Christelle Dieppois, Gael Chambonnier, Frederic Gallardo, Magali Torres, Alassane Thiam, Babacar Mbengue, Alioune Dieye, Pascal Rihet, Pascale Paul
Background Malaria remains a major health challenge in sub-Saharan Africa despite extensive control measures. Host genetic variation influences susceptibility, but the role of inhibitory receptors such as LILRB1—targeted by Plasmodium falciparum RIFINs—remains unclear. We investigated whether regulatory variants in LILRB1 modulate malaria risk. Methods Regulatory variants were prioritized from African expression quantitative trait locus (eQTL) datasets by integrating linkage disequilibrium, chromatin accessibility, transcription factor binding, and immune cell–specific expression. Three non-coding variants (rs10416697, rs10423364, rs7246537) and one coding variant (rs1061680) were selected. Genotyping was performed in 267 Senegalese individuals (116 severe malaria, 74 mild malaria, 77 healthy controls). Logistic regression adjusted for age assessed genetic associations. The effect of rs7246537 on promoter activity was tested using luciferase assays. Results Among 10,110 candidate eQTLs, 49 were associated with LILRB1 expression in African populations; three overlapped open chromatin near the distal promoter. Only rs7246537 showed significant association with malaria: allele A carriers had lower risk of clinical malaria (OR = 0.50, 95% CI: 0.28-0.88, p = 0.0165) and cerebral malaria (OR = 0.44, 95% CI: 0.22-0.86, p = 0.0176). rs7246537 colocalized with a YY1-binding site, and luciferase assays confirmed allele-specific effects, with the A allele driving twofold lower promoter activity compared with the G allele. Conclusions rs7246537 is a functional regulatory variant that reduces malaria susceptibility in Senegalese populations by modulating LILRB1 expression. These findings underscore the importance of non-coding variants and inhibitory immune pathways in malaria pathogenesis.
背景尽管采取了广泛的控制措施，但疟疾仍然是撒哈拉以南非洲的一个主要卫生挑战。宿主遗传变异影响易感性，但抑制受体如lilrb1（恶性疟原虫rifins靶向）的作用尚不清楚。我们调查了LILRB1的调节变异是否调节疟疾风险。方法通过整合连锁不平衡、染色质可及性、转录因子结合和免疫细胞特异性表达，从非洲表达数量性状位点（eQTL）数据集中优选调节变异。选择3个非编码变体（rs10416697、rs10423364、rs7246537）和1个编码变体（rs1061680）。对267名塞内加尔人（116名重度疟疾患者，74名轻度疟疾患者，77名健康对照者）进行了基因分型。逻辑回归调整了年龄评估的遗传关联。采用荧光素酶法检测rs7246537对启动子活性的影响。结果在10,110个候选eqtl中，49个与非洲人群的LILRB1表达相关；在远端启动子附近有三个重叠的开放染色质。只有rs7246537与疟疾有显著相关性：携带等位基因A的临床疟疾（OR = 0.50, 95% CI: 0.28-0.88, p = 0.0165）和脑疟疾（OR = 0.44, 95% CI: 0.22-0.86, p = 0.0176）的风险较低。rs7246537与yy1结合位点共定位，荧光素酶测定证实了等位基因特异性效应，a等位基因驱动的启动子活性比G等位基因低两倍。结论rs7246537是一种通过调节LILRB1表达降低塞内加尔人群疟疾易感性的功能性调节变异。这些发现强调了非编码变异体和抑制免疫途径在疟疾发病机制中的重要性。
{"title":"A Functional Intronic Variant of LILRB1 Associated with Clinical Malaria in the Senegalese Population","authors":"Christelle Dieppois, Gael Chambonnier, Frederic Gallardo, Magali Torres, Alassane Thiam, Babacar Mbengue, Alioune Dieye, Pascal Rihet, Pascale Paul","doi":"10.1093/infdis/jiag007","DOIUrl":"https://doi.org/10.1093/infdis/jiag007","url":null,"abstract":"Background Malaria remains a major health challenge in sub-Saharan Africa despite extensive control measures. Host genetic variation influences susceptibility, but the role of inhibitory receptors such as LILRB1—targeted by Plasmodium falciparum RIFINs—remains unclear. We investigated whether regulatory variants in LILRB1 modulate malaria risk. Methods Regulatory variants were prioritized from African expression quantitative trait locus (eQTL) datasets by integrating linkage disequilibrium, chromatin accessibility, transcription factor binding, and immune cell–specific expression. Three non-coding variants (rs10416697, rs10423364, rs7246537) and one coding variant (rs1061680) were selected. Genotyping was performed in 267 Senegalese individuals (116 severe malaria, 74 mild malaria, 77 healthy controls). Logistic regression adjusted for age assessed genetic associations. The effect of rs7246537 on promoter activity was tested using luciferase assays. Results Among 10,110 candidate eQTLs, 49 were associated with LILRB1 expression in African populations; three overlapped open chromatin near the distal promoter. Only rs7246537 showed significant association with malaria: allele A carriers had lower risk of clinical malaria (OR = 0.50, 95% CI: 0.28-0.88, p = 0.0165) and cerebral malaria (OR = 0.44, 95% CI: 0.22-0.86, p = 0.0176). rs7246537 colocalized with a YY1-binding site, and luciferase assays confirmed allele-specific effects, with the A allele driving twofold lower promoter activity compared with the G allele. Conclusions rs7246537 is a functional regulatory variant that reduces malaria susceptibility in Senegalese populations by modulating LILRB1 expression. These findings underscore the importance of non-coding variants and inhibitory immune pathways in malaria pathogenesis.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903545","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
João Vitor Mahler, Philippe A Bilodeau, Monique Anderson, Takahisa Mikami, Natasha Bobrowski-Khoury, Mulan Jiang, Huimin Zhu, James Nguyen, Marcelo Matiello, Michael Levy, Kjetil Bjornevik, Natalia Drosu
Low anti-EBNA-1 antibody titers are associated with reduced risk of EBV-related diseases. We hypothesized that individuals with exceptionally low anti-EBNA-1 levels represent a biologically distinct subgroup. Twenty healthy adults were classified by their antibody titers into 17 individuals with typical-range titers and 3 low outliers. Participants provided 204 saliva samples longitudinally. Typical-range participants frequently shed EBV, while low outliers had no detectable shedding (p = 0.0002). While all participants were confirmed to be EBV-positive, non-shedders showed restricted antibody diversity limited to latent and immediate-early antigens. Our findings define a distinct non-shedder phenotype that suppresses viral replication despite harboring latent virus.
