Medical Microbiology and Immunology最新文献

{"title":"The Moraxella catarrhalis AdhC-FghA system is important for formaldehyde detoxification and protection against pulmonary clearance.","authors":"Dina Othman, Noha M Elhosseiny, Wafaa N Eltayeb, Ahmed S Attia","doi":"10.1007/s00430-024-00785-0","DOIUrl":"10.1007/s00430-024-00785-0","url":null,"abstract":"<p><p>Multidrug-resistant clinical isolates of Moraxella catarrhalis have emerged, increasing the demand for the identification of new treatment and prevention strategies. A thorough understanding of how M. catarrhalis can establish an infection and respond to different stressors encountered in the host is crucial for new drug-target identification. Formaldehyde is a highly cytotoxic compound that can be produced endogenously as a by-product of metabolism and exogenously from environmental sources. Pathways responsible for formaldehyde detoxification are thus essential and are found in all domains of life. The current work investigated the role of the system consisting of the S-hydroxymethyl alcohol dehydrogenase (AdhC), a Zn-dependent class III alcohol dehydrogenase, and the S-formyl glutathione hydrolase (FghA) in the formaldehyde detoxification process in M. catarrhalis. Bioinformatics showed that the components of the system are conserved across the species and are highly similar to those of Streptococcus pneumoniae, which share the same biological niche. Isogenic mutants were constructed to study the function of the system in M. catarrhalis. A single fghA knockout mutant did not confer sensitivity to formaldehyde, while the adhC-fghA double mutant is formaldehyde-sensitive. In addition, both mutants were significantly cleared in a murine pulmonary model of infection as compared to the wild type, demonstrating the system's importance for this pathogen's virulence. The respective phenotypes were reversed upon the genetic complementation of the mutants. To date, this is the first study investigating the role of the AdhC-FghA system in formaldehyde detoxification and pathogenesis of M. catarrhalis.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-03-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10917845/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140049842","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Inflammation, the kynurenines, and mucosal injury during human experimental enterotoxigenic Escherichia coli infection.","authors":"Sehee Rim, Oda Barth Vedøy, Ingeborg Brønstad, Adrian McCann, Klaus Meyer, Hans Steinsland, Kurt Hanevik","doi":"10.1007/s00430-024-00786-z","DOIUrl":"10.1007/s00430-024-00786-z","url":null,"abstract":"<p><p>Enterotoxigenic Escherichia coli (ETEC) is an important cause of diarrhea in children and travelers, especially in low- and middle-income countries. ETEC is a non-invasive gut pathogen colonizing the small intestinal wall before secreting diarrhea-inducing enterotoxins. We sought to investigate the impact of ETEC infection on local and systemic host defenses by examining plasma markers of inflammation and mucosal injury as well as kynurenine pathway metabolites. Plasma samples from 21 volunteers experimentally infected with ETEC were collected before and 1, 2, 3, and 7 days after ingesting the ETEC dose, and grouped based on the level of intestinal ETEC proliferation: 14 volunteers experienced substantial proliferation (SP) and 7 had low proliferation (LP). Plasma markers of inflammation, kynurenine pathway metabolites, and related cofactors (vitamins B2 and B6) were quantified using targeted mass spectrometry, whereas ELISA was used to quantify the mucosal injury markers, regenerating islet-derived protein 3A (Reg3a), and intestinal fatty acid-binding protein 2 (iFABP). We observed increased concentrations of plasma C-reactive protein (CRP), serum amyloid A (SAA), neopterin, kynurenine/tryptophan ratio (KTR), and Reg3a in the SP group following dose ingestion. Vitamin B6 forms, pyridoxal 5'-phosphate and pyridoxal, decreased over time in the SP group. CRP, SAA, and pyridoxic acid ratio correlated with ETEC proliferation levels. The changes following experimental ETEC infection indicate that ETEC, despite causing a non-invasive infection, induces systemic inflammation and mucosal injury when proliferating substantially, even in cases without diarrhea. It is conceivable that ETEC infections, especially when repeated, contribute to negative health impacts on children in ETEC endemic areas.