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MASP1 modulation as a novel therapeutic target in severe pediatric pertussis: insights from a multi-omics approach. MASP1调节作为重症小儿百日咳的新治疗靶点:来自多组学方法的见解。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2025-01-22 DOI: 10.1128/iai.00271-24
Lin Xu, Caiying Wang, Yuhuan Liu, Yanlan Zhang, Zhen Li, Lin Pang

Pertussis, a severe infectious disease in children, has become increasingly prominent in recent years. This study aims to investigate the role of the MASP1 protein in severe pertussis in children through multi-omics analysis, providing a theoretical basis for the development of novel therapeutic strategies. The study retrieved macro-genome and 16S rRNA data of pediatric pertussis from public databases to analyze microbial diversity and specific flora abundance, conducting pathway functional enrichment analysis. Differential expression analysis of transcriptome data and Gene Ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) functional enrichment analysis, combined with machine learning, identified the key gene MASP1. A Bordetella pertussis infection model was established using human bronchial epithelial cell line HBE135-E6E7 to validate MASP1 expression changes and investigate its relationship with airway epithelial cell damage by constructing cell lines overexpressing and knocking down MASP1. Finally, the impact of inhibiting MASP1 expression on infection symptoms was evaluated using a mouse pertussis infection model. The results revealed significant differences in microbial diversity and specific flora abundance between healthy children and those with pertussis, with MASP1 significantly upregulated in severe pertussis and its inhibition alleviating infection symptoms. The study highlights the critical role of MASP1 in pertussis, providing a crucial foundation for developing therapeutic strategies targeting MASP1.

百日咳是一种严重的儿童传染病,近年来日益突出。本研究旨在通过多组学分析探讨MASP1蛋白在儿童重症百日咳中的作用,为开发新的治疗策略提供理论依据。本研究从公共数据库中检索儿童百日咳宏基因组和16S rRNA数据,分析微生物多样性和特定菌群丰度,进行途径功能富集分析。通过转录组数据的差异表达分析和基因本体(GO)/京都基因与基因组百科全书(KEGG)功能富集分析,结合机器学习,鉴定出关键基因MASP1。利用人支气管上皮细胞系HBE135-E6E7建立百日咳杆菌感染模型,通过构建过表达和低表达MASP1的细胞系,验证MASP1的表达变化,探讨其与气道上皮细胞损伤的关系。最后,利用小鼠百日咳感染模型评估抑制MASP1表达对感染症状的影响。结果显示,健康儿童和百日咳儿童的微生物多样性和特定菌群丰度存在显著差异,MASP1在严重百日咳中显著上调,其抑制作用减轻了感染症状。该研究强调了MASP1在百日咳中的关键作用,为开发针对MASP1的治疗策略提供了重要的基础。
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引用次数: 0
Expression of Concern for Herrera et al., "Protection against Malaria in Aotus Monkeys Immunized with a Recombinant Blood-Stage Antigen Fused to a Universal T-Cell Epitope: Correlation of Serum Gamma Interferon Levels with Protection". 表达对Herrera等人的关注,“用与通用t细胞表位融合的重组血期抗原免疫的猕猴对疟疾的保护:血清γ干扰素水平与保护的相关性”。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2025-01-13 DOI: 10.1128/iai.00541-24
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引用次数: 0
Airway Corynebacterium interfere with Streptococcus pneumoniae and Staphylococcus aureus infection and express secreted factors selectively targeting each pathogen. 气道棒状杆菌干扰肺炎链球菌和金黄色葡萄球菌感染,并选择性地表达针对每种病原体的分泌因子。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2024-12-20 DOI: 10.1128/iai.00445-24
Emily Tamkin, Brian P Lorenz, Arianna McCarty, Sam Fulte, Elan Eisenmesser, Alexander R Horswill, Sarah E Clark

The composition of the respiratory tract microbiome is a notable predictor of infection-related morbidities and mortalities among both adults and children. Species of Corynebacterium, which are largely present as commensals in the upper airway and other body sites, are associated with lower colonization rates of opportunistic bacterial pathogens such as Streptococcus pneumoniae and Staphylococcus aureus. In this study, Corynebacterium-mediated protective effects against S. pneumoniae and S. aureus were directly compared using in vivo and in vitro models. Pre-exposure to Corynebacterium pseudodiphtheriticum reduced the ability of S. aureus and S. pneumoniae to infect the lungs of mice, indicating a broadly protective effect. Adherence of both pathogens to human respiratory tract epithelial cells was significantly impaired following pre-exposure to C. pseudodiphtheriticum or Corynebacterium accolens, and this effect was dependent on live Corynebacterium colonizing the epithelial cells. However, Corynebacterium-secreted factors had distinct effects on each pathogen. Corynebacterium lipase activity was bactericidal against S. pneumoniae, but not S. aureus. Instead, the hemolytic activity of pore-forming toxins produced by S. aureus was directly blocked by a novel Corynebacterium-secreted factor with protease activity. Taken together, these results suggest diverse mechanisms by which Corynebacterium contribute to the protective effect of the airway microbiome against opportunistic bacterial pathogens.