{"title":"A threshold in anti-EBNA-1 antibody titers distinguishes salivary EBV shedders from non-shedders","authors":"João Vitor Mahler, Philippe A Bilodeau, Monique Anderson, Takahisa Mikami, Natasha Bobrowski-Khoury, Mulan Jiang, Huimin Zhu, James Nguyen, Marcelo Matiello, Michael Levy, Kjetil Bjornevik, Natalia Drosu","doi":"10.1093/infdis/jiag010","DOIUrl":"https://doi.org/10.1093/infdis/jiag010","url":null,"abstract":"Low anti-EBNA-1 antibody titers are associated with reduced risk of EBV-related diseases. We hypothesized that individuals with exceptionally low anti-EBNA-1 levels represent a biologically distinct subgroup. Twenty healthy adults were classified by their antibody titers into 17 individuals with typical-range titers and 3 low outliers. Participants provided 204 saliva samples longitudinally. Typical-range participants frequently shed EBV, while low outliers had no detectable shedding (p = 0.0002). While all participants were confirmed to be EBV-positive, non-shedders showed restricted antibody diversity limited to latent and immediate-early antigens. Our findings define a distinct non-shedder phenotype that suppresses viral replication despite harboring latent virus.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"42 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903727","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Background Streptococcus pneumoniae commonly colonizes the nasopharynx of children asymptomatically, but under certain conditions, it can cause invasive diseases such as pneumonia. The mechanisms driving this transition are not fully understood. Methods In this study, we utilized a pneumococcal nasopharyngeal colonization model and subsequent respiratory syncytial virus (RSV) infection to investigate the mechanism of bacterial expansion. We observed loads in nasal and bronchoalveolar lavage fluids. We also measured the expression of the growth arrest-specific protein 6 (Gas6) in the nasal lavage. We further assessed the effect of selective inhibition of the Axl receptor using BGB324 on RSV-mediated growth. Macrophage phenotypes were analyzed in vivo using M1-like markers and confirmed in vitro using Gas6-treated bone marrow-derived macrophages. Results We observed increased loads in nasal and bronchoalveolar lavage fluids following RSV infection. RSV infection also upregulated the expression of Gas6 in the nasal lavage, and selective inhibition of the Axl receptor using BGB324 effectively attenuated RSV-mediated growth. In addition, compared with mice with colonization alone, mice with subsequent RSV infection exhibited decreased expression of M1-like macrophage markers in the nasal cavity. In vitro assays confirmed that Gas6 suppressed M1 macrophage polarization, fostering an immunosuppressive microenvironment conducive to bacterial proliferation. Conclusions Our findings reveal that the RSV infection–induced Gas6/Axl axis facilitates pneumococcal overgrowth by modulating macrophage function. Targeting the RSV-induced Gas6/Axl axis or modulating macrophage polarization may offer novel therapeutic strategies for preventing or managing severe pneumococcal infections exacerbated by viral pathogens such as RSV.