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-03-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10908629/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"140012847","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Advances in the understanding of circRNAs that influence viral replication in host cells.","authors":"Siya Wang, Xiaoyun Li, Geng Liu, Zhenyu Qiu, Jiamin Wang, Di Yang, Zilin Qiao, Zhongren Ma, Zhenbin Liu, Xiaoming Yang","doi":"10.1007/s00430-023-00784-7","DOIUrl":"10.1007/s00430-023-00784-7","url":null,"abstract":"<p><p>Circular RNAs (circRNAs) are non-coding RNAs discovered in recent years, which are produced by back-splicing involving the 3' and 5' ends of RNA molecules. There is increasing evidence that circRNAs have important roles in cancer, neurological diseases, cardiovascular and cerebrovascular diseases, and other diseases. In addition, host circRNAs and virus-encoded circRNAs participate in the body's immune response, with antiviral roles. This review summarizes the mechanisms by which host and viral circRNAs interact during the host immune response. Comprehensive investigations have revealed that host circRNAs function as miRNA sponges in a particular manner, primarily by inhibiting viral replication. Viral circRNAs have more diverse functions, which generally involve promoting viral replication. In addition, in contrast to circRNAs from RNA viruses, circRNAs from DNA viruses can influence host cell migration, proliferation, and apoptosis, along with their effects on viral replication. In summary, circRNAs have potential as diagnostic and therapeutic targets, offering a foundation for the diagnosis and treatment of viral diseases.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2024-02-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"139702888","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Expression of mammalian cell entry genes in clinical isolates of M. tuberculosis and the cell entry potential and immunological reactivity of the Rv0590A protein.","authors":"Chanchal Kumar,&nbsp;Kamal Shrivastava,&nbsp;Anupriya Singh,&nbsp;Varsha Chauhan,&nbsp;Astha Giri,&nbsp;Shraddha Gupta,&nbsp;Naresh Kumar Sharma,&nbsp;Mridula Bose,&nbsp;Sadhna Sharma,&nbsp;Mandira Varma-Basil","doi":"10.1007/s00430-023-00781-w","DOIUrl":"10.1007/s00430-023-00781-w","url":null,"abstract":"<p><p>Mammalian cell entry (mce) operons play a vital role in cell invasion and survival of M. tuberculosis. Of the mce genes, the function of Rv0590A is still unknown. The present study was performed to investigate the function and immunogenic properties of the protein Rv0590A. Human leukemia monocytic cell line (THP-1) derived macrophages were infected with M. tuberculosis H37Rv at 3, 6, and 24 h of infection. The maximum colony forming units (CFU) were observed at 6 h (p < 0.005), followed by 3 h after infection. M. tuberculosis H37Rv and clinical isolates representative of Delhi/CAS, EAI, Beijing, Haarlem and Euro-American-superlineage were included in the study for expression analysis of mce1A, mce2A, mce3A, mce4A, and Rv0590A genes. Maximum upregulation of all mce genes was observed at 3 h of infection. All the five clinical isolates and H37Rv upregulated Rv0590A at various time points. Macrophage infection with M. tuberculosis H37Rv-overexpressing Rv0590A gene showed higher intracellular CFU as compared to that of wild-type H37Rv. Further, purified Rv0590A protein stimulated the production of TNFα, IFNγ, and IL-10 in macrophages. Thus, Rv0590A was found to be involved in cell invasion and showed good immunological response.