呼吸道微生物群的组成是预测成人和儿童感染相关发病率和死亡率的一个重要指标。主要作为共生菌存在于上呼吸道和身体其他部位的棒状杆菌属菌种与肺炎链球菌和金黄色葡萄球菌等机会性细菌病原体的较低定植率有关。本研究利用体内和体外模型直接比较了科里纳菌介导的对肺炎链球菌和金黄色葡萄球菌的保护作用。预先接触假双歧杆菌可降低金黄色葡萄球菌和肺炎双球菌感染小鼠肺部的能力,这表明假双歧杆菌具有广泛的保护作用。预先暴露于假白喉棒状杆菌或棒状杆菌后,这两种病原体在人类呼吸道上皮细胞上的附着力明显减弱,而且这种效果依赖于活的棒状杆菌在上皮细胞上定植。然而,棒状杆菌分泌的因子对每种病原体都有不同的影响。棒状杆菌的脂肪酶活性对肺炎双球菌有杀菌作用,但对金黄色葡萄球菌没有杀菌作用。相反,金黄色葡萄球菌产生的孔隙形成毒素的溶血活性直接被一种具有蛋白酶活性的新型棒状杆菌分泌因子所阻断。综上所述,这些结果表明,科里纳菌可通过多种机制促进气道微生物群对机会性细菌病原体的保护作用。
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引用次数: 0
TSST-1 promotes colonization of Staphylococcus aureus within the vaginal tract by activation of CD8+ T cells. TSST-1通过激活CD8+ T细胞促进金黄色葡萄球菌在阴道内的定植。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2025-01-22 DOI: 10.1128/iai.00439-24
Karine Dufresne, Kait F Al, Heather C Craig, Charlotte E M Coleman, Katherine J Kasper, Jeremy P Burton, John K McCormick

Toxic shock syndrome toxin-1 (TSST-1) is a superantigen produced by Staphylococcus aureus and is the determinant of menstrual toxic shock syndrome (mTSS); however, the impact of TSST-1 on the vaginal environment beyond mTSS is not understood. Herein, we assessed how TSST-1 affects vaginal colonization by S. aureus, host inflammatory responses, and changes in microbial communities within the murine vagina. We demonstrated that TSST-1 induced a CD8+ T-cell-dependent inflammatory response in 24 h that correlated with S. aureus persistence within the vaginal tract. This increase was due to superantigen-dependent T-cell activation that triggered a change in microbial composition within the vaginal tract. Altogether, this study demonstrates that within the vaginal tract, TSST-1 modulates the vaginal microbiota to favor the survival of S. aureus in the absence of mTSS.IMPORTANCEToxic shock syndrome toxin-1 (TSST-1) is a superantigen toxin produced from Staphylococcus aureus that causes the menstrual form of toxic shock syndrome. This research demonstrates that TSST-1 also has a wider function within the vaginal tract than previously expected. We show that TSST-1, by activating CD8+ T cells, induces an inflammatory environment that modifies the vaginal microbiota to favor colonization by S. aureus. These are important findings as S. aureus can colonize the human vaginal tract efficiently and subsequently trigger dysbiosis within the microbial communities leading to several adverse outcomes such as decreased fertility, increased risks for sexually transmitted diseases, and issues related to pregnancy and birth.