{"title":"Respiratory syncytial virus–mediated Gas6/Axl axis induces hyporesponsive macrophages to promote pneumococcal proliferation in the nasopharynx","authors":"Saki Ishikawa, Nanami Okada, Yuzu Fukui, Rumi Ueha, Toshihiro Ito, Shigeki Nakamura, Takehiko Shibata","doi":"10.1093/infdis/jiag004","DOIUrl":"https://doi.org/10.1093/infdis/jiag004","url":null,"abstract":"Background Streptococcus pneumoniae commonly colonizes the nasopharynx of children asymptomatically, but under certain conditions, it can cause invasive diseases such as pneumonia. The mechanisms driving this transition are not fully understood. Methods In this study, we utilized a pneumococcal nasopharyngeal colonization model and subsequent respiratory syncytial virus (RSV) infection to investigate the mechanism of bacterial expansion. We observed loads in nasal and bronchoalveolar lavage fluids. We also measured the expression of the growth arrest-specific protein 6 (Gas6) in the nasal lavage. We further assessed the effect of selective inhibition of the Axl receptor using BGB324 on RSV-mediated growth. Macrophage phenotypes were analyzed in vivo using M1-like markers and confirmed in vitro using Gas6-treated bone marrow-derived macrophages. Results We observed increased loads in nasal and bronchoalveolar lavage fluids following RSV infection. RSV infection also upregulated the expression of Gas6 in the nasal lavage, and selective inhibition of the Axl receptor using BGB324 effectively attenuated RSV-mediated growth. In addition, compared with mice with colonization alone, mice with subsequent RSV infection exhibited decreased expression of M1-like macrophage markers in the nasal cavity. In vitro assays confirmed that Gas6 suppressed M1 macrophage polarization, fostering an immunosuppressive microenvironment conducive to bacterial proliferation. Conclusions Our findings reveal that the RSV infection–induced Gas6/Axl axis facilitates pneumococcal overgrowth by modulating macrophage function. Targeting the RSV-induced Gas6/Axl axis or modulating macrophage polarization may offer novel therapeutic strategies for preventing or managing severe pneumococcal infections exacerbated by viral pathogens such as RSV.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903729","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Lena Ostermann, Benjamin Seeliger, Konrad Peukert, Lara-Kristin Steinmetz, Carolin Flasche, Regina Maus, Jennifer Stolper, Thomas Vogl, Andreas Pich, Christian Bode, Konstantin Neumann, Korbinian Brand, Philippe A Tessier, Johannes Roth, Ulrich A Maus
Background We recently showed that S100A9 is indispensable for lung antibacterial immunity, making it crucial for the survival of pneumococcal pneumonia. However, the role of S100A8 in lung antibacterial immunity is ill-defined. Methods S100A8 levels in BAL fluid (BALF) samples of patients with pneumonia were quantified by ELISA. WT and S100A8 KO mice were orotracheally infected with Streptococcus pneumoniae (S. pneumoniae) and bacterial clearance, disease progression, lung histopathology and leukocyte recruitment were analyzed at defined time points. Results S100A8 protein levels were particularly increased in BALF of patients with bacterial as compared to viral pneumonia. Similarly, WT mice responded with S100A8 and S100A9 protein release upon pneumococcal challenge. However, S100A8 deficiency led to decreased S100A9 levels and significantly increased bacterial loads in lungs of S. pneumoniae-challenged mice. S. pneumoniae-infected S100A8 KO mice developed a severe neutrophil-dominated purulent bronchopneumonia with interstitial and alveolar edema and intravascular coagulation leading to early mortality. Mechanistically, S100A8 deficiency resulted in neutrophil elastase (NE) dependent degradation of surfactant proteins A (SP-A) and D (SP-D) in lungs of mice. Incubation of WT BALF with recombinant NE confirmed NE-dependent SP-D degradation in vitro, which could be blocked by the NE-specific inhibitor Sivelestat. Therapy with recombinant S100A8/A9 protein rescued S100A8 KO mice from fatal pneumococcal pneumonia. Conclusion Deletion of S100A8 disturbs lung protective immunity against S. pneumoniae in mice. At the same time, analysis of the S100A8/A9 protein complex in clinical samples may help to distinguish between patients with bacterial versus viral pneumonia.
