PLoS Pathogens最新文献

{"title":"HBV polymerase recruits the phosphatase PP1 to dephosphorylate HBc-Ser170 to complete encapsidation.","authors":"Chi-Ling Hsieh, Li-Yang Chang, Pei-Jer Chen, Shiou-Hwei Yeh","doi":"10.1371/journal.ppat.1012905","DOIUrl":"10.1371/journal.ppat.1012905","url":null,"abstract":"<p><p>The HBV core (HBc) protein contains an N-terminal domain (NTD) for capsid assembly and an arginine-rich C-terminal domain (CTD) for pregenomic RNA (pgRNA) encapsidation. Phosphorylation of the HBc CTD, especially at Ser162 and Ser170, is essential for nucleation with the polymerase (Pol) to initiate pgRNA encapsidation. As capsids mature, the HBc CTD undergoes dephosphorylation, suggesting the involvement of a phosphatase in the late stage of encapsidation, which remains to be determined. Using a C-S170 antibody specific for non-phosphorylated HBc-Ser170, we observed a transition from a phosphorylated to a dephosphorylated state during pgRNA packaging. The Pol-dependent dephosphorylation of HBc-Ser170 was confirmed by the substitution of one single amino acid at Val782 in the RNase H domain, which abolished the dephosphorylation of HBc-Ser170. Immunoprecipitation, mass spectrometry analyses, and the protein structural analyses showed that the recruitment of the host phosphatase PP1 is dependent on the Pol-Val782 domain. This recruitment does not require HBc but does require Pol via epsilon RNA signal, suggesting that the Pol-pgRNA complex plays a key role in PP1 recruitment. Pol-pgRNA-PP1-mediated dephosphorylation of HBc-Ser170 is essential for the completion of pgRNA encapsidation and appears to be associated with late endosomes/multivesicular bodies (MVBs). Therefore, HBV Pol may play a dual role by initially bringing pgRNA to phosphorylated HBc and recruiting PP1 for later completion of RNA packaging into the capsids. These findings not only decipher the mechanism by which Pol-mediated dephosphorylation of HBc regulates pgRNA encapsulation, but also reveal the possibility of PP1 as a potential target for antiviral development.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012905"},"PeriodicalIF":5.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813143/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400600","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Mechanisms of resistance against allylamine and azole antifungals in Trichophyton: A renewed call for innovative molecular diagnostics in susceptibility testing.