中毒性休克综合征毒素-1 (TSST-1)是金黄色葡萄球菌产生的一种超抗原,是月经中毒性休克综合征(mTSS)的决定因素;然而,除mTSS外,TSST-1对阴道环境的影响尚不清楚。在此,我们评估了TSST-1如何影响金黄色葡萄球菌的阴道定植、宿主炎症反应以及小鼠阴道内微生物群落的变化。我们证明了TSST-1在24小时内诱导CD8+ t细胞依赖性炎症反应,这与金黄色葡萄球菌在阴道内的持久性有关。这种增加是由于超级抗原依赖的t细胞激活引发了阴道内微生物组成的变化。总之,本研究表明,在阴道内,TSST-1调节阴道微生物群,有利于金黄色葡萄球菌在没有mTSS的情况下存活。中毒性休克综合征毒素-1 (TSST-1)是一种由金黄色葡萄球菌产生的超抗原毒素,可引起月经期中毒性休克综合征。这项研究表明,TSST-1在阴道内的功能也比以前预期的更广泛。我们发现TSST-1通过激活CD8+ T细胞,诱导炎症环境,改变阴道微生物群,有利于金黄色葡萄球菌的定植。这些是重要的发现,因为金黄色葡萄球菌可以有效地在人类阴道内定植,并随后引发微生物群落的生态失调,导致一些不良后果,如生育能力下降,性传播疾病风险增加,以及与怀孕和分娩相关的问题。
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引用次数: 0
Expression of Concern for Perlaza et al., "Immunogenicity of Four Plasmodium falciparum Preerythrocytic Antigens in Aotus lemurinus Monkeys". 对Perlaza等人“四种恶性疟原虫红细胞前抗原在猕猴中的免疫原性”的关注表达。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2025-01-13 DOI: 10.1128/iai.00542-24
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引用次数: 0
Effect of tryptophan starvation on inclusion membrane composition and chlamydial-host interactions. 色氨酸饥饿对包涵膜组成和衣原体与宿主相互作用的影响。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2025-01-13 DOI: 10.1128/iai.00532-24
Camille M Riffaud-Widner, Ray E Widner, Scot P Ouellette, Elizabeth A Rucks

Chlamydia is an obligate intracellular bacterial pathogen that develops within a membrane-bound vacuole called an inclusion. Throughout its developmental cycle, Chlamydia modifies the inclusion membrane (IM) with type III secreted (T3S) membrane proteins, known as inclusion membrane proteins (Incs). Via the IM, Chlamydia manipulates the host cell to acquire lipids and nutrients necessary for its growth. One key nutrient is tryptophan (Trp). As a Trp auxotroph, Chlamydia is very sensitive to Trp starvation and, in response to low Trp levels induced by the immune response, enters a viable but nonreplicating state called persistence. To maintain viability during persistence, Chlamydia must necessarily maintain both the integrity of the IM and its ability to modify host cell responses, but how Trp starvation affects IM composition and subsequent interactions with the host cell remains poorly understood. We hypothesize that, under Trp starvation conditions, Inc expression/stability or T3S function during persistence alters IM composition but that key host-Chlamydia interactions will be preserved. To examine host-Chlamydia interactions during persistence, we examined sphingomyelin, cholesterol, and transferrin trafficking to the inclusion, as well as localization of host proteins that bind to specific Incs. We identified IM composition changes during persistence by monitoring endogenous Inc abundance at the IM. Chlamydial T3S is generally functional during persistence. Specific changes in Inc composition in the IM can be linked to Trp content of a specific Inc or effector-specific defects in chlamydial T3S. Overall, our findings reveal that critical host-Chlamydia interactions are maintained during persistence mediated by Trp starvation.

衣原体是一种专性细胞内细菌病原体,在称为包涵体的膜结合液泡内发展。在整个发育周期中,衣原体用III型分泌(T3S)膜蛋白修饰包涵膜(IM),称为包涵膜蛋白(Incs)。衣原体通过IM操纵宿主细胞获取其生长所必需的脂质和营养物质。一种关键的营养物质是色氨酸(Trp)。衣原体作为一种色氨酸营养不良体,对色氨酸饥饿非常敏感,在免疫反应诱导的低色氨酸水平下,衣原体进入一种可存活但不复制的状态,称为持久性。为了在持续过程中保持活力,衣原体必须保持IM的完整性及其修改宿主细胞反应的能力,但是色氨酸饥饿如何影响IM的组成以及随后与宿主细胞的相互作用仍然知之甚少。我们假设,在色氨酸缺乏的条件下,在持续过程中,Inc的表达/稳定性或T3S功能改变了IM的组成,但关键的宿主-衣原体相互作用将被保留。为了检查宿主-衣原体在持续过程中的相互作用,我们检查了鞘磷脂、胆固醇和转铁蛋白向包涵体的运输,以及与特定Incs结合的宿主蛋白的定位。我们通过监测内源性Inc在IM的丰度来确定在持续过程中的IM组成变化。衣原体T3S在持续期间通常具有功能。IM中Inc组成的特定变化可能与衣原体T3S中特定Inc的色氨酸含量或效应特异性缺陷有关。总的来说,我们的研究结果表明,在色氨酸饥饿介导的持久性中,关键的宿主-衣原体相互作用得以维持。
