Background The incidence of metabolic-associated steatotic liver disease in patients with chronic hepatitis B is increasing annually; however, the interaction between hepatitis B virus (HBV) infection and lipid metabolism remains unclear. This study attempted to clarify whether fatty acid metabolism regulation could alleviate mitochondrial dysfunction caused by HBV infection. Methods Public gene set of human livers was analyzed, and a proteomic analysis on mouse livers was conducted to explore metabolic disorders and affected organelles associated with HBV infection. The effect of decanoylcarnitine on fatty acid β-oxidation and mitochondria was investigated in vivo and in vitro. The pathways involved were shown by proteomic analysis and confirmed by Western blot. Results HBV infection could cause fatty acid β-oxidation disorder and mitochondrial dysfunction in vivo and in vitro. CPT1A overexpression could improve mitochondrial function in hepatocytes. Furthermore, decanoylcarnitine supplementation could activate CPT1A expression, thus improving fatty acid metabolism and repairing mitochondrial dysfunction. Proteomic analysis of mouse livers suggests that decanoylcarnitine stimulates the peroxisome proliferator-activated receptor (PPAR) signaling pathway, and the PPARα was the most important among PPARs. Conclusions Impaired fatty acid metabolism and mitochondrial dysfunction in hepatocytes caused by HBV infection could be partially restored by exogenous supplementation of decanoylcarnitine. It elucidated the therapeutic potential of decanoylcarnitine in HBV infection and provided a new approach for diseases related to mitochondrial dysfunction.
{"title":"Decanoylcarnitine improves liver mitochondrial dysfunction in hepatitis B virus infection by enhancing fatty acid β-oxidation","authors":"Ye Sun, Qingling Chen, Yuxiao Liu, Mengfan Jiao, Zixing Dai, Xiaoxue Hou, Rui Liu, Yuwen Li, Chuanlong Zhu","doi":"10.1093/infdis/jiaf014","DOIUrl":"https://doi.org/10.1093/infdis/jiaf014","url":null,"abstract":"Background The incidence of metabolic-associated steatotic liver disease in patients with chronic hepatitis B is increasing annually; however, the interaction between hepatitis B virus (HBV) infection and lipid metabolism remains unclear. This study attempted to clarify whether fatty acid metabolism regulation could alleviate mitochondrial dysfunction caused by HBV infection. Methods Public gene set of human livers was analyzed, and a proteomic analysis on mouse livers was conducted to explore metabolic disorders and affected organelles associated with HBV infection. The effect of decanoylcarnitine on fatty acid β-oxidation and mitochondria was investigated in vivo and in vitro. The pathways involved were shown by proteomic analysis and confirmed by Western blot. Results HBV infection could cause fatty acid β-oxidation disorder and mitochondrial dysfunction in vivo and in vitro. CPT1A overexpression could improve mitochondrial function in hepatocytes. Furthermore, decanoylcarnitine supplementation could activate CPT1A expression, thus improving fatty acid metabolism and repairing mitochondrial dysfunction. Proteomic analysis of mouse livers suggests that decanoylcarnitine stimulates the peroxisome proliferator-activated receptor (PPAR) signaling pathway, and the PPARα was the most important among PPARs. Conclusions Impaired fatty acid metabolism and mitochondrial dysfunction in hepatocytes caused by HBV infection could be partially restored by exogenous supplementation of decanoylcarnitine. It elucidated the therapeutic potential of decanoylcarnitine in HBV infection and provided a new approach for diseases related to mitochondrial dysfunction.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"35 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936835","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}
Objectives It has been suggested that the emergence of ceftriaxone-resistant strains of Neisseria gonorrhoeae involves the incorporation of the penA gene from commensal Neisseria spp. that are resistant to ceftriaxone. However, the mechanism of this mosaic penA generation is unknown. Methods We obtained 10 strains of commensal Neisseria spp. showing ceftriaxone MIC >0.5 mg/L. The similarity of the penA gene region of these commensal Neisseria spp. strains and some ceftriaxone-resistant N. gonorrhoeae strains was investigated. To obtain transformants, commensal Neisseria spp., Neisseria lactamica, gDNA was used as donor DNA and a N. gonorrhoeae strain as the recipient. Results The sequence similarity in certain regions of penA-murE between some of the commensal Neisseria spp. strains and the N. gonorrhoeae FC428 strain was very high. The sequence of these regions was very similar among some ceftriaxone-resistant strains of Neisseria spp. The PenA of the transformants matched the full PenA 60 of the original FC428 strain. Furthermore, our findings indicated that the source of resistance could have been a penA fragment derived from Neisseria spp. that originally carried the same sequence. Conclusions We suggest that FC428 developed ceftriaxone resistance by acquiring part of the penA–murE gene region from N. lactamica through horizontal gene transfer. The ceftriaxone-resistant N. lactamica shown here may also have emerged by acquiring part of penA from other Neisseria spp. From this work, our data provide insights into the understanding of the mechanism underlying the evolution of drug-resistant gonorrhea-causing strains.
