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关键词： chronic mucocutaneous candidiasis   IL23R   Inborn errors of immunity   TH-17  

摘要： Chronic mucocutaneous candidiasis can be caused by an Inborn Error of Immunity, especially those affecting TH-17 / IL-17 responses. Through in-depth immunophenotyping and functional assays, we reveal the association between homozygous carriage of the common p.R381Q IL-23R genetic variant and increased candidiasis susceptibility, relying on disrupted IL-23-mediated IL-17 immunity.

关键词： Ovarian dysfunction   Metabolic syndrome   Inflammation   Mitochondrial oxidative stress   Nervonic acid  

摘要： Introduction: Metabolic syndrome is a serious public health concern across the globe. However, the typical metabolites and mechanisms underlying the decreased fertility related to metabolic syndrome is still elusive. Objectives: The aim of the present study was to explore the typical metabolites and mechanisms underlying the decreased fertility related with metabolic syndrome. Methods: Utilizing metabolomics, a comparative analysis was conducted on fatty acid compositions in various tissues of sows with high and low reproductive performance. Additionally, serum fatty acid compositions in a metabolic syndrome model (obese mice) induced by a high-fat diet (HFD) were investigated to elucidate the lipid metabolites associated with metabolic syndrome. Furthermore, the impact of nervonic acid (NA) on ovarian function was examined using rodent animal models (rats and mice). Through biological techniques such as transcriptomics, CUT&Tag, and analysis of post-translational protein modifications, the molecular mechanisms underlying NA mediated ovarian inflammation were further elucidated based on models utilizing ovarian granulosa cells from pigs, humans, and mice. Finally, validation was performed on ovaries from patients diagnosed with polycystic ovary syndrome. Results: In vitro, targeted serum lipidomic analysis revealed that sows with low embryo survival rates exhibited abnormal lipid metabolism characterized by abnormal accumulation of NA in the liver, ovary, and adipose tissue. Additionally, elevated NA levels trigger ovarian inflammation to cause ovarian dysfunction in both sows and rats. Mechanistically, NA induce mitochondrial oxidative stress through inhibiting respiratory chain proteins CYTB and NDFUB8 to activate NLRP3 inflammasome, which triggers procaspase-1 into active caspase-1, and convert the cytokine precursors pro-IL-1(3 into biologically active IL-1(3 in ovarian granulosa cells. Notably, we evidenced that NA promotes IL-1(3 activities by increasing H3K9a

摘要： The interaction between peptides and Major Histocompatibility Complex Class I (MHC-I) molecules plays a critical role in adaptive immune recognition. Although computational prediction algorithms have advanced over traditional experimental methods, challenges still remain. There is a scarcity of standardized datasets that provide comprehensive profiles of MHC-peptide structure. The polymorphism of MHC molecules introduces diverse binding patterns, complicating the characterization of specific amino acid interaction pairs. To address these issues, we introduce GSM, a novel deep learning model that combines a Graph Attention Neural Network with a Self-Attention Convolutional Neural Network to predict MHC-peptide binding affinities. By integrating self-attention mechanisms to capture global peptide-MHC interactions and graph-based modeling to represent local amino acid pairwise interactions, GSM provides a comprehensive understanding of binding mode. Compared to existing algorithms, GSM shows superior performance and greater stability across diverse allele datasets, as demonstrated on the benchmarks. Furthermore, by leveraging real 3D structural data and attention visualization, GSM is capacity of selecting interaction sites, offering valuable insights for vaccine design and advancing immunological research.

关键词： brain atrophy   CD8 T cell   MHC class I molecule   mouse model   multiple sclerosis   neurodegeneration   neuroinflammation   neurotropic virus  

摘要： Brain atrophy is a common feature of neurodegenerative disorders, including Alzheimer's disease, Parkinson's disease, multiple sclerosis, and more recently SARS-CoV-2 infection for which the neuroinflammatory mechanism is not fully understood. Nevertheless, neuroinflammation and CD8 T cell accumulation is frequently observed in postmortem brain tissue of patients with neurodegeneration. We therefore developed a murine model of brain atrophy using the Theiler's murine encephalomyelitis virus (TMEV) infection model of multiple sclerosis. We employ single major histocompatibility complex (MHC) class I molecule conditional knockout mice generated by our program to analyze the contribution of immune cell infiltration and onset of atrophy. TMEV infected C57BL/6 mice that singularly express H-2K(b) or H-2D(b) were evaluated. TMEV infection of these mice resulted in ventricular atrophy at 14 d.p.i. However, H-2D(b) expressing mice presented with significantly greater and continuous ventricular atrophy compared to H-2K(b) expressing mice and MHC class I knockout control mice. Flow cytometric analysis revealed H-2D(b) expressing mice had greater brain infiltrating CD8 T cell responses at 7 and 28 dpi which correlated with the extent of ventricular atrophy. Meanwhile, H-2K(b) and MHC class I knockout mice also had distinct positive correlations with ventricular atrophy and global neuroinflammation in general. These findings support the role of immune cell infiltration into the CNS as a putative mechanism of ventricular atrophy following TMEV infection, with the progressive enlargement of ventricular atrophy observed in H-2D(b) mice being associated with the presence of long-lived memory CD8 T cells residing in the brain.