{"title":"Effect of tryptophan starvation on inclusion membrane composition and chlamydial-host interactions.","authors":"Camille M Riffaud-Widner, Ray E Widner, Scot P Ouellette, Elizabeth A Rucks","doi":"10.1128/iai.00532-24","DOIUrl":"10.1128/iai.00532-24","url":null,"abstract":"<p><p><i>Chlamydia</i> is an obligate intracellular bacterial pathogen that develops within a membrane-bound vacuole called an inclusion. Throughout its developmental cycle, <i>Chlamydia</i> modifies the inclusion membrane (IM) with type III secreted (T3S) membrane proteins, known as inclusion membrane proteins (Incs). Via the IM, <i>Chlamydia</i> manipulates the host cell to acquire lipids and nutrients necessary for its growth. One key nutrient is tryptophan (Trp). As a Trp auxotroph, <i>Chlamydia</i> is very sensitive to Trp starvation and, in response to low Trp levels induced by the immune response, enters a viable but nonreplicating state called persistence. To maintain viability during persistence, <i>Chlamydia</i> must necessarily maintain both the integrity of the IM and its ability to modify host cell responses, but how Trp starvation affects IM composition and subsequent interactions with the host cell remains poorly understood. We hypothesize that, under Trp starvation conditions, Inc expression/stability or T3S function during persistence alters IM composition but that key host-<i>Chlamydia</i> interactions will be preserved. To examine host-<i>Chlamydia</i> interactions during persistence, we examined sphingomyelin, cholesterol, and transferrin trafficking to the inclusion, as well as localization of host proteins that bind to specific Incs. We identified IM composition changes during persistence by monitoring endogenous Inc abundance at the IM. Chlamydial T3S is generally functional during persistence. Specific changes in Inc composition in the IM can be linked to Trp content of a specific Inc or effector-specific defects in chlamydial T3S. Overall, our findings reveal that critical host-<i>Chlamydia</i> interactions are maintained during persistence mediated by Trp starvation.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0053224"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834466/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970516","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}
引用次数: 0
Immunometabolic reprogramming in macrophages infected with active and dormant Cryptococcus neoformans: differential modulation of respiration, glycolysis, and fatty acid utilization. 感染活性和休眠新型隐球菌的巨噬细胞的免疫代谢重编程:呼吸、糖酵解和脂肪酸利用的差异调节
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2024-12-23 DOI: 10.1128/iai.00487-24
Clara Luna Marina, Raffael J Araújo de Castro, Paula Bellozi, Ana M Cruz, Pedro Henrique Bürgel, Paul G Weightman Potter, Craig Beall, Aldo Henrique Tavares, Andreza De Bem, Alexandre Alanio, Carolina Coelho, Anamélia Lorenzetti Bocca

Dormancy is an adaptation in which cells reduce their metabolism, transcription, and translation to stay alive under stressful conditions, preserving the capacity to reactivate once the environment reverts to favorable conditions. Dormancy and reactivation of Cryptococcus neoformans (Cn) are closely linked to intracellular residency within macrophages. Our previous work showed that in vitro murine macrophages rely on the viable but not cultivable (VBNC-a dormancy phenotype) fungus from active Cn, with striking differences in immunometabolic gene expression. Here, we analyzed the influence of VBNC and active Cn on the immunometabolism of infected macrophages, combining metabolic gene expression, mitochondrial membrane potential (ΔΨm), oxygen consumption analysis, and uptake of glucose and fatty acids. The active fungus induced mitochondrial depolarization, and increased glycolysis and mitochondrial oxygen consumption. VBNC infection in bone marrow-derived macrophage (BMDM) caused an attenuated modification in mitochondrial metabolism. However, we found differences in BMDM infected with VBNC vs those infected with active fungus, where VBNC induced an increment in fatty acid uptake in M0 and M1 BMDM, measured by incorporation of BODIPY-palmitate, accompanied by an increase in expression of fatty acid transporters Fabp1 and Fabp4. Overall, distinct fatty acid-related responses induced by VBNC and active Cn suggest different immunomodulatory reactions, depending on the microbial growth stage. We posit that, for VBNC, some of these macrophage metabolic responses reflect the establishment of prolonged microbial intracellular residency and possibly initial stages of granuloma formation.