{"title":"Emergence of ceftriaxone-resistant Neisseria gonorrhoeae through horizontal gene transfer among Neisseria spp","authors":"Ken Shimuta, Yuki Ohama, Shin Ito, Shinji Hoshina, Hideyuki Takahashi, Gene Igawa, Misato Dorin Yamamoto, Yukihiro Akeda, Makoto Ohnishi","doi":"10.1093/infdis/jiaf008","DOIUrl":"https://doi.org/10.1093/infdis/jiaf008","url":null,"abstract":"Objectives It has been suggested that the emergence of ceftriaxone-resistant strains of Neisseria gonorrhoeae involves the incorporation of the penA gene from commensal Neisseria spp. that are resistant to ceftriaxone. However, the mechanism of this mosaic penA generation is unknown. Methods We obtained 10 strains of commensal Neisseria spp. showing ceftriaxone MIC >0.5 mg/L. The similarity of the penA gene region of these commensal Neisseria spp. strains and some ceftriaxone-resistant N. gonorrhoeae strains was investigated. To obtain transformants, commensal Neisseria spp., Neisseria lactamica, gDNA was used as donor DNA and a N. gonorrhoeae strain as the recipient. Results The sequence similarity in certain regions of penA-murE between some of the commensal Neisseria spp. strains and the N. gonorrhoeae FC428 strain was very high. The sequence of these regions was very similar among some ceftriaxone-resistant strains of Neisseria spp. The PenA of the transformants matched the full PenA 60 of the original FC428 strain. Furthermore, our findings indicated that the source of resistance could have been a penA fragment derived from Neisseria spp. that originally carried the same sequence. Conclusions We suggest that FC428 developed ceftriaxone resistance by acquiring part of the penA–murE gene region from N. lactamica through horizontal gene transfer. The ceftriaxone-resistant N. lactamica shown here may also have emerged by acquiring part of penA from other Neisseria spp. From this work, our data provide insights into the understanding of the mechanism underlying the evolution of drug-resistant gonorrhea-causing strains.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"16 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142936833","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}
W Zane Billings, Yang Ge, Jessica H Knight, Hayley Hemme, Savannah M Hammerton, Amanda L Skarlupka, Wangnan Cao, Ye Shen, Justin Bahl, Paul G Thomas, Ted M Ross, Andreas Handel
Background Older adults often mount a weak immune response to standard inactivated influenza vaccines. To induce a stronger response and better protection, a high-dose (HD) version of the inactivated Fluzone vaccine is recommended for individuals >65 years of age. While better immunogenicity and protection against the vaccine strain has been shown, it is not known if the HD vaccine also induces a robust antibody response to heterologous strains. Methods We fit bayesian multilevel regression models to hemagglutination inhibition (HAI) antibody data from an influenza vaccine cohort spanning the 2013/14-2021/22 influenza seasons. We used this model to estimate the average causal effect (ACE) of obtaining the HD vaccine, relative to the SD vaccine. Results We show that while there is generally a benefit derived from the HD vaccine, the impact is small and inconsistent. For some strains, the HD vaccine might even result in less robust heterologous responses. Conclusions We suggest that further increases in dose might be worth investigating to help induce a stronger broad response.