{"title":"Lack of S100A8 impairs lung protective immunity against Streptococcus pneumoniae","authors":"Lena Ostermann, Benjamin Seeliger, Konrad Peukert, Lara-Kristin Steinmetz, Carolin Flasche, Regina Maus, Jennifer Stolper, Thomas Vogl, Andreas Pich, Christian Bode, Konstantin Neumann, Korbinian Brand, Philippe A Tessier, Johannes Roth, Ulrich A Maus","doi":"10.1093/infdis/jiaf647","DOIUrl":"https://doi.org/10.1093/infdis/jiaf647","url":null,"abstract":"Background We recently showed that S100A9 is indispensable for lung antibacterial immunity, making it crucial for the survival of pneumococcal pneumonia. However, the role of S100A8 in lung antibacterial immunity is ill-defined. Methods S100A8 levels in BAL fluid (BALF) samples of patients with pneumonia were quantified by ELISA. WT and S100A8 KO mice were orotracheally infected with Streptococcus pneumoniae (S. pneumoniae) and bacterial clearance, disease progression, lung histopathology and leukocyte recruitment were analyzed at defined time points. Results S100A8 protein levels were particularly increased in BALF of patients with bacterial as compared to viral pneumonia. Similarly, WT mice responded with S100A8 and S100A9 protein release upon pneumococcal challenge. However, S100A8 deficiency led to decreased S100A9 levels and significantly increased bacterial loads in lungs of S. pneumoniae-challenged mice. S. pneumoniae-infected S100A8 KO mice developed a severe neutrophil-dominated purulent bronchopneumonia with interstitial and alveolar edema and intravascular coagulation leading to early mortality. Mechanistically, S100A8 deficiency resulted in neutrophil elastase (NE) dependent degradation of surfactant proteins A (SP-A) and D (SP-D) in lungs of mice. Incubation of WT BALF with recombinant NE confirmed NE-dependent SP-D degradation in vitro, which could be blocked by the NE-specific inhibitor Sivelestat. Therapy with recombinant S100A8/A9 protein rescued S100A8 KO mice from fatal pneumococcal pneumonia. Conclusion Deletion of S100A8 disturbs lung protective immunity against S. pneumoniae in mice. At the same time, analysis of the S100A8/A9 protein complex in clinical samples may help to distinguish between patients with bacterial versus viral pneumonia.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145847303","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Rongling Zhang, Xiao Shang, Chunlei Wang, Hong Zhou, Nana Liu, Xiaochen Shen, Zeyi Wang, Jiuyang Xu, Dingrong Zhong, Hui Li, Bin Cao
Background The role of human rhinovirus (HRV) in adult lower respiratory tract infections (LRTIs) remains controversial due to limited direct evidence of alveolar tropism and age-specific clinical characterization. Objectives To determine HRV’s clinical impact, validate its capacity to infect lower respiratory tract cells, and identify predictors for HRV-associated pneumonia in adults. Methods In this retrospective study (January 2020–December 2023), all hospitalized adults screened for HRV via RT-PCR were enrolled for analysis. In BALF HRV RNA-positive patients with available transbronchial lung biopsy (TBLB) or transbronchial cryobiopsy (TBCB) specimens, immunofluorescence (IF) staining was used to assess infection of LRT cells. Multivariable logistic regression analyzed demographics, comorbidities, and symptoms. Results HRV was detected in 4.6% (437/9,544) of patients, with bimodal seasonal peaks (February–April and September–November). Co-infection occurred in 49.0% (214/437), predominantly bacteria (34.1%) and viruses (25.7%). Among the 437 HRV-positive patients, 224 cases complicated with pneumonia, but only 34 (7.8%) met the diagnostic criteria for simple viral pneumonia. Multivariate analysis identified male (OR 2.69, 95% CI 1.04-6.99, P = 0.042), fever (OR 3.79, 95% CI 1.52–9.44, P = 0.004) and cough (OR 7.33, 95% CI 1.64–32.83, P = 0.009) as independent predictors of simple rhinovirus pneumonia. IF staining confirmed HRV VP3 protein in TBLB/TBCB specimens in 61.5% (8/13) of cases, resolving debates about HRV’s LRT cells tropism. Conclusions This study provides the first histological evidence of HRV’s LRT cells infection in immunocompetent adults. Despite high co-infection rates, HRV independently drives pneumonia, particularly in males and those with fever or cough.
人类鼻病毒（HRV）在成人下呼吸道感染（LRTIs）中的作用仍然存在争议，因为关于肺泡性和年龄特异性临床特征的直接证据有限。目的确定HRV的临床影响，验证其感染下呼吸道细胞的能力，并确定成人HRV相关肺炎的预测因素。方法在这项回顾性研究中（2020年1月- 2023年12月），所有通过RT-PCR筛查的住院成人纳入分析。在可获得经支气管肺活检（TBLB）或经支气管低温活检（TBCB）标本的BALF HRV rna阳性患者中，使用免疫荧光（IF）染色来评估LRT细胞的感染。多变量logistic回归分析了人口统计学、合并症和症状。结果HRV检出率为4.6%(437/ 9544)，呈双峰型季节性高峰（2 - 4月和9 - 11月）。合并感染发生率为49.0%(214/437)，以细菌（34.1%）和病毒（25.7%）为主。437例hrv阳性患者中合并肺炎224例，但符合单纯性病毒性肺炎诊断标准的仅有34例（7.8%）。多因素分析发现，男性（OR 2.69, 95% CI 1.04-6.99, P = 0.042）、发烧（OR 3.79, 95% CI 1.52-9.44, P = 0.004）和咳嗽（OR 7.33, 95% CI 1.64-32.83, P = 0.009）是单纯鼻病毒肺炎的独立预测因子。IF染色在61.5%（8/13）的TBLB/TBCB标本中证实HRV VP3蛋白，解决了关于HRV LRT细胞趋向性的争论。结论本研究首次提供了免疫功能正常成人HRV LRT细胞感染的组织学证据。尽管合并感染率很高，但HRV独立驱动肺炎，特别是在男性和发烧或咳嗽患者中。