休眠是细胞在应激条件下减少新陈代谢、转录和翻译以保持存活的一种适应过程,一旦环境恢复到有利条件,就保留重新激活的能力。新生隐球菌(Cn)的休眠和再激活与巨噬细胞内的细胞内驻留密切相关。我们之前的工作表明,体外小鼠巨噬细胞依赖于活性Cn的活菌但不可培养(vbnc -一种休眠表型)真菌,在免疫代谢基因表达上存在显著差异。本研究结合代谢基因表达、线粒体膜电位(ΔΨm)、耗氧量分析、葡萄糖和脂肪酸摄取,分析了VBNC和活性Cn对感染巨噬细胞免疫代谢的影响。活性真菌诱导线粒体去极化,增加糖酵解和线粒体耗氧量。骨髓源性巨噬细胞(BMDM)的VBNC感染引起线粒体代谢的减弱。然而,我们发现受VBNC感染的BMDM与受活性真菌感染的BMDM存在差异,VBNC诱导M0和M1 BMDM脂肪酸摄取增加,通过掺入bodipy -棕榈酸酯来测量,同时脂肪酸转运体Fabp1和Fabp4的表达增加。总体而言,VBNC和活性Cn诱导的不同脂肪酸相关反应表明不同的免疫调节反应,这取决于微生物的生长阶段。我们假设,对于VBNC,这些巨噬细胞代谢反应中的一些反映了微生物在细胞内长期驻留的建立,可能是肉芽肿形成的初始阶段。
{"title":"Immunometabolic reprogramming in macrophages infected with active and dormant <i>Cryptococcus neoformans</i>: differential modulation of respiration, glycolysis, and fatty acid utilization.","authors":"Clara Luna Marina, Raffael J Araújo de Castro, Paula Bellozi, Ana M Cruz, Pedro Henrique Bürgel, Paul G Weightman Potter, Craig Beall, Aldo Henrique Tavares, Andreza De Bem, Alexandre Alanio, Carolina Coelho, Anamélia Lorenzetti Bocca","doi":"10.1128/iai.00487-24","DOIUrl":"10.1128/iai.00487-24","url":null,"abstract":"<p><p>Dormancy is an adaptation in which cells reduce their metabolism, transcription, and translation to stay alive under stressful conditions, preserving the capacity to reactivate once the environment reverts to favorable conditions. Dormancy and reactivation of <i>Cryptococcus neoformans</i> (<i>Cn</i>) are closely linked to intracellular residency within macrophages. Our previous work showed that <i>in vitro</i> murine macrophages rely on the viable but not cultivable (VBNC-a dormancy phenotype) fungus from active <i>Cn</i>, with striking differences in immunometabolic gene expression. Here, we analyzed the influence of VBNC and active <i>Cn</i> on the immunometabolism of infected macrophages, combining metabolic gene expression, mitochondrial membrane potential (ΔΨm), oxygen consumption analysis, and uptake of glucose and fatty acids. The active fungus induced mitochondrial depolarization, and increased glycolysis and mitochondrial oxygen consumption. VBNC infection in bone marrow-derived macrophage (BMDM) caused an attenuated modification in mitochondrial metabolism. However, we found differences in BMDM infected with VBNC vs those infected with active fungus, where VBNC induced an increment in fatty acid uptake in M0 and M1 BMDM, measured by incorporation of BODIPY-palmitate, accompanied by an increase in expression of fatty acid transporters <i>Fabp1</i> and <i>Fabp4</i>. Overall, distinct fatty acid-related responses induced by VBNC and active <i>Cn</i> suggest different immunomodulatory reactions, depending on the microbial growth stage. We posit that, for VBNC, some of these macrophage metabolic responses reflect the establishment of prolonged microbial intracellular residency and possibly initial stages of granuloma formation.</p>","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0048724"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834436/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142876923","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}
引用次数: 0
Expression of Concern for Lopez-Perez et al., "IgG Responses to the Plasmodium falciparum Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to Plasmodium vivax". 对Lopez-Perez等人发表的“哥伦比亚对恶性疟原虫抗原VAR2CSA的IgG反应仅限于妊娠,并不是暴露于间日疟原虫引起的”表示关注。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2025-01-13 DOI: 10.1128/iai.00545-24
{"title":"Expression of Concern for Lopez-Perez et al., \"IgG Responses to the <i>Plasmodium falciparum</i> Antigen VAR2CSA in Colombia Are Restricted to Pregnancy and Are Not Induced by Exposure to <i>Plasmodium vivax</i>\".","authors":"","doi":"10.1128/iai.00545-24","DOIUrl":"10.1128/iai.00545-24","url":null,"abstract":"","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0054524"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834399/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142970519","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}