{"title":"High dose inactivated influenza vaccine inconsistently improves heterologous antibody responses in an elderly human cohort","authors":"W Zane Billings, Yang Ge, Jessica H Knight, Hayley Hemme, Savannah M Hammerton, Amanda L Skarlupka, Wangnan Cao, Ye Shen, Justin Bahl, Paul G Thomas, Ted M Ross, Andreas Handel","doi":"10.1093/infdis/jiaf003","DOIUrl":"https://doi.org/10.1093/infdis/jiaf003","url":null,"abstract":"Background Older adults often mount a weak immune response to standard inactivated influenza vaccines. To induce a stronger response and better protection, a high-dose (HD) version of the inactivated Fluzone vaccine is recommended for individuals >65 years of age. While better immunogenicity and protection against the vaccine strain has been shown, it is not known if the HD vaccine also induces a robust antibody response to heterologous strains. Methods We fit bayesian multilevel regression models to hemagglutination inhibition (HAI) antibody data from an influenza vaccine cohort spanning the 2013/14-2021/22 influenza seasons. We used this model to estimate the average causal effect (ACE) of obtaining the HD vaccine, relative to the SD vaccine. Results We show that while there is generally a benefit derived from the HD vaccine, the impact is small and inconsistent. For some strains, the HD vaccine might even result in less robust heterologous responses. Conclusions We suggest that further increases in dose might be worth investigating to help induce a stronger broad response.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"77 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935936","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}
Rodolphe Suspène, Vincent Caval, Pierre Khalfi, Emmanuelle Pitré, Agnès Marchio, Pascal Pineau, Jean-Pierre Vartanian
Background Restriction factors are host cell proteins that play a role in limiting virus replication. They form part of the intrinsic immune system and function as a first line of defense against viral infections. Hepatitis B virus (HBV) does not escape this rule and TREX1, a host restriction enzyme acts as an antiviral factor, leading to the inhibition of the virus. Methods TREX1-expressing constructs were generated and modified by site-directed mutagenesis. The location and activity of the different TREX1 constructs were analyzed by Immunofluorescence and FACS. HepaD38 cells were either transfected or transduced with the different TREX1 constructs in presence or absence of cobalt chloride-mimicked hypoxia and released HBV was quantified by qPCR. Results We identified TREX1 as a restriction factor that suppresses HBV replication. Furthermore, TREX1 expression was increased in the presence of cobalt chloride, a chemical agent mimicking hypoxia. Thus, by treating cells with cobalt chloride, TREX1 reduced HBV replication by a factor of 2, demonstrating that under hypoxic conditions, TREX1 restricts HBV replication. Finally, an analysis of 36 HBV-infected patients with hepatocellular carcinoma revealed that TREX1 expression was inversely correlated to the HBV viral and HBV cccDNA. Conclusion Current treatments are unable to eliminate HBV genomic reservoirs, which persist as covalently closed episomal circular DNA. TREX1 is a novel restriction factor that blocks HBV replication. It would be therapeutically relevant to study whether HBV nucleocapsid recycling containing TREX1 enzyme could be released into the nucleus and degrade the viral and nuclear DNA of infected cells.
{"title":"Cobalt chloride-mimicked hepatocyte cell hypoxia induces TREX1 leading to Hepatitis B virus restriction","authors":"Rodolphe Suspène, Vincent Caval, Pierre Khalfi, Emmanuelle Pitré, Agnès Marchio, Pascal Pineau, Jean-Pierre Vartanian","doi":"10.1093/infdis/jiaf002","DOIUrl":"https://doi.org/10.1093/infdis/jiaf002","url":null,"abstract":"Background Restriction factors are host cell proteins that play a role in limiting virus replication. They form part of the intrinsic immune system and function as a first line of defense against viral infections. Hepatitis B virus (HBV) does not escape this rule and TREX1, a host restriction enzyme acts as an antiviral factor, leading to the inhibition of the virus. Methods TREX1-expressing constructs were generated and modified by site-directed mutagenesis. The location and activity of the different TREX1 constructs were analyzed by Immunofluorescence and FACS. HepaD38 cells were either transfected or transduced with the different TREX1 constructs in presence or absence of cobalt chloride-mimicked hypoxia and released HBV was quantified by qPCR. Results We identified TREX1 as a restriction factor that suppresses HBV replication. Furthermore, TREX1 expression was increased in the presence of cobalt chloride, a chemical agent mimicking hypoxia. Thus, by treating cells with cobalt chloride, TREX1 reduced HBV replication by a factor of 2, demonstrating that under hypoxic conditions, TREX1 restricts HBV replication. Finally, an analysis of 36 HBV-infected patients with hepatocellular carcinoma revealed that TREX1 expression was inversely correlated to the HBV viral and HBV cccDNA. Conclusion Current treatments are unable to eliminate HBV genomic reservoirs, which persist as covalently closed episomal circular DNA. TREX1 is a novel restriction factor that blocks HBV replication. It would be therapeutically relevant to study whether HBV nucleocapsid recycling containing TREX1 enzyme could be released into the nucleus and degrade the viral and nuclear DNA of infected cells.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"56 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935146","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}