{"title":"Rhinovirus-associated lower respiratory tract infection in hospitalized adult patients: a retrospective cohort study","authors":"Rongling Zhang, Xiao Shang, Chunlei Wang, Hong Zhou, Nana Liu, Xiaochen Shen, Zeyi Wang, Jiuyang Xu, Dingrong Zhong, Hui Li, Bin Cao","doi":"10.1093/infdis/jiaf651","DOIUrl":"https://doi.org/10.1093/infdis/jiaf651","url":null,"abstract":"Background The role of human rhinovirus (HRV) in adult lower respiratory tract infections (LRTIs) remains controversial due to limited direct evidence of alveolar tropism and age-specific clinical characterization. Objectives To determine HRV’s clinical impact, validate its capacity to infect lower respiratory tract cells, and identify predictors for HRV-associated pneumonia in adults. Methods In this retrospective study (January 2020–December 2023), all hospitalized adults screened for HRV via RT-PCR were enrolled for analysis. In BALF HRV RNA-positive patients with available transbronchial lung biopsy (TBLB) or transbronchial cryobiopsy (TBCB) specimens, immunofluorescence (IF) staining was used to assess infection of LRT cells. Multivariable logistic regression analyzed demographics, comorbidities, and symptoms. Results HRV was detected in 4.6% (437/9,544) of patients, with bimodal seasonal peaks (February–April and September–November). Co-infection occurred in 49.0% (214/437), predominantly bacteria (34.1%) and viruses (25.7%). Among the 437 HRV-positive patients, 224 cases complicated with pneumonia, but only 34 (7.8%) met the diagnostic criteria for simple viral pneumonia. Multivariate analysis identified male (OR 2.69, 95% CI 1.04-6.99, P = 0.042), fever (OR 3.79, 95% CI 1.52–9.44, P = 0.004) and cough (OR 7.33, 95% CI 1.64–32.83, P = 0.009) as independent predictors of simple rhinovirus pneumonia. IF staining confirmed HRV VP3 protein in TBLB/TBCB specimens in 61.5% (8/13) of cases, resolving debates about HRV’s LRT cells tropism. Conclusions This study provides the first histological evidence of HRV’s LRT cells infection in immunocompetent adults. Despite high co-infection rates, HRV independently drives pneumonia, particularly in males and those with fever or cough.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"36 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145847262","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Seher H Anjum, Jessica Hargarten, Brittany Dulek, Francisco Otaizo-Carrasquero, Winnie Trang, Shelley Kalsi, Morgan Similuk, Rajarshi Ghosh, Magdelena Walkiewicz-Yvon, Mari Tokita, Dima A Hammoud, Andrea Beri, Peter R Williamson
Background Cryptococcal meningitis (CM) is a leading cause of fungal meningitis globally. Cerebral venous sinus thrombosis (CVST), though a recognized complication, has been rarely reported in both HIV-positive and HIV-negative individuals. This study investigates the incidence, clinical course, genetic factors, and neuroimaging features of CVST in a retrospective cohort of previously healthy, non-HIV CM patients. Methods We reviewed medical records of 89 immunocompetent CM patients admitted to the NIH Clinical Center between January 2005 and April 2024. CVST incidence, clinical course, neuroimaging, and laboratory data were analyzed. Genetic analysis was performed to detect any thrombophilia-associated variants. To explore thrombosis-related gene expression during neuroinflammation, cerebrospinal fluid (CSF) cells collected at the time of cryptococcal post-infectious inflammatory response syndrome (cPIIRS) diagnosis were subjected to single-cell RNA sequencing. Results CVST occurred in 5.6% (CI 1.9% - 12.6%) of CM patients, a rate comparable to bacterial CNS infections. No known pathogenic or likely pathogenic variants in known thrombophilia-associated genes were identified. However, 44 genes previously linked to thrombosis showed elevated expression—defined as ≥150 single-cell sequencing reads—in a cPIIRS patient. Conclusion CVST is a clinically significant and potentially treatable complication of CM, even in individuals without prior clotting abnormalities. MRI and MRV of the brain are valuable diagnostic tools. The absence of identifiable thrombophilia mutations suggests that neurologic infection itself contributes to thrombotic risk. Notably, CSF gene expression patterns may serve as biomarkers for CVST susceptibility. Future case-control studies may validate these findings and uncover genetic risk factors contributing to this severe complication.