引用次数: 0
The importance of Fcγ and C-type lectin receptors in host immune responses during Pneumocystis pneumonia. Fcγ和c型凝集素受体在肺囊虫肺炎期间宿主免疫应答中的重要性
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2024-12-31 DOI: 10.1128/iai.00276-24
Theodore J Kottom, Eva M Carmona, Kyle Schaefbauer, Kimberly E Stelzig, Madeline R Pellegrino, Marc Bindzus, Andrew H Limper
<p><p><i>Pneumocystis jirovecii</i> pneumonia (PJP) remains a significant cause of morbidity and mortality during AIDS. In AIDS, the absence of CD4 immunity results in exuberant and often fatal PJP. In addition, organism clearance requires a balanced macrophage response since excessive inflammation promotes lung injury and respiratory failure. Corticosteroids given in addition to antibiotics significantly improve outcomes during PJP. However, concerns exist that corticosteroids further suppress immunity and increase co-infections. New strategies to promote killing and clearance of <i>Pneumocystis</i> while balancing lung inflammation are required. Prior studies have shown that innate immunity to <i>Pneumocystis</i> is mediated by C-type lectin receptors (CLRs) on macrophages and involves downstream CARD9 activation. CARD9 can be targeted by a novel specific small molecule inhibitor (BRD5529) that significantly reduces inflammatory signaling by macrophages. CARD9 serves as the central intracellular molecule through which Dectin-1, Dectin-2, Mincle, and other CLRs signal. Dectin-1 CLR is activated through its own intracytoplasmic domain, whereas other innate CLRs (e.g., Dectin-2 and Mincle) require interactions with a common Fc-gamma receptor (FcγR) accessory chain to mediate responses. We now observe that mice double deficient in both Dectin-1 and Fcer1g (which lack the FcγR gamma chain) exhibit markedly reduced organism clearance compared with <i>Card9</i><sup>-/-</sup> infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody responses, further implicating altered humoral responses in <i>Pneumocystis</i> killing. We further demonstrate in the <i>Pneumocystis</i> pneumonia (PCP) mouse model that BRD5529 administration successfully suppresses inflammatory cytokines. Our data support that innate immune responses through the CLR-CARD9 axis and humoral response act together to mediate effective responses resulting in optimal organism killing and generation of host inflammatory responses. Furthermore, host lung inflammation during PCP may be successfully reduced with a novel CARD9 small molecule inhibitor.IMPORTANCE<i>Pneumocystis</i> pneumonia (PCP) causes severe respiratory impairment in hosts with suppressed immunity, particularly those with CD4 deficiencies, such as HIV. In addition to lymphocytic immunity, both innate and humoral immunities also participate in host defense against <i>Pneumocystis</i>. In the current studies, we defined the relative roles of CLR receptor-mediated inflammation, as well as FcgR-related inflammation and clearance of <i>Pneumocystis</i> organisms. Our studies reveal important roles for CLR activities for inducing lung inflammation, which can be ameliorated with a novel small molecule inhibitor of the CARD9 adaptor protein that is necessary for CLR signaling. In contrast, FcgR has a dominant role in organism clearance, underscoring an integral role of humoral