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41121276","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Comparative genotyping of SARS-CoV-2 among Egyptian patients: near-full length genomic sequences versus selected spike and nucleocapsid regions.","authors":"Rasha Emad,&nbsp;Iman S Naga","doi":"10.1007/s00430-023-00783-8","DOIUrl":"10.1007/s00430-023-00783-8","url":null,"abstract":"<p><p>Several tools have been developed for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) genotyping based on either whole genome or spike sequencing. We aimed to highlight the molecular epidemiological landscape of SARS-CoV-2 in Egypt since the start of the pandemic, to describe discrepancies between the 3 typing tools: Global Initiative on Sharing Avian Influenza Data (GISAID), Nextclade, and Phylogenetic Assignment of Named Global Outbreak Lineages (PANGOLIN) and to assess the fitness of spike and nucleocapsid regions for lineage assignment compared to the whole genome. A total of 3935 sequences isolated from Egypt (March 2020-2023) were retrieved from the GISAID database. A subset of data (n = 1212) with high coverage whole genome was used for tool discrimination and agreement analyses. Among 1212 sequences, the highest discriminatory power was 0.895 for PANGOLIN, followed by GISAID (0.872) and Nextclade (0.866). There was a statistically significant difference (p = 0.0418) between lineages assigned via spike (30%) and nucleocapsid (46%) compared to their whole genome-assigned lineages. The first 3 pandemic waves were dominated by B.1, followed by C.36 and then C.36.3, while the fourth to sixth waves were dominated by the B.1.617.2, BA, and BA.5.2 lineages, respectively. Current shift in lineage typing to recombinant forms. The 3 typing tools showed comparable discrimination among SARS-CoV-2 lineages. The nucleocapsid region could be used for lineage assignment.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10618331/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41137582","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Echinacoside, a promising sortase A inhibitor, combined with vancomycin against murine models of MRSA-induced pneumonia.","authors":"Tao Jiang,&nbsp;Dai Yuan,&nbsp;Rong Wang,&nbsp;Chunhui Zhao,&nbsp;Yangming Xu,&nbsp;Yinghui Liu,&nbsp;Wu Song,&nbsp;Xin Su,&nbsp;Bingmei Wang","doi":"10.1007/s00430-023-00782-9","DOIUrl":"10.1007/s00430-023-00782-9","url":null,"abstract":"<p><p>Methicillin-resistant Staphylococcus aureus (MRSA) is a pathogenic bacterium responsible for a range of severe infections, such as skin infections, bacteremia, and pneumonia. Due to its antibiotic-resistant nature, current research focuses on targeting its virulence factors. Sortase A (SrtA) is a transpeptidase that anchors surface proteins to the bacterial cell wall and is involved in adhesion and invasion to host cells. Through fluorescence resonance energy transfer (FRET), we identified echinacoside (ECH), a natural polyphenol, as a potential SrtA inhibitor with an IC₅₀ of 38.42 μM in vitro. It was demonstrated that ECH inhibited SrtA-mediated S. aureus fibrinogen binding, surface protein A anchoring, and biofilm formation. The fluorescence quenching assay determined the binding mode of ECH to SrtA and calculated the K_A-binding constant of 3.09 × 10⁵ L/mol, demonstrating the direct interaction between the two molecules. Molecular dynamics simulations revealed that ECH-SrtA interactions occurred primarily at the binding sites of A92G, A104G, V168A, G192A, and R197A. Importantly, the combination of ECH and vancomycin offered protection against murine models of MRSA-induced pneumonia. Therefore, ECH may serve as a potential antivirulence agent against S. aureus infections, either alone or in combination with vancomycin.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2023-12-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"41149813","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Ten rapid antigen tests for SARS-CoV-2 widely differ in their ability to detect Omicron-BA.4 and -BA.5.","authors":"Franziska Krenn, Christopher Dächert, Irina Badell, Gaia Lupoli, Gamze Naz Öztan, Tianle Feng, Nikolas Schneider, Melanie Huber, Hanna Both, Patricia M Späth, Maximilian Muenchhoff, Alexander Graf, Stefan Krebs, Helmut Blum, Jürgen Durner, Ludwig Czibere, Lars Kaderali, Oliver T Keppler, Hanna-Mari Baldauf, Andreas Osterman","doi":"10.1007/s00430-023-00775-8","DOIUrl":"10.1007/s00430-023-00775-8","url":null,"abstract":"<p><p>Since late 2021, the variant landscape