{"title":"Cerebral Venous Thrombosis in Previously Healthy Patients with Cryptococcal Meningitis","authors":"Seher H Anjum, Jessica Hargarten, Brittany Dulek, Francisco Otaizo-Carrasquero, Winnie Trang, Shelley Kalsi, Morgan Similuk, Rajarshi Ghosh, Magdelena Walkiewicz-Yvon, Mari Tokita, Dima A Hammoud, Andrea Beri, Peter R Williamson","doi":"10.1093/infdis/jiaf653","DOIUrl":"https://doi.org/10.1093/infdis/jiaf653","url":null,"abstract":"Background Cryptococcal meningitis (CM) is a leading cause of fungal meningitis globally. Cerebral venous sinus thrombosis (CVST), though a recognized complication, has been rarely reported in both HIV-positive and HIV-negative individuals. This study investigates the incidence, clinical course, genetic factors, and neuroimaging features of CVST in a retrospective cohort of previously healthy, non-HIV CM patients. Methods We reviewed medical records of 89 immunocompetent CM patients admitted to the NIH Clinical Center between January 2005 and April 2024. CVST incidence, clinical course, neuroimaging, and laboratory data were analyzed. Genetic analysis was performed to detect any thrombophilia-associated variants. To explore thrombosis-related gene expression during neuroinflammation, cerebrospinal fluid (CSF) cells collected at the time of cryptococcal post-infectious inflammatory response syndrome (cPIIRS) diagnosis were subjected to single-cell RNA sequencing. Results CVST occurred in 5.6% (CI 1.9% - 12.6%) of CM patients, a rate comparable to bacterial CNS infections. No known pathogenic or likely pathogenic variants in known thrombophilia-associated genes were identified. However, 44 genes previously linked to thrombosis showed elevated expression—defined as ≥150 single-cell sequencing reads—in a cPIIRS patient. Conclusion CVST is a clinically significant and potentially treatable complication of CM, even in individuals without prior clotting abnormalities. MRI and MRV of the brain are valuable diagnostic tools. The absence of identifiable thrombophilia mutations suggests that neurologic infection itself contributes to thrombotic risk. Notably, CSF gene expression patterns may serve as biomarkers for CVST susceptibility. Future case-control studies may validate these findings and uncover genetic risk factors contributing to this severe complication.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145822759","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Francesco Branda,Giancarlo Ceccarelli,Marta Giovanetti,Fabio Scarpa,Massimo Ciccozzi
{"title":"Polio-Free, Not Risk-Free: Wastewater as Early Warning.","authors":"Francesco Branda,Giancarlo Ceccarelli,Marta Giovanetti,Fabio Scarpa,Massimo Ciccozzi","doi":"10.1093/infdis/jiaf643","DOIUrl":"https://doi.org/10.1093/infdis/jiaf643","url":null,"abstract":"","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"45 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Mia Aguirre,Doris Ayala,Juan Ignacio Garcia,Yoscelina E Martinez-Lopez,Amberlee D Hicks,Nadine Chacon,Ashley Gay-Cobb,Alyssa Schami,Selena Zavala-Perez,Ilse A Dominguez-Trejo,America M Cruz-Gonzalez,Raul Loera-Salazar,Javier E Rodríguez-Herrera,Esperanza M Garcia-Oropesa,Miryoung Lee,Adrian Rendón,Shu-Hua Wang,Marcel Yotebieng,Carlton A Evans,Jordi B Torrelles,Blanca I Restrepo
BACKGROUNDWith >10 million new tuberculosis (TB) cases/year, a limitation to TB control is the lack of simple and accurate tests for TB diagnosis and drug-susceptibility testing (DST) in endemic regions. We evaluated the accuracy of the first-generation, low-complexity phenotypic TB test (1G test), designed for simultaneous Mtb detection and resistance to isoniazid, rifampicin and moxifloxacin, suitable for resource-limited settings.METHODSA cross-sectional study was conducted using sputa from 426 possible pulmonary TB subjects from two small Mexican cities bordering Texas. The 1G test was compared against phenotypic TB detection tests in the region [acid fast bacilli smear microscopy and Mycobacteria Growth Indicator Tube (MGIT) culture], and to MGIT-DST for resistance to isoniazid, rifampicin and moxifloxacin.FINDINGSThe 1G test demonstrated ≥98% sensitivity for Mtb detection, 100% sensitivity and 91% (rifampicin), 94% (isoniazid) and 97% (moxifloxacin) specificity for DST, and less contamination than the MGIT (3.5% vs. 8.1%; p<0.05). The 1G test time to detection (TTD) of Mtb and simultaneous DST was 17-days, while the MGIT-DST required two steps: 7 days for Mtb detection plus 14 more (total 21 days) for DST. Our study site DR-TB prevalence was 14% when testing all consecutively-enrolled participants vs. 6% by passive reporting.INTERPRETATIONThe 1G test is a low-complexity phenotypic TB diagnostic method that is a practical replacement to current culture-based tests. Future studies are warranted to evaluate the implementation of the 1G test in decentralized clinics that lack molecular tools, resources and expertise.