耶氏肺囊虫肺炎(PJP)仍然是艾滋病发病和死亡的重要原因。在艾滋病中,CD4免疫的缺失导致大量且往往致命的PJP。此外,机体清除需要平衡的巨噬细胞反应,因为过度的炎症会促进肺损伤和呼吸衰竭。除抗生素外给予皮质类固醇可显著改善PJP期间的预后。然而,存在皮质类固醇进一步抑制免疫力和增加合并感染的担忧。需要新的策略来促进肺囊虫的杀死和清除,同时平衡肺部炎症。先前的研究表明,对肺囊虫的先天免疫是由巨噬细胞上的c型凝集素受体(CLRs)介导的,并涉及下游CARD9的激活。CARD9可以被一种新的特异性小分子抑制剂(BRD5529)靶向,它可以显著减少巨噬细胞的炎症信号传导。CARD9是细胞内的中心分子,Dectin-1、Dectin-2、Mincle等clr通过CARD9进行信号传递。Dectin-1 CLR通过其自身的胞浆内结构域被激活,而其他先天CLR(例如Dectin-2和Mincle)需要与共同的fc - γ受体(fc - γ r)副链相互作用来介导反应。我们现在观察到,与Card9-/-感染的动物相比,Dectin-1和Fcer1g(缺乏fc γ - r γ链)双重缺陷的小鼠表现出明显降低的生物体清除率。这些小鼠也缺乏直接介导抗体反应的免疫球蛋白(Ig) Fc受体,进一步暗示了肺囊虫杀死过程中体液反应的改变。我们在肺囊虫肺炎(PCP)小鼠模型中进一步证明,BRD5529成功抑制了炎症细胞因子。我们的数据支持先天免疫反应通过CLR-CARD9轴和体液反应共同作用,介导有效的反应,导致最佳的生物体杀伤和宿主炎症反应的产生。此外,一种新的CARD9小分子抑制剂可能成功地减少PCP期间宿主肺部炎症。肺囊虫肺炎(PCP)在免疫抑制的宿主中引起严重的呼吸障碍,特别是那些CD4缺陷的宿主,如艾滋病毒。除了淋巴细胞免疫外,先天免疫和体液免疫也参与宿主对肺囊虫的防御。在目前的研究中,我们定义了CLR受体介导的炎症,以及fcgr相关炎症和肺囊虫有机体清除的相对作用。我们的研究揭示了CLR活性在诱导肺部炎症中的重要作用,这可以通过一种新的小分子抑制剂来改善,这种小分子抑制剂是CLR信号转导所必需的CARD9接头蛋白。相反,FcgR在机体清除中起主导作用,强调了体液反应在消除这种感染中的整体作用。
{"title":"The importance of Fcγ and C-type lectin receptors in host immune responses during <i>Pneumocystis</i> pneumonia.","authors":"Theodore J Kottom, Eva M Carmona, Kyle Schaefbauer, Kimberly E Stelzig, Madeline R Pellegrino, Marc Bindzus, Andrew H Limper","doi":"10.1128/iai.00276-24","DOIUrl":"10.1128/iai.00276-24","url":null,"abstract":"&lt;p&gt;&lt;p&gt;&lt;i&gt;Pneumocystis jirovecii&lt;/i&gt; pneumonia (PJP) remains a significant cause of morbidity and mortality during AIDS. In AIDS, the absence of CD4 immunity results in exuberant and often fatal PJP. In addition, organism clearance requires a balanced macrophage response since excessive inflammation promotes lung injury and respiratory failure. Corticosteroids given in addition to antibiotics significantly improve outcomes during PJP. However, concerns exist that corticosteroids further suppress immunity and increase co-infections. New strategies to promote killing and clearance of &lt;i&gt;Pneumocystis&lt;/i&gt; while balancing lung inflammation are required. Prior studies have shown that innate immunity to &lt;i&gt;Pneumocystis&lt;/i&gt; is mediated by C-type lectin receptors (CLRs) on macrophages and involves downstream CARD9 activation. CARD9 can be targeted by a novel specific small molecule inhibitor (BRD5529) that significantly reduces inflammatory signaling by macrophages. CARD9 serves as the central intracellular molecule through which Dectin-1, Dectin-2, Mincle, and other CLRs signal. Dectin-1 CLR is activated through its own intracytoplasmic domain, whereas other innate CLRs (e.g., Dectin-2 and Mincle) require interactions with a common Fc-gamma receptor (FcγR) accessory chain to mediate responses. We now observe that mice double deficient in both Dectin-1 and Fcer1g (which lack the FcγR gamma chain) exhibit markedly reduced organism clearance compared with &lt;i&gt;Card9&lt;/i&gt;&lt;sup&gt;-/-&lt;/sup&gt; infected animals. These mice also possess deficiencies in immunoglobulin (Ig) Fc receptors directly mediating antibody responses, further implicating altered humoral responses in &lt;i&gt;Pneumocystis&lt;/i&gt; killing. We further demonstrate in the &lt;i&gt;Pneumocystis&lt;/i&gt; pneumonia (PCP) mouse model that BRD5529 administration successfully suppresses inflammatory cytokines. Our data support that innate immune responses through the CLR-CARD9 axis and humoral response act together to mediate effective responses resulting in optimal organism killing and generation of host inflammatory responses. Furthermore, host lung inflammation during PCP may be successfully reduced with a novel CARD9 small molecule inhibitor.IMPORTANCE&lt;i&gt;Pneumocystis&lt;/i&gt; pneumonia (PCP) causes severe respiratory impairment in hosts with suppressed immunity, particularly those with CD4 deficiencies, such as HIV. In addition