of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been dominated by the variant of concern (VoC) Omicron and its sublineages. We and others have shown that the detection of Omicron-BA.1 and -BA.2-positive respiratory specimens by rapid antigen tests (RATs) is impaired compared to Delta VoC-containing samples. Here, in a single-center retrospective laboratory study, we evaluated the performance of ten most commonly used RATs for the detection of Omicron-BA.4 and -BA.5 infections. We used 171 respiratory swab specimens from SARS-CoV-2 RNA-positive patients, of which 71 were classified as BA.4 and 100 as BA.5. All swabs were collected between July and September 2022. 50 SARS-CoV-2 PCR-negative samples from healthy individuals, collected in October 2022, showed high specificity in 9 out of 10 RATs. When assessing analytical sensitivity using clinical specimens, the 50% limit of detection (LoD50) ranged from 7.6 × 10⁴ to 3.3 × 10⁶ RNA copies subjected to the RATs for BA.4 compared to 6.8 × 10⁴ to 3.0 × 10⁶ for BA.5. Overall, intra-assay differences for the detection of these two Omicron subvariants were not significant for both respiratory swabs and tissue culture-expanded virus isolates. In contrast, marked heterogeneity was observed among the ten RATs: to be positive in these point-of-care tests, up to 443-fold (BA.4) and up to 56-fold (BA.5) higher viral loads were required for the worst performing RAT compared to the best performing RAT. True-positive rates for Omicron-BA.4- or -BA.5-containing specimens in the highest viral load category (C_t values < 25) ranged from 94.3 to 34.3%, dropping to 25.6 to 0% for samples with intermediate C_t values (25-30). We conclude that the high heterogeneity in the performance of commonly used RATs remains a challenge for the general public to obtain reliable results in the evolving Omicron subvariant-driven pandemic.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.5,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10501931/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10633597","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"CD146 deficiency promotes inflammatory type 2 responses in pulmonary cryptococcosis.","authors":"Zhengxia Wang,&nbsp;Wei Liu,&nbsp;Huidi Hu,&nbsp;Jingxian Jiang,&nbsp;Chen Yang,&nbsp;Xijie Zhang,&nbsp;Qi Yuan,&nbsp;Xiaofan Yang,&nbsp;Mao Huang,&nbsp;Yanming Bao,&nbsp;Ningfei Ji,&nbsp;Mingshun Zhang","doi":"10.1007/s00430-023-00780-x","DOIUrl":"10.1007/s00430-023-00780-x","url":null,"abstract":"<p><p>Cryptococcus neoformans (C. neoformans) is an important opportunistic fungal pathogen for pulmonary cryptococcosis. Previously, we demonstrated that CD146 mediated the adhesion of C. neoformans to the airway epithelium. CD146 is more than an adhesion molecule. In the present study, we aimed to explore the roles of CD146 in the inflammatory response in pulmonary cryptococcosis. CD146 was decreased in lung tissues from patients with pulmonary cryptococcosis. Similarly, C. neoformans reduced pulmonary CD146 expression in mice following intratracheal inoculation. To explore the pathological roles of CD146 reduction in pulmonary cryptococcosis, CD146 knockout (KO) mice were inoculated with C. neoformans via intratracheal instillation. CD146 deficiency aggravated C. neoformans infection, as evidenced by a shortened survival time and increased fungal burdens in the lung. Inflammatory type 2 cytokines (IL-4, IL-5, and TNF-α) and alternatively activated macrophages were increased in the pulmonary tissues of CD146 KO-infected mice. CD146 is expressed in immune cells (macrophages, etc.) and nonimmune cells, i.e., epithelial cells and endothelial cells. Bone marrow chimeric mice were established and infected with C. neoformans. CD146 deficiency in immune cells but not in nonimmune cells increased fungal burdens in the lung. Mechanistically, upon C. neoformans challenge, CD146 KO macrophages produced more neutrophil chemokine KC and inflammatory cytokine TNF-α. Meanwhile, CD146 KO macrophages decreased the fungicidity and production of reactive oxygen species. Collectively, C. neoformans infection decreased CD146 in pulmonary tissues, leading to inflammatory type 2 responses, while CD146 deficiency worsened pulmonary cryptococcosis.