Angela Chun, Abraham Bautista-Castillo, Isabella Osuna, Kristiana Nasto, Flor M Munoz, Gordon E Schutze, Sridevi Devaraj, Eyal Muscal, Marietta M de Guzman, Kristen Sexson Tejtel, Tiphanie P Vogel, Ioannis A Kakadiaris
Background The pandemic emergent disease multisystem inflammatory syndrome in children (MIS-C) following coronavirus disease-19 infection can mimic endemic typhus. We aimed to use artificial intelligence (AI) to develop a clinical decision support system that accurately distinguishes MIS-C versus Endemic Typhus (MET). Methods Demographic, clinical, and laboratory features rapidly available following presentation were extracted for 133 patients with MIS-C and 87 patients hospitalized due to typhus. An attention module assigned importance to inputs used to create the two-phase AI-MET. Phase 1 uses 17 features to arrive at a classification manually (MET-17). If the confidence level is not surpassed, 13 additional features are added to calculate MET-30 using a recurrent neural network. Results While 24 of 30 features differed statistically, the values overlapped sufficiently that the features were clinically irrelevant distinguishers as individual parameters. However, AI-MET successfully classified typhus and MIS-C with 100% accuracy. A validation cohort of 111 additional patients with MIS-C was classified with 99% accuracy. Conclusions Artificial intelligence can successfully distinguish MIS-C from typhus using rapidly available features. This decision support system will be a valuable tool for front-line providers facing the difficulty of diagnosing a febrile child in endemic areas.
{"title":"Distinguishing Multisystem Inflammatory Syndrome in Children from Typhus Using Artificial Intelligence: MIS-C vs. Endemic Typhus (AI-MET)","authors":"Angela Chun, Abraham Bautista-Castillo, Isabella Osuna, Kristiana Nasto, Flor M Munoz, Gordon E Schutze, Sridevi Devaraj, Eyal Muscal, Marietta M de Guzman, Kristen Sexson Tejtel, Tiphanie P Vogel, Ioannis A Kakadiaris","doi":"10.1093/infdis/jiaf004","DOIUrl":"https://doi.org/10.1093/infdis/jiaf004","url":null,"abstract":"Background The pandemic emergent disease multisystem inflammatory syndrome in children (MIS-C) following coronavirus disease-19 infection can mimic endemic typhus. We aimed to use artificial intelligence (AI) to develop a clinical decision support system that accurately distinguishes MIS-C versus Endemic Typhus (MET). Methods Demographic, clinical, and laboratory features rapidly available following presentation were extracted for 133 patients with MIS-C and 87 patients hospitalized due to typhus. An attention module assigned importance to inputs used to create the two-phase AI-MET. Phase 1 uses 17 features to arrive at a classification manually (MET-17). If the confidence level is not surpassed, 13 additional features are added to calculate MET-30 using a recurrent neural network. Results While 24 of 30 features differed statistically, the values overlapped sufficiently that the features were clinically irrelevant distinguishers as individual parameters. However, AI-MET successfully classified typhus and MIS-C with 100% accuracy. A validation cohort of 111 additional patients with MIS-C was classified with 99% accuracy. Conclusions Artificial intelligence can successfully distinguish MIS-C from typhus using rapidly available features. This decision support system will be a valuable tool for front-line providers facing the difficulty of diagnosing a febrile child in endemic areas.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"22 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935149","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}
Lamin B Cham, Bradley Whitehead, Marvin Werner, Frederikke Jensen, Mads Zippor, Trine H Mogensen, Mihai G Netea, Andrew R Williams, Peter Nejsum
Heligmosomoides polygyrus co-infection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for two weeks. Bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) were generated and stimulated with TLR agonists. We found increased expression of type 1 interferon genes (Ifnα1, Ifnα4, Ifnβ1, Mx1, Isg15), increased TNF, IL-6, IL-10 secretion, and higher expression of antigen presentation markers in BM-derived-pDCs from infected mice compared to naïve control. Our findings may partly explain the mechanism of the antiviral protection previously reported in acute helminth infections.