to lymphocytic immunity, both innate and humoral immunities also participate in host defense against &lt;i&gt;Pneumocystis&lt;/i&gt;. In the current studies, we defined the relative roles of CLR receptor-mediated inflammation, as well as FcgR-related inflammation and clearance of &lt;i&gt;Pneumocystis&lt;/i&gt; organisms. Our studies reveal important roles for CLR activities for inducing lung inflammation, which can be ameliorated with a novel small molecule inhibitor of the CARD9 adaptor protein that is necessary for CLR signaling. In contrast, FcgR has a dominant role in organism clearance, underscoring an integral role of humoral","PeriodicalId":13541,"journal":{"name":"Infection and Immunity","volume":" ","pages":"e0027624"},"PeriodicalIF":2.9,"publicationDate":"2025-02-18","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11834440/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142914691","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}
引用次数: 0
Morphogenetic penicillin-binding proteins control virulence-associated type III secretion systems in Salmonella. 形态发生青霉素结合蛋白控制沙门氏菌毒力相关的III型分泌系统。
IF 2.9 3区 医学 Q3 IMMUNOLOGY Pub Date : 2025-02-18 Epub Date: 2024-12-31 DOI: 10.1128/iai.00555-24
Sónia Castanheira, Sara Torronteras, Juan J Cestero, Francisco García-Del Portillo

Type III protein secretion systems (T3SSs) function as multiprotein devices that span the envelope of Gram-negative bacteria using the peptidoglycan (PG) layer as scaffold. This spatial arrangement explains why modifications in PG structure can alter T3SS activity. In Salmonella, incorporation of non-canonical D-amino acids in the PG was shown to decrease the activity of the T3SS encoded by the pathogenicity island-1 (SPI-1) without affecting other T3SS, like the flagellum apparatus. Enigmatically, following invasion of host cell Salmonella enterica serovar Typhimurium modifies PG synthesis by upregulating two pathogen-specific enzymes, the penicillin-binding proteins PBP2SAL and PBP3SAL, with roles in cell elongation and division, respectively. In the mouse typhoid model, the amount of PBP2SAL and PBP3SAL produced by the pathogen exceeds by large those of the canonical enzymes PBP2 and PBP3. This change responds to acidity and high osmolarity, the same cues that intra-phagosomal S. Typhimurium perceives to switch the SPI-1 T3SS by that encoded in SPI-2. Using isogenic mutants lacking each of the four morphogenetic PBPs, we tested whether their activities and those of the T3SS encoded by SPI-1 and SPI-2, are interconnected. Our data show that PBP2 is required for proper function of SPI-1 T3SS but dispensable for motility, whereas the lack of any of the morphogenetic PBPs increases SPI-2 T3SS activity. The positive control exerted by PBP2 on SPI-1 takes place via the SPI-1-specific regulators HilA and InvF. To our knowledge, these findings provide the first evidence linking morphogenetic enzymes that synthesize PG with T3SS associated to virulence.

III型蛋白分泌系统(t3ss)作为多蛋白装置,利用肽聚糖(PG)层作为支架,跨越革兰氏阴性菌的包膜。这种空间排列解释了为什么PG结构的改变可以改变T3SS活性。在沙门氏菌中,在PG中掺入非规范d-氨基酸可降低致病性岛-1 (SPI-1)编码的T3SS的活性,而不会影响其他T3SS,如鞭毛装置。令人费解的是,在入侵宿主细胞后,鼠伤寒沙门氏菌通过上调两种病原体特异性酶(青霉素结合蛋白PBP2SAL和PBP3SAL)来修饰PG的合成,这两种酶分别参与细胞的延伸和分裂。在小鼠伤寒模型中,病原体产生的PBP2SAL和PBP3SAL的量大大超过了典型酶PBP2和PBP3的量。这种变化对酸度和高渗透压作出反应,吞噬体内鼠伤寒沙门氏菌感知到通过SPI-2编码的信号来切换SPI-1 T3SS。利用缺乏四种形态发生PBPs的等基因突变体,我们测试了它们的活性是否与SPI-1和SPI-2编码的T3SS的活性相互关联。我们的数据表明,PBP2对于SPI-1 T3SS的正常功能是必需的,但对于运动是必不可少的,而缺乏任何一种形态发生的PBPs都会增加SPI-2 T3SS的活性。PBP2通过SPI-1特异性调节因子HilA和InvF对SPI-1进行阳性控制。据我们所知,这些发现提供了将合成PG和T3SS的形态发生酶与毒力联系起来的第一个证据。
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Infection and Immunity
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