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10631469","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Prediction of outcome using CD14⁺⁺CD16^-, CD14⁺⁺CD16⁺ and CD14⁺CD16⁺⁺ monocyte subpopulations in patients with complicated intra-abdominal infections.","authors":"Evgeni Dimitrov,&nbsp;Krasimira Halacheva,&nbsp;Georgi Minkov,&nbsp;Emil Enchev,&nbsp;Yovcho Yovtchev","doi":"10.1007/s00430-023-00779-4","DOIUrl":"10.1007/s00430-023-00779-4","url":null,"abstract":"<p><p>There is still no study investigating the prognostic performance of CD14⁺⁺CD16^-, CD14⁺⁺CD16⁺ and CD14⁺CD16⁺⁺ monocyte subpopulations in complicated intra-abdominal infections (cIAIs); therefore, we aimed to evaluate the association between monocyte subtypes and outcome in such patients. A single-center prospective study was conducted at a University Hospital Stara Zagora between November 2018 and August 2021. Preoperatively and on the 3rd postoperative day (POD), we measured the levels of CD14⁺⁺CD16^-, CD14⁺⁺CD16⁺ and CD14⁺CD16⁺⁺ monocytes in peripheral blood using flow cytometry in 62 patients with cIAIs and 31 healthy controls. Nine of the 62 patients died during hospitalization. Survivors had higher pre-surgery percentages of CD14⁺⁺CD16^- classical monocytes and higher percentage of these cells predicted favorable outcome in ROC analysis (AUROC = 0.781, p = 0.008). The CD14⁺⁺CD16⁺ intermediate monocyte percentages were higher in non-survivors both pre- and postoperatively but only the higher preoperative values predicted a lethal outcome (AUROC = 0.722, p = 0.035). For CD14⁺CD16⁺⁺ non-classical monocytes, non-survivors had lower percentages on day 3 post-surgery and low percentage was predictive of lethal outcome (AUROC = 0.752, p = 0.046). Perioperative levels of monocyte subpopulations in peripheral blood show a great potential for prognostication of outcome in patients with cIAIs.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10186186","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Histone methyltransferase SETD2 inhibits M1 macrophage polarization and glycolysis by suppressing HIF-1α in sepsis-induced acute lung injury.","authors":"Yan Meng,&nbsp;Kai-Wen Kong,&nbsp;Yong-Qing Chang,&nbsp;Xiao-Ming Deng,&nbsp;Tao Yang","doi":"10.1007/s00430-023-00778-5","DOIUrl":"10.1007/s00430-023-00778-5","url":null,"abstract":"<p><p>Sepsis is a severe syndrome caused by the imbalance of the host response to infection, accompanied by multiple organ damage, especially acute lung injury. SET Domain-Containing 2 (SETD2) is a methyltransferase catalyzing H3 lysine 36 trimethylation (H3K36me3) that regulates multiple biological processes. This study focused on explicating the action of SETD2 on macrophage function in sepsis and the precise mechanism involved. Enzyme-linked immunosorbent assay, real-time quantitative polymerase chain reaction (RT-qPCR), and Western blotting were used to determine expression. Luciferase reporter assay and chromatin immunoprecipitation assay were conducted to detect the binding of SETD2 or H3K36me3 with the hypoxia-inducible factor 1, alpha subunit (Hif1a) gene. A sepsis-induced acute lung injury model was constructed via cecal ligation and puncture (CLP). SETD2 was decreased in RAW 264.7 cells stimulated by lipopolysaccharide (LPS). Besides, SETD2 suppressed M1 macrophage polarization and glycolysis caused by LPS. HIF-1α was enhanced in RAW 264.7 cells stimulated by LPS and inversely related to SETD2 expression. In addition, SETD2-catalyzed H3K36me3 bound to the Hif1a gene to modulate HIF-1α expression. Furthermore, Hif1a silencing suppressed Setd2 silencing-induced M1 macrophage polarization and glycolysis in RAW 264.7 cells. Moreover, overexpression of Setd2 inhibited CLP-induced lung injury and M1 macrophage polarization in mice. SETD2 suppressed M1 macrophage polarization and glycolysis via regulating HIF-1α through catalyzing H3K36me3 in sepsis.</p>","PeriodicalId":18369,"journal":{"name":"Medical Microbiology and Immunology","volume":null,"pages":null},"PeriodicalIF":5.4,"publicationDate":"2023-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"10240378","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}