背景：结核病流行地区每年新发结核病病例高达1000万，结核病控制面临的一个限制是缺乏简单而准确的结核病诊断和药敏试验（DST）检测。我们评估了第一代低复杂性表型结核试验（1G试验）的准确性，该试验设计用于同时检测结核分枝杆菌和对异烟肼、利福平和莫西沙星的耐药性，适用于资源有限的环境。方法横断面研究使用来自德克萨斯州边境两个墨西哥小城市的426名疑似肺结核患者的痰液。将1G试验与该地区[抗酸杆菌涂片镜检和分枝杆菌生长指示管（MGIT）培养]表型结核检测试验进行比较，并与MGIT- dst试验比较异烟肼、利福平和莫西沙星的耐药性。结果：1G试验对Mtb的检测灵敏度≥98%，对DST的检测灵敏度为100%，利福平为91%，异烟肼为94%，莫西沙星为97%，污染小于MGIT （3.5% vs. 8.1%; p<0.05）。Mtb和同步DST的1G检测到检测时间（TTD）为17天，而mgt -DST需要两个步骤：Mtb检测7天加上DST 14天（共21天）。在我们的研究现场，当对所有连续入组的参与者进行检测时，耐药结核病患病率为14%，而被动报告为6%。解释：1G测试是一种低复杂性的表型结核诊断方法，是目前基于培养的测试的实用替代品。未来的研究需要评估1G测试在缺乏分子工具、资源和专业知识的分散诊所中的实施情况。
{"title":"Accuracy of the phenotypic 1G test to detect Mycobacterium tuberculosis and drug resistance from sputa in the US-Mexico border.","authors":"Mia Aguirre,Doris Ayala,Juan Ignacio Garcia,Yoscelina E Martinez-Lopez,Amberlee D Hicks,Nadine Chacon,Ashley Gay-Cobb,Alyssa Schami,Selena Zavala-Perez,Ilse A Dominguez-Trejo,America M Cruz-Gonzalez,Raul Loera-Salazar,Javier E Rodríguez-Herrera,Esperanza M Garcia-Oropesa,Miryoung Lee,Adrian Rendón,Shu-Hua Wang,Marcel Yotebieng,Carlton A Evans,Jordi B Torrelles,Blanca I Restrepo","doi":"10.1093/infdis/jiaf638","DOIUrl":"https://doi.org/10.1093/infdis/jiaf638","url":null,"abstract":"BACKGROUNDWith >10 million new tuberculosis (TB) cases/year, a limitation to TB control is the lack of simple and accurate tests for TB diagnosis and drug-susceptibility testing (DST) in endemic regions. We evaluated the accuracy of the first-generation, low-complexity phenotypic TB test (1G test), designed for simultaneous Mtb detection and resistance to isoniazid, rifampicin and moxifloxacin, suitable for resource-limited settings.METHODSA cross-sectional study was conducted using sputa from 426 possible pulmonary TB subjects from two small Mexican cities bordering Texas. The 1G test was compared against phenotypic TB detection tests in the region [acid fast bacilli smear microscopy and Mycobacteria Growth Indicator Tube (MGIT) culture], and to MGIT-DST for resistance to isoniazid, rifampicin and moxifloxacin.FINDINGSThe 1G test demonstrated ≥98% sensitivity for Mtb detection, 100% sensitivity and 91% (rifampicin), 94% (isoniazid) and 97% (moxifloxacin) specificity for DST, and less contamination than the MGIT (3.5% vs. 8.1%; p<0.05). The 1G test time to detection (TTD) of Mtb and simultaneous DST was 17-days, while the MGIT-DST required two steps: 7 days for Mtb detection plus 14 more (total 21 days) for DST. Our study site DR-TB prevalence was 14% when testing all consecutively-enrolled participants vs. 6% by passive reporting.INTERPRETATIONThe 1G test is a low-complexity phenotypic TB diagnostic method that is a practical replacement to current culture-based tests. Future studies are warranted to evaluate the implementation of the 1G test in decentralized clinics that lack molecular tools, resources and expertise.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"118 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145807928","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Benedikt Strunz, Qiuyao Zhan, Tanvi Khera, Julia Hengst, Marija Jankovic, Katja Deterding, Annika Niehrs, Markus Cornberg, Cheng-Jian Xu, Heiner Wedemeyer, Niklas K Björkström
Acute infection with hepatitis C virus (HCV) is a rare event that can be treated successfully with direct-acting antivirals (DAAs). As Natural killer (NK) cells play an important role during the natural course of acute HCV, we assessed the NK cell compartment via flow cytometry and single-cell sequencing in longitudinally sampled patients with acute HCV and compared this to healthy controls and patients with chronic HCV. At the transcriptomic level, we identified a subset of highly activated NK cells with a robust type-I interferon imprint. While the population of activated NK cells vanished after DAA-mediated cure, a long-term phenotypic imprint of infection was observed in comparison to healthy controls. Collectively, these data suggest an interferon-driven rise of an activated NK cell population during acute hepatitis C, that is largely restored upon viral clearance. This study provides insights into the immunological basis for successful antiviral response to hepatitis C.
{"title":"Transient interferon-driven NK cell activation in acute hepatitis C","authors":"Benedikt Strunz, Qiuyao Zhan, Tanvi Khera, Julia Hengst, Marija Jankovic, Katja Deterding, Annika Niehrs, Markus Cornberg, Cheng-Jian Xu, Heiner Wedemeyer, Niklas K Björkström","doi":"10.1093/infdis/jiaf654","DOIUrl":"https://doi.org/10.1093/infdis/jiaf654","url":null,"abstract":"Acute infection with hepatitis C virus (HCV) is a rare event that can be treated successfully with direct-acting antivirals (DAAs). As Natural killer (NK) cells play an important role during the natural course of acute HCV, we assessed the NK cell compartment via flow cytometry and single-cell sequencing in longitudinally sampled patients with acute HCV and compared this to healthy controls and patients with chronic HCV. At the transcriptomic level, we identified a subset of highly activated NK cells with a robust type-I interferon imprint. While the population of activated NK cells vanished after DAA-mediated cure, a long-term phenotypic imprint of infection was observed in comparison to healthy controls. Collectively, these data suggest an interferon-driven rise of an activated NK cell population during acute hepatitis C, that is largely restored upon viral clearance. This study provides insights into the immunological basis for successful antiviral response to hepatitis C.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"8 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145836136","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
Eyal Elias, Danielle Keidar-Friedman, Nadav Sorek, Orit Raz, Sharon Ovnat Tamir, Liam Aspit, Dan Bar Yaacov
Background Adenosine-to-inosine (A-to-I) mRNA editing can alter protein sequence and function, enabling bacteria to express two RNA and protein versions encoded by the same gene. However, its prevalence and significance in clinical bacterial settings remain unclear. Methods We collected ten Escherichia coli and seven Pseudomonas aeruginosa isolates from hospitalized patients with urinary tract infections (UTI) or ear infections. Whole-genome and transcriptome sequencing were performed for each isolate, followed by Sanger sequencing for selected sites. Results We present the first comprehensive analysis of A-to-I RNA editing in pathogenic bacteria isolated from hospitalized patients. We identified dozens of A-to-I RNA editing sites, including novel sites not previously reported in non-pathogenic E. coli and P. aeruginosa strains. We found that E. coli exhibits higher editing levels and a greater number of editing sites than P. aeruginosa. Most editing sites are embedded within a conserved 7-base motif and are frequently located in predicted stem-loop RNA secondary structures, highlighting the importance of both sequence and structure for editing site recognition in both the examined species. Most editing events occur in mRNA and often result in non-synonymous amino acid changes, with a notable prevalence of tyrosine-to-cysteine substitutions. Finally, we observed that editing patterns are similar between antibiotic-resistant and sensitive isolates, suggesting a more general role in the biology of the examined species. Conclusions A-to-I RNA editing is a feature of pathogenic bacteria isolated from clinical samples. Our findings expand current knowledge of bacterial RNA editing in clinical contexts and provide a framework for future functional investigations.
