Katherine A Davies, Stephen R Welch, JoAnn D Coleman-McCray, Teresa E Sorvillo, Virginia Aida-Ficken, Shilpi Jain, César G Albariño, Biao He, Christina F Spiropoulou, Jessica R Spengler
Marburgviruses cause severe hemorrhagic disease in humans, yet characterization of rodent models for pathogenesis and medical countermeasure development remains limited. Here, we investigated clinical course, blood chemistry, viral dissemination, and mucosal viral detection in inbred BALB/c and outbred CD-1 mice infected with MA-Marburg virus (MARV)/Angola or MA-Ravn virus (RAVV) to further mouse model development. Regardless of virus or mouse strain, infection resulted in widespread viral dissemination in animals sampled up to 5 days post-infection. However, in animals followed to study end, MA-MARV/Angola caused severe disease and lethality in both mouse strains, whereas MA-RAVV caused only mild or asymptomatic infection.
{"title":"Characterization of mouse-adapted Marburg and Ravn viruses in inbred BALB/c and outbred CD-1 mice","authors":"Katherine A Davies, Stephen R Welch, JoAnn D Coleman-McCray, Teresa E Sorvillo, Virginia Aida-Ficken, Shilpi Jain, César G Albariño, Biao He, Christina F Spiropoulou, Jessica R Spengler","doi":"10.1093/infdis/jiag019","DOIUrl":"https://doi.org/10.1093/infdis/jiag019","url":null,"abstract":"Marburgviruses cause severe hemorrhagic disease in humans, yet characterization of rodent models for pathogenesis and medical countermeasure development remains limited. Here, we investigated clinical course, blood chemistry, viral dissemination, and mucosal viral detection in inbred BALB/c and outbred CD-1 mice infected with MA-Marburg virus (MARV)/Angola or MA-Ravn virus (RAVV) to further mouse model development. Regardless of virus or mouse strain, infection resulted in widespread viral dissemination in animals sampled up to 5 days post-infection. However, in animals followed to study end, MA-MARV/Angola caused severe disease and lethality in both mouse strains, whereas MA-RAVV caused only mild or asymptomatic infection.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"30 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145920334","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}
Joshua N Monteith,Emma L Ledger,Michelle N Chamoun,Ian R Henderson,Joanna B Goldberg,Daniel Smith,Daniel C Chambers,Simon H Apte,Timothy J Wells
BACKGROUNDPeople with cystic fibrosis (pwCF) are susceptible to chronic lung infections, particularly with Pseudomonas aeruginosa. During infection, a subset of patients develop cloaking antibodies (cAb) specific to O-antigen lipopolysaccharide (LPS) that impair complement-mediated bactericidal killing. These antibodies associate with worse disease and their removal via plasmapheresis has been used as a successful treatment for multi-drug-resistant P. aeruginosa. Whether a similar mechanism of antibody-mediated serum resistance exists towards common polysaccharide antigen (CPA) LPS is unknown.METHODSForty-two serum samples and 63 matched P. aeruginosa isolates were collected from pwCF. The titres of antibodies specific to CPA in patient sera were determined, and the ability of these antibodies to inhibit serum-mediated killing of P. aeruginosa was assessed.RESULTSDespite widespread anti-CPA antibodies, only one serum-strain pair showed evidence of complement inhibition. Patient serum IgG and IgA responses to CPA were elevated in 86% and 69% of sera, respectively. Further, 69% of pwCF were colonised with CPA-expressing isolates. Despite high prevalence of elevated anti-CPA antibodies, only one patient had antibodies capable of inhibiting complement killing of their cognate P. aeruginosa. This isolate, CFP3A, had significantly higher expression of CPA than all other strains. Complement-mediated killing towards it was inhibited by anti-CPA antibodies in a titre dependent manner.CONCLUSIONThis investigation reveals that although antibody specific for CPA is prevalent in pwCF, it cannot inhibit complement-killing of the majority of CPA expressing strains. Thus, when treating Pseudomonas by removing cloaking antibodies, it is unlikely that CPA-specific antibodies will also need to be eliminated.