{"title":"Helminth infection induces innate immune priming in plasmacytoid dendritic cells","authors":"Lamin B Cham, Bradley Whitehead, Marvin Werner, Frederikke Jensen, Mads Zippor, Trine H Mogensen, Mihai G Netea, Andrew R Williams, Peter Nejsum","doi":"10.1093/infdis/jiaf009","DOIUrl":"https://doi.org/10.1093/infdis/jiaf009","url":null,"abstract":"Heligmosomoides polygyrus co-infection is reported to have protective antiviral effects against pulmonary viral infections. To investigate a potential underlying mechanism, we infected C57BL/6 mice with H. polygyrus larvae for two weeks. Bone marrow (BM)-derived plasmacytoid dendritic cells (pDCs) were generated and stimulated with TLR agonists. We found increased expression of type 1 interferon genes (Ifnα1, Ifnα4, Ifnβ1, Mx1, Isg15), increased TNF, IL-6, IL-10 secretion, and higher expression of antigen presentation markers in BM-derived-pDCs from infected mice compared to naïve control. Our findings may partly explain the mechanism of the antiviral protection previously reported in acute helminth infections.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2025-01-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142935928","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}
Yi Li, Nagendra N Mishra, Liang Chen, Adhar C Manna, Ambrose L Cheung, Richard A Proctor, Yan Q Xiong
Background Methicillin-resistant Staphylococcus aureus (MRSA) is a leading pathogen causing severe endovascular infections. The prophage-encoded protein Gp05 has been identified as a critical virulence factor that contributes to MRSA persistence during vancomycin (VAN) treatment in an experimental endocarditis model. However, the underlining mechanisms driving this persistence phenotype remain poorly understood. Methods The current study aimed to elucidate the genetic factors contributing to Gp05-associated MRSA persistence by utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate (PB 300-169), its isogenic chromosomal gp05 deletion mutant, and gp05-complemented strains. Results RNA-seq analysis revealed significantly downregulation of the graSR-vraFG regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. Notably, this downregulation led to a substantial shift in cell membrane composition, with a marked increase in negatively charged phosphatidylglycerol (PG) and a concomitant decrease in positively charged lysyl-PG (LPG). These changes in membrane lipid composition resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, polymorphonuclear neutrophil (PMN) and VAN. Similar findings were observed in an isogenic gp05 overexpression strain set with different genetic background (MRSA USA300 JE2). Conclusions These findings suggest that Gp05 plays a pivotal role in MRSA persistence by modulating cell surface components and surface charge. This study provides new insights into the molecular mechanisms underlying Gp05-mediated persistence in MRSA endovascular infections and highlights potential therapeutic targets to combat persistent MRSA infections.
{"title":"Phage-Encoded Virulence Factor, Gp05, Alters Membrane Phospholipids and Reduces Antimicrobial Susceptibility in Methicillin-Resistant Staphylococcus aureus","authors":"Yi Li, Nagendra N Mishra, Liang Chen, Adhar C Manna, Ambrose L Cheung, Richard A Proctor, Yan Q Xiong","doi":"10.1093/infdis/jiae640","DOIUrl":"https://doi.org/10.1093/infdis/jiae640","url":null,"abstract":"Background Methicillin-resistant Staphylococcus aureus (MRSA) is a leading pathogen causing severe endovascular infections. The prophage-encoded protein Gp05 has been identified as a critical virulence factor that contributes to MRSA persistence during vancomycin (VAN) treatment in an experimental endocarditis model. However, the underlining mechanisms driving this persistence phenotype remain poorly understood. Methods The current study aimed to elucidate the genetic factors contributing to Gp05-associated MRSA persistence by utilizing RNA sequencing (RNA-seq) on an isogenic MRSA strain set, including a clinical persistent bacteremia isolate (PB 300-169), its isogenic chromosomal gp05 deletion mutant, and gp05-complemented strains. Results RNA-seq analysis revealed significantly downregulation of the graSR-vraFG regulatory system and its downstream genes, mprF and dltABCD, in the gp05 deletion mutant compared to the wild-type and gp05-complemented strains. Notably, this downregulation led to a substantial shift in cell membrane composition, with a marked increase in negatively charged phosphatidylglycerol (PG) and a concomitant decrease in positively charged lysyl-PG (LPG). These changes in membrane lipid composition resulted in increased susceptibility of the gp05 deletion mutant to human cationic antimicrobial peptide (CAMP) LL-37, polymorphonuclear neutrophil (PMN) and VAN. Similar findings were observed in an isogenic gp05 overexpression strain set with different genetic background (MRSA USA300 JE2). Conclusions These findings suggest that Gp05 plays a pivotal role in MRSA persistence by modulating cell surface components and surface charge. This study provides new insights into the molecular mechanisms underlying Gp05-mediated persistence in MRSA endovascular infections and highlights potential therapeutic targets to combat persistent MRSA infections.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"3 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908298","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}