腺苷-肌苷（A-to-I） mRNA编辑可以改变蛋白质序列和功能，使细菌能够表达由同一基因编码的两种RNA和蛋白质版本。然而，其患病率和意义在临床细菌设置仍不清楚。方法从尿路感染或耳部感染住院患者中分离10株大肠杆菌和7株铜绿假单胞菌。对每个分离物进行全基因组和转录组测序，然后对选定的位点进行Sanger测序。我们首次对从住院患者中分离的致病菌中的A-to-I RNA编辑进行了全面分析。我们鉴定了数十个A-to-I RNA编辑位点，包括以前未在非致病性大肠杆菌和铜绿假单胞菌菌株中报道的新位点。我们发现大肠杆菌比铜绿假单胞菌表现出更高的编辑水平和更多的编辑位点。大多数编辑位点都嵌入在保守的7碱基基序中，并且经常位于预测的茎环RNA二级结构中，这突出了序列和结构对两种被研究物种中编辑位点识别的重要性。大多数编辑事件发生在mRNA中，通常导致非同义氨基酸的变化，酪氨酸到半胱氨酸的替换显著流行。最后，我们观察到耐药菌株和敏感菌株之间的编辑模式相似，这表明在所检测物种的生物学中具有更普遍的作用。结论a -to- i RNA编辑是临床分离致病菌的一个特征。我们的发现扩大了目前在临床环境中对细菌RNA编辑的了解，并为未来的功能研究提供了一个框架。
{"title":"The landscape and regulatory determinants of A-to-I RNA editing in Escherichia coli and Pseudomonas aeruginosa isolated from patients with urinary tract and ear infections","authors":"Eyal Elias, Danielle Keidar-Friedman, Nadav Sorek, Orit Raz, Sharon Ovnat Tamir, Liam Aspit, Dan Bar Yaacov","doi":"10.1093/infdis/jiaf645","DOIUrl":"https://doi.org/10.1093/infdis/jiaf645","url":null,"abstract":"Background Adenosine-to-inosine (A-to-I) mRNA editing can alter protein sequence and function, enabling bacteria to express two RNA and protein versions encoded by the same gene. However, its prevalence and significance in clinical bacterial settings remain unclear. Methods We collected ten Escherichia coli and seven Pseudomonas aeruginosa isolates from hospitalized patients with urinary tract infections (UTI) or ear infections. Whole-genome and transcriptome sequencing were performed for each isolate, followed by Sanger sequencing for selected sites. Results We present the first comprehensive analysis of A-to-I RNA editing in pathogenic bacteria isolated from hospitalized patients. We identified dozens of A-to-I RNA editing sites, including novel sites not previously reported in non-pathogenic E. coli and P. aeruginosa strains. We found that E. coli exhibits higher editing levels and a greater number of editing sites than P. aeruginosa. Most editing sites are embedded within a conserved 7-base motif and are frequently located in predicted stem-loop RNA secondary structures, highlighting the importance of both sequence and structure for editing site recognition in both the examined species. Most editing events occur in mRNA and often result in non-synonymous amino acid changes, with a notable prevalence of tyrosine-to-cysteine substitutions. Finally, we observed that editing patterns are similar between antibiotic-resistant and sensitive isolates, suggesting a more general role in the biology of the examined species. Conclusions A-to-I RNA editing is a feature of pathogenic bacteria isolated from clinical samples. Our findings expand current knowledge of bacterial RNA editing in clinical contexts and provide a framework for future functional investigations.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"13 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-12-21","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145812935","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":0,"RegionCategory":"","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}
京公网安备 11010802042870号
京ICP备2023020795号-1
扫码关注我们
求助内容：
应助结果提醒方式：