{"title":"Treatment of Pseudomonas by removal of cloaking antibodies; is common polysaccharide antigen a factor?","authors":"Joshua N Monteith,Emma L Ledger,Michelle N Chamoun,Ian R Henderson,Joanna B Goldberg,Daniel Smith,Daniel C Chambers,Simon H Apte,Timothy J Wells","doi":"10.1093/infdis/jiag002","DOIUrl":"https://doi.org/10.1093/infdis/jiag002","url":null,"abstract":"BACKGROUNDPeople with cystic fibrosis (pwCF) are susceptible to chronic lung infections, particularly with Pseudomonas aeruginosa. During infection, a subset of patients develop cloaking antibodies (cAb) specific to O-antigen lipopolysaccharide (LPS) that impair complement-mediated bactericidal killing. These antibodies associate with worse disease and their removal via plasmapheresis has been used as a successful treatment for multi-drug-resistant P. aeruginosa. Whether a similar mechanism of antibody-mediated serum resistance exists towards common polysaccharide antigen (CPA) LPS is unknown.METHODSForty-two serum samples and 63 matched P. aeruginosa isolates were collected from pwCF. The titres of antibodies specific to CPA in patient sera were determined, and the ability of these antibodies to inhibit serum-mediated killing of P. aeruginosa was assessed.RESULTSDespite widespread anti-CPA antibodies, only one serum-strain pair showed evidence of complement inhibition. Patient serum IgG and IgA responses to CPA were elevated in 86% and 69% of sera, respectively. Further, 69% of pwCF were colonised with CPA-expressing isolates. Despite high prevalence of elevated anti-CPA antibodies, only one patient had antibodies capable of inhibiting complement killing of their cognate P. aeruginosa. This isolate, CFP3A, had significantly higher expression of CPA than all other strains. Complement-mediated killing towards it was inhibited by anti-CPA antibodies in a titre dependent manner.CONCLUSIONThis investigation reveals that although antibody specific for CPA is prevalent in pwCF, it cannot inhibit complement-killing of the majority of CPA expressing strains. Thus, when treating Pseudomonas by removing cloaking antibodies, it is unlikely that CPA-specific antibodies will also need to be eliminated.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"177 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-06","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145907582","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}
Yuya Ito,Tracey-Ann Hoeltermann,Seher Anjum,Londyn Robinson,Jessica S Little,Michael Kiritsy,Julie M Steinbrink,Andrea Finocchi,Lorne W Walker,Robin K Avery,Shmuel Shoham,Omer E Beaird,Song C Ong,Cornelius N Van Dam,Ina Stephens,Ambar Haleem,Peter R Williamson
BACKGROUNDPost-infectious inflammatory response syndrome (PIIRS) is recognized as a cause of neurologic deterioration in previously healthy patients with cryptococcal meningoencephalitis (CM). However, data on non-human immunodeficiency virus (HIV), immunosuppressed patients remain limited.METHODSBetween July 2018 and April 2025, 13 non-HIV immunosuppressed patients with CM who subsequently developed PIIRS were included. Clinical features, Karnofsky performance scores, cerebrospinal fluid (CSF) parameters, and magnetic resonance imaging (MRI) findings were compared at PIIRS diagnosis and during follow-up after corticosteroid therapy.RESULTSAll patients showed evidence of CNS inflammation, including abnormal CSF, MRI findings, and neurological symptoms such as altered mental status or visual/hearing loss. Corticosteroid therapy was associated with significant improvements in Karnofsky scores at 1 month (P = .001), with sustained benefit at 6 and twelve months (P = .002); all 10 surviving patients demonstrated resolution of neurological symptoms. CSF inflammatory parameters including white blood cell (WBC) count, protein, and CSF/serum glucose ratio also significantly improved at 1 month. Brain MRI findings also showed a trend toward improvement. All patients remained culture-negative post-PIIRS diagnosis. Three patients died: 1 from complications of alcoholic cirrhosis, the second from liver failure in the setting of systemic lupus erythematosus and immunosuppression, and the third from sepsis after initiation of corticosteroids.CONCLUSIONSCorticosteroids were associated with improvement in neurological status and neuroinflammation in non-HIV, immunosuppressed patients with PIIRS following CM. These findings support its potential role as salvage therapy in this population and highlight the need for systematic data collection or randomized trials to better guide corticosteroid use.