Scott M Baliban, Surekha Shridhar, Kun Luo, Jacqueline Kolasny, Sang Hyun, Zhiyong Zhao, Sharon M Tennant, Alan S Cross
Background Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A in addition to gastroenteritis and invasive disease, predominantly attributable to nontyphoidal Salmonella serovars Typhimurium and Enteritidis, are major causes of death and disability across the globe. A broad-spectrum vaccine that protects against disease caused by typhoidal and nontyphoidal serovars of Salmonella is not available for humans but would prevent a considerable burden of disease worldwide. Methods We previously developed a broad-spectrum vaccine for Gram-negative bacteria that is based on the inner core domain of detoxified Escherichia coli O111, Rc (J5) mutant lipooligosaccharide, a highly conserved antigen across Gram-negative bacteria, complexed with an outer membrane protein of group B Neisseria meningitidis. In this study, mice and rabbits were immunized with the J5 core/outer membrane protein subunit vaccine. We assessed the cross-reactivity of antisera with various Salmonella species lipopolysaccharides and the protective efficacy of passive and active immunization with J5 vaccine against experimental nontyphoidal Salmonella infection in mice. Results Vaccination with J5 induced IgG responses that strongly recognized lipopolysaccharide from both typhoidal and nontyphoidal Salmonella and imparted a survival benefit against lethal heterologous challenges with S. Typhimurium and S. Enteritidis. Additionally, passive transfer studies with rabbit hyperimmune sera raised against the J5 vaccine revealed that anti-core antibodies were protective against lipopolysaccharide challenge in D-galactosamine-sensitized mice. Conclusions Our findings support the development of core glycolipids as a novel Salmonella vaccine candidate. Further investigation is warranted to determine the efficacy of the J5 core/outer membrane protein vaccine against other Salmonella serovars of concern.
{"title":"A core glycolipid vaccine elicits cross-reactive antibodies against Salmonella spp. and protects against invasive nontyphoidal Salmonella disease in mice","authors":"Scott M Baliban, Surekha Shridhar, Kun Luo, Jacqueline Kolasny, Sang Hyun, Zhiyong Zhao, Sharon M Tennant, Alan S Cross","doi":"10.1093/infdis/jiae641","DOIUrl":"https://doi.org/10.1093/infdis/jiae641","url":null,"abstract":"Background Enteric fever caused by Salmonella enterica serovars Typhi and Paratyphi A in addition to gastroenteritis and invasive disease, predominantly attributable to nontyphoidal Salmonella serovars Typhimurium and Enteritidis, are major causes of death and disability across the globe. A broad-spectrum vaccine that protects against disease caused by typhoidal and nontyphoidal serovars of Salmonella is not available for humans but would prevent a considerable burden of disease worldwide. Methods We previously developed a broad-spectrum vaccine for Gram-negative bacteria that is based on the inner core domain of detoxified Escherichia coli O111, Rc (J5) mutant lipooligosaccharide, a highly conserved antigen across Gram-negative bacteria, complexed with an outer membrane protein of group B Neisseria meningitidis. In this study, mice and rabbits were immunized with the J5 core/outer membrane protein subunit vaccine. We assessed the cross-reactivity of antisera with various Salmonella species lipopolysaccharides and the protective efficacy of passive and active immunization with J5 vaccine against experimental nontyphoidal Salmonella infection in mice. Results Vaccination with J5 induced IgG responses that strongly recognized lipopolysaccharide from both typhoidal and nontyphoidal Salmonella and imparted a survival benefit against lethal heterologous challenges with S. Typhimurium and S. Enteritidis. Additionally, passive transfer studies with rabbit hyperimmune sera raised against the J5 vaccine revealed that anti-core antibodies were protective against lipopolysaccharide challenge in D-galactosamine-sensitized mice. Conclusions Our findings support the development of core glycolipids as a novel Salmonella vaccine candidate. Further investigation is warranted to determine the efficacy of the J5 core/outer membrane protein vaccine against other Salmonella serovars of concern.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"15 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-31","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142908407","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 Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent >50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. Methods We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry. Results Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p<0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A. Conclusion Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.