关键词： IFN   invertebrate   JAK-STAT   SOCS   Vago   virus  

摘要： The arms race between hosts and viruses for dominance over the Janus kinase-signal transducer and activator of transcription (JAK-STAT) pathway has been extensively studied in vertebrates but remains poorly explored in invertebrates. Recent studies have revealed that the antiviral Vago/JAK-STAT pathway in invertebrates operates as a parallel mechanism to the vertebrate interferon (IFN)/JAK-STAT pathway, suggesting a highly conserved antiviral mechanism across the animal kingdom. Moreover, invertebrates appear to employ multifaceted strategies to modulate the JAK-STAT pathway to inhibit viral replication or enhance host tolerance, while viruses can counteract by manipulating the JAK-STAT pathway to their advantage. Thus, the competition between hosts and viruses for control of the JAK-STAT pathway also exists in invertebrates, indicating this arms race is also conserved in evolution. This review summarizes the discovery of the Vago/JAK-STAT pathway, its comparison to the IFN/JAK-STAT pathway, and the mechanisms underlying the host-virus tug-of-war over the JAK-STAT pathway in invertebrates. These insights shed light on this highly conserved immune strategy, its implication for host-virus interaction, and its potential application in disease control.

关键词： Down syndrome   RSV   airway epithelial cell   interferon  

摘要： Trisomy 21 (TS21), also known as Down syndrome (DS), increases pediatric mortality risk due to respiratory syncytial virus (RSV) by ninefold. However, the underlying immunological basis remains unclear. To define the biological implications of TS21 in airway epithelial cells (AECs), the primary site of respiratory virus entry and host defense, in this study we investigated RSV-induced responses in primary nasal AECs from euploid and trisomic pediatric donors. We employed comprehensive approaches to assess baseline interferon (IFN)-JAK/STAT signaling, viral infectivity, and the production of type III IFN /λ1, pro-inflammatory cytokines, and chemokines, before and after RSV ***21 AECs exhibited baseline hyperactive IFN-JAK/STAT signaling and reduced RSV infectivity but also showed impaired type-III IFN responses during viral infection. Furthermore, TS21 AECs demonstrated a robust pro-inflammatory state, with upregulated leukocyte/neutrophil chemotaxis pathways and heightened CXCL5/CXCL10 production before and after RSV exposure. This pattern was recapitulated in infants with DS who had severe viral bronchiolitis, exhibiting a dysregulated airway immune response characterized by diminished type-III IFN and excessive CXCL5/CXCL10 production. Our results suggest that RSV severity in DS is not due to enhanced viral infectivity but rather to dysregulated airway pro-inflammatory responses, offering new therapeutic opportunities to mitigate the severity of RSV infection in children with DS.

关键词： 拟南芥   AtYbeY   原核表达   多克隆抗体  

摘要： AtYbeY是拟南芥（Arabidopsis thaliana）含有PF0054和HAD的双结构域蛋白,行使内切核糖核酸酶功能,参与叶绿体rRNA加工和成熟,在70S核糖体的组装和核糖体的质量控制方面起到重要作用。基于TAIR公布的AtYbeY基因序列,同源克隆了PF0054结构域和HAD结构域的基因片段,利用双酶切法成功构建了pET32a-UPF0054和pET32a-HAD原核表达载体,成功表达了2个重组蛋白,经Ni2+亲和层析法纯化重组蛋白,SDS-PAGE结果显示,目标蛋白分子量与预期值一致,纯化的目标蛋白满足免疫抗原要求。Western blot检测结果表明,制备的AtYbeY-UPF0054与AtYbeY-HAD 2个多克隆抗体可以与拟南芥和玉米（Zea mays）叶片中的YbeY抗原蛋白具有良好的特异性免疫反应,制备的2个抗体具有较好的特异性和保守性。该研究将为拟南芥AtYbeY蛋白功能的解析和不同结构域的进化系统分析奠定基础。

关键词： GADD45A   interferon-beta   peste des petits ruminants virus   TANK-binding kinase 1   V protein  

摘要： Peste des petits ruminants virus (PPRV) is a highly contagious pathogen that severely impacts goats and sheep due to its high contagiousness and pathogenicity. Viruses rely on host proteins for their pathogenicity and replication, but the specific mechanisms facilitating PPRV replication by host proteins remain poorly understood. In this study, we identified goat growth arrest and DNA damage protein 45A (GADD45A) as a positive regulator of PPRV replication. Overexpression of GADD45A enhances PPRV replication, while its knockdown significantly inhibits PPRV replication. Furthermore, GADD45A suppresses SeV- or Poly(I:C)-induced IFN-beta promoter and ISRE activation in a dose-dependent manner, as well as the transcription of interferon-stimulated genes (ISGs). We also demonstrate that goat GADD45A interacts with TANK-binding kinase 1 (TBK1), leading to the downregulation of TBK1 expression. Co-immunoprecipitation and confocal microscopy confirmed that GADD45A interacts with the PPRV V protein. Both GADD45A and V synergistically inhibit IFN-beta promoter activation and TBK1 expression, thereby promoting PPRV replication. Our findings suggest that GADD45A promotes PPRV replication by downregulating TBK1, offering new insights into host proteins that counteract innate immune responses during PPRV infection. These findings offer valuable insights into the role of host proteins in viral replication and immune evasion, shedding new light on how PPRV antagonizes innate immunity.