{"title":"Corticosteroid Therapy and Long-Term Outcomes of Post-Infectious Inflammatory Syndrome in Non-HIV Immunosuppressed Cryptococcal Meningitis: A Multicenter Case Series.","authors":"Yuya Ito,Tracey-Ann Hoeltermann,Seher Anjum,Londyn Robinson,Jessica S Little,Michael Kiritsy,Julie M Steinbrink,Andrea Finocchi,Lorne W Walker,Robin K Avery,Shmuel Shoham,Omer E Beaird,Song C Ong,Cornelius N Van Dam,Ina Stephens,Ambar Haleem,Peter R Williamson","doi":"10.1093/infdis/jiaf620","DOIUrl":"https://doi.org/10.1093/infdis/jiaf620","url":null,"abstract":"BACKGROUNDPost-infectious inflammatory response syndrome (PIIRS) is recognized as a cause of neurologic deterioration in previously healthy patients with cryptococcal meningoencephalitis (CM). However, data on non-human immunodeficiency virus (HIV), immunosuppressed patients remain limited.METHODSBetween July 2018 and April 2025, 13 non-HIV immunosuppressed patients with CM who subsequently developed PIIRS were included. Clinical features, Karnofsky performance scores, cerebrospinal fluid (CSF) parameters, and magnetic resonance imaging (MRI) findings were compared at PIIRS diagnosis and during follow-up after corticosteroid therapy.RESULTSAll patients showed evidence of CNS inflammation, including abnormal CSF, MRI findings, and neurological symptoms such as altered mental status or visual/hearing loss. Corticosteroid therapy was associated with significant improvements in Karnofsky scores at 1 month (P = .001), with sustained benefit at 6 and twelve months (P = .002); all 10 surviving patients demonstrated resolution of neurological symptoms. CSF inflammatory parameters including white blood cell (WBC) count, protein, and CSF/serum glucose ratio also significantly improved at 1 month. Brain MRI findings also showed a trend toward improvement. All patients remained culture-negative post-PIIRS diagnosis. Three patients died: 1 from complications of alcoholic cirrhosis, the second from liver failure in the setting of systemic lupus erythematosus and immunosuppression, and the third from sepsis after initiation of corticosteroids.CONCLUSIONSCorticosteroids were associated with improvement in neurological status and neuroinflammation in non-HIV, immunosuppressed patients with PIIRS following CM. These findings support its potential role as salvage therapy in this population and highlight the need for systematic data collection or randomized trials to better guide corticosteroid use.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"40 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-05","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145897516","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 The persistence of immunological memory after immunization against monkeypox virus (MPXV) is unclear. This study assessed MPXV-specific neutralizing antibodies (NAbs) at >2 years from Mpox or Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) vaccination. Methods Retrospective study including individuals with previous Mpox or vaccination with MVA-BN, whose MPXV-specific NAb titers were already assessed at six months from either event at our center. Neutralizing titers were determined at >2 years from Mpox or vaccination by Plaque Reduction Neutralization Test (PRNT) [positive≥1:10] as the maximum dilution with reduction of cytopathic effect of 90% and 50% (IC90-IC50). Groups were compared using chi-square test, Fisher’s exact test or Wilcoxon rank-sum test. Association between titers at >2 years and individuals characteristics was evaluated with ordinal logistic regression. Results Overall, 48 individuals with previous Mpox and 42 vaccinees were included, all were men. At >2 years from Mpox or vaccination, 22/90 (24.44%) and 53/90 (58.8%) had positive NAb titers respectively at IC90 and IC50. At IC50 previous Mpox was associated with positive titers (68.75% vs 47.62%; p=0.042), with univariate analysis associating higher titers at six months to higher titers at >2 years (OR=6.45,95%CI=1.89–22.07;p=0.003). At multivariate analysis, historical smallpox vaccination was associated to higher titers at >2 years (OR=5.37,95%CI=1.31-22.00;p=0.020), whilst previous Mpox was marginally associated (OR=2.08,95%CI=0.94-4.62;p=0.073). Conclusions MPXV-specific NAbs waned at >2 years from previous infection or vaccination, often becoming undetectable. Higher NAb titers at six months (univariate) and prior smallpox vaccination (multivariate) were associated with NAb detection at >2 years, whilst previous Mpox was marginally associated.