背景：抗逆转录病毒治疗（ART）导致骨质疏松和骨折，增加艾滋病毒感染者（PLH）的发病率和死亡率。ART诱导免疫重建骨质流失（IRBL），一种与免疫系统再激活相关的炎症反应。女性占PLH的50%，其中许多人现在正处于更年期，这是绝经后骨质疏松症的主要原因，也增加了骨折的风险。然而，IRBL与绝经后骨质流失之间的相互作用尚不清楚，本研究对此进行了调查。方法采用小鼠IRBL模型，与卵巢切除术（Ovx）同时或先后应用，这是一种绝经后骨质疏松小鼠模型。采用微计算机断层扫描（µCT）评估椎骨和股骨的皮质骨和小梁骨，通过ELISA测定骨吸收和形成的血清标志物量化骨转换。流式细胞术分析T细胞生成破骨细胞因子。结果虽然Ovx和IRBL同时发生没有累加效应，但Ovx和IRBL相继发生可引起累积性骨质流失。抗炎剂Abatacept （Δ=-13.9 vs. Control: p=不显著）和益生菌鼠李糖乳杆菌GG （Δ=-8.6 vs. Control: p=不显著）显著减少Ovx和IRBL联合导致的椎体骨丢失（Δ=-42.6 vs. Control: p=不显著）。两种治疗均可减少骨吸收，刺激骨形成，抑制CD4+ T细胞产生破骨细胞因子TNF-α和IL-17A。结论序贯IRBL和绝经后骨质流失是累积性的。如果在人类中得到验证，早期筛查和预防可以降低绝经后感染艾滋病毒（WLH）的妇女骨折风险。益生菌疗法可能提供一种有益的替代药物治疗。
{"title":"Combined Sequential Antiretroviral Therapy-Induced Immune Reconstitution Bone Loss and Estrogen Deficiency Bone Loss are Cumulative in Mice Models","authors":"Sadaf Dabeer, Ashish Kumar Tripathi, Daiana Weiss, Tatyana Vikulina, Ighovwerha Ofotokun, M Neale Weitzmann","doi":"10.1093/infdis/jiae643","DOIUrl":"https://doi.org/10.1093/infdis/jiae643","url":null,"abstract":"Background Antiretroviral therapy (ART) causes osteoporosis and bone fractures, increasing morbidity and mortality in people living with HIV (PLH). ART induces immune reconstitution bone loss (IRBL), an inflammatory reaction associated with immune system reactivation. Women represent &gt;50% of PLH, and many are now undergoing menopause, a major cause of postmenopausal osteoporosis that also increases fracture risk. However, the interactions between IRBL and postmenopausal bone loss are poorly understood and were investigated in this study. Methods We used a mouse model of IRBL, applied simultaneously or sequentially with surgical ovariectomy (Ovx), a mouse model of postmenopausal osteoporosis. Cortical and trabecular bone in vertebrae and femurs was assessed using micro-computed tomography (µCT) and bone turnover quantified by serum markers of bone resorption and formation via ELISA. T cell production of osteoclastogenic cytokines was analyzed by flow cytometry. Results Although simultaneous Ovx and IRBL did not have additive effects, sequential Ovx and IRBL caused cumulative bone loss. Vertebral bone loss from combined Ovx and IRBL (Δ=-42.6 vs. Control: p&lt;0.01) was significantly reduced by the anti-inflammatory agent Abatacept (Δ=-13.9 vs. Control: p=not significant) and the probiotic Lactobacillus rhamnosus GG (LGG) (Δ=-8.6 vs. Control: p=not significant). Both treatments reduced bone resorption, stimulated formation, and suppressed CD4+ T cell production of the osteoclastogenic cytokines TNF-α and IL-17A. Conclusion Sequential IRBL and postmenopausal bone loss appear to be cumulative. If validated in humans, early screening and prophylaxis could reduce fracture risk in postmenopausal women living with HIV (WLH). Probiotic therapy may provide a beneficial alternative to pharmacotherapy.","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"41 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887693","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}
Shibani S Mukerji, Petra Bachanová, Hemi Park, Linzy V Rosen, Rommi Kashlan, Pia Kivisäkk, Albert M Anderson, Felicia C Chow, Kunling Wu, Raha M Dastgheyb, Leah H Rubin, Katherine Tassiopoulos, Robert A Parker, Emily P Hyle
