led to a 21,6% increase in TReg cells in vehicle group (p&lt;0.05) and minimal specific immune response. As expected, MPTP insult induced a significant 80% and 84% depletion of striatal dopamine content (p&lt;0.01), as well as a 31% and 45% nigral DAergic neuron loss (p&lt;0.001) in the Control and IVIg group, respectively. Moreover, two-way ANOVA analyses revealed a significant downregulating effect of IVIg on striatal tyrosine hydroxylase protein level (-16%, p&lt;0.05) and on the number of nigral DAergic neurons (-29%, p&lt;0.05), paralleling the toxic effect of MPTP. Collectively, our results provide no evidence of a neurorestorative effect of IVIg on the nigrostriatal system of the MPTP-treated mouse, and suggest that we need to proceed with caution before treating PD patients with IVIg.
TLR3 signaling is either protective or pathogenic for the development of TMEV-IDD depending on the time of viral infection (76.5)
Authors: Jin Young-Hee , Kaneyama Tomoki , Kang Hyun Seok , Koh Chang-Sung , Kim Byung S. 
Published: January 2023

Abstract
We have previously shown that toll-like receptor 3 (TLR3)-mediated signaling plays an important role in the induction of innate cytokine responses to Theiler’s murine encephalomyelitis virus (TMEV) infection. In addition, cytokine levels produced after TMEV infection are significantly higher in the glial cells of susceptible SJL mice compared to those of resistant C57BL/6 mice. However, it is not known whether TLR3-mediated signaling plays a protective or pathogenic role in the development of demyelinating disease. In this study, we investigated the role of TLR3-mediated signaling in the protection and pathogenesis of TMEV-induced demyelinating disease. Our results indicate that TLR3-mediated signaling plays an important role in protecting mice from the development of disease during viral infection, as a lack of TLR3 signals in TLR3-deficient mice exacerbates the disease. However, activation of TLR3 with poly IC prior to viral infection also exacerbated disease development, whereas administration of poly IC after viral infection restrained disease development. These results suggest that TLR3-mediated signaling during viral infection protects against demyelinating disease by reducing the viral load and modulating immune responses. In contrast, premature activation of TLR3 signal transduction during early viral infection may lead to pathogenesis via over-activation of the pathogenic immune response.