背景猴痘病毒（MPXV）免疫后免疫记忆的持久性尚不清楚。本研究评估了mpxv特异性中和抗体（nab）在；接种m痘或改良安卡拉巴伐利亚北欧牛痘（MVA-BN）疫苗2年。方法回顾性研究纳入既往m痘或接种MVA-BN的个体，其mpxv特异性NAb滴度已在我们中心的任何事件发生后6个月进行评估。中和效价在&；gt；通过斑块减少中和试验（PRNT）[阳性≥1:10]作为最大稀释剂，减少90%和50%的细胞病变效应（IC90-IC50），从m痘或接种疫苗2年。组间比较采用卡方检验、Fisher精确检验或Wilcoxon秩和检验。滴度&；gt；采用有序logistic回归评价2年及个体特征。结果共纳入48例既往m痘患者和42例接种者，均为男性。在和gt;接种Mpox或疫苗2年后，22/90（24.44%）和53/90（58.8%）的NAb滴度分别为IC90和IC50阳性。IC50时，既往m痘与阳性滴度相关（68.75% vs 47.62%; p=0.042），单变量分析将6个月时较高的滴度与&；gt时较高的滴度联系起来；2年（OR=6.45,95%CI=1.89 ~ 22.07;p=0.003）。在多变量分析中，历史天花疫苗接种与较高滴度相关。2年（OR=5.37,95%CI=1.31-22.00;p=0.020），而既往m痘患者与m痘相关（OR=2.08,95%CI=0.94-4.62;p=0.073）。结论mpxv特异性nab在&；gt；距离上次感染或接种疫苗2年，通常无法检测到。6个月时较高的NAb滴度（单变量）和先前的天花疫苗接种（多变量）与NAb在&；gt；2年，而以前的m痘有轻微的相关性。
{"title":"A humoral dilemma: reassessing monkeypox virus neutralizing antibodies at more than two years from Mpox or MVA-BN vaccination","authors":"Nicolò Moschetta, Elena Criscuolo, Angelo Roberto Raccagni, Nicolò Capra, Riccardo Lolatto, Gabriele Loi, Diana Canetti, Antonella Castagna, Silvia Nozza, Nicola Clementi","doi":"10.1093/infdis/jiag009","DOIUrl":"https://doi.org/10.1093/infdis/jiag009","url":null,"abstract":"Background The persistence of immunological memory after immunization against monkeypox virus (MPXV) is unclear. This study assessed MPXV-specific neutralizing antibodies (NAbs) at >2 years from Mpox or Modified Vaccinia Ankara Bavarian Nordic (MVA-BN) vaccination. Methods Retrospective study including individuals with previous Mpox or vaccination with MVA-BN, whose MPXV-specific NAb titers were already assessed at six months from either event at our center. Neutralizing titers were determined at >2 years from Mpox or vaccination by Plaque Reduction Neutralization Test (PRNT) [positive≥1:10] as the maximum dilution with reduction of cytopathic effect of 90% and 50% (IC90-IC50). Groups were compared using chi-square test, Fisher’s exact test or Wilcoxon rank-sum test. Association between titers at >2 years and individuals characteristics was evaluated with ordinal logistic regression. Results Overall, 48 individuals with previous Mpox and 42 vaccinees were included, all were men. At >2 years from Mpox or vaccination, 22/90 (24.44%) and 53/90 (58.8%) had positive NAb titers respectively at IC90 and IC50. At IC50 previous Mpox was associated with positive titers (68.75% vs 47.62%; p=0.042), with univariate analysis associating higher titers at six months to higher titers at >2 years (OR=6.45,95%CI=1.89–22.07;p=0.003). At multivariate analysis, historical smallpox vaccination was associated to higher titers at >2 years (OR=5.37,95%CI=1.31-22.00;p=0.020), whilst previous Mpox was marginally associated (OR=2.08,95%CI=0.94-4.62;p=0.073). Conclusions MPXV-specific NAbs waned at >2 years from previous infection or vaccination, often becoming undetectable. Higher NAb titers at six months (univariate) and prior smallpox vaccination (multivariate) were associated with NAb detection at >2 years, whilst previous Mpox was marginally associated.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"38 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2026-01-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"145903728","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}
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}
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：