Background This study examined the relationship between neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and cognition in people living with HIV (PLWH) at baseline and over time. Methods Plasma and clinical data were available from PLWH aged ≥45 years with HIV RNA <200 copies/mL enrolled in the AIDS Clinical Trials Group HAILO cohort study. We measured plasma NfL and GFAP using a single molecule array platform. Four neuropsychological assessments, standardized to z-scores and averaged (NPZ-4), were used as a marker of cognitive function. Date of plasma collection marked study baseline; longitudinal changes in NPZ-4 were summarized by slope. Linear regressions between biomarkers and baseline NPZ-4 were adjusted for demographic factors. Regressions of longitudinal data were adjusted for baseline NPZ-4 and weighted by number of visits. Results The study included 503 participants with a median [IQR] age of 52 [48, 57] years, observation of 6 [5, 7] years, and 26% had baseline cognitive impairment defined by HAILO. Cross-sectionally, higher NfL (β=-0.76, p<0.01) and GFAP (β=-0.44, p=0.02) were associated with worse baseline NPZ-4. Longitudinally, the median [IQR] NPZ-4 slope was 0.003 [-0.06, 0.06] units/year with 48% demonstrating cognitive decline (slope<0). Higher NfL (β=-0.08, p<0.01), but not GFAP (β=-0.03, p=0.08), was associated with cognitive decline. Conclusions NfL and GFAP were associated with worse cognition cross-sectionally; only NfL was associated with longitudinal cognitive decline. However, the clinical utility of NfL and GFAP is uncertain given small effect sizes and should be studied in populations with more rapid decline (e.g., aged ≥60).
{"title":"Plasma Neurofilament Light Chain and Glial Fibrillary Acidic Protein as Biomarkers of Cognitive Decline in People Living with HIV","authors":"Shibani S Mukerji, Petra Bachanová, Hemi Park, Linzy V Rosen, Rommi Kashlan, Pia Kivisäkk, Albert M Anderson, Felicia C Chow, Kunling Wu, Raha M Dastgheyb, Leah H Rubin, Katherine Tassiopoulos, Robert A Parker, Emily P Hyle","doi":"10.1093/infdis/jiae623","DOIUrl":"https://doi.org/10.1093/infdis/jiae623","url":null,"abstract":"Background This study examined the relationship between neurofilament light chain (NfL) and glial fibrillary acidic protein (GFAP) and cognition in people living with HIV (PLWH) at baseline and over time. Methods Plasma and clinical data were available from PLWH aged ≥45 years with HIV RNA &lt;200 copies/mL enrolled in the AIDS Clinical Trials Group HAILO cohort study. We measured plasma NfL and GFAP using a single molecule array platform. Four neuropsychological assessments, standardized to z-scores and averaged (NPZ-4), were used as a marker of cognitive function. Date of plasma collection marked study baseline; longitudinal changes in NPZ-4 were summarized by slope. Linear regressions between biomarkers and baseline NPZ-4 were adjusted for demographic factors. Regressions of longitudinal data were adjusted for baseline NPZ-4 and weighted by number of visits. Results The study included 503 participants with a median [IQR] age of 52 [48, 57] years, observation of 6 [5, 7] years, and 26% had baseline cognitive impairment defined by HAILO. Cross-sectionally, higher NfL (β=-0.76, p&lt;0.01) and GFAP (β=-0.44, p=0.02) were associated with worse baseline NPZ-4. Longitudinally, the median [IQR] NPZ-4 slope was 0.003 [-0.06, 0.06] units/year with 48% demonstrating cognitive decline (slope&lt;0). Higher NfL (β=-0.08, p&lt;0.01), but not GFAP (β=-0.03, p=0.08), was associated with cognitive decline. Conclusions NfL and GFAP were associated with worse cognition cross-sectionally; only NfL was associated with longitudinal cognitive decline. However, the clinical utility of NfL and GFAP is uncertain given small effect sizes and should be studied in populations with more rapid decline (e.g., aged ≥60).","PeriodicalId":501010,"journal":{"name":"The Journal of Infectious Diseases","volume":"114 1","pages":""},"PeriodicalIF":0.0,"publicationDate":"2024-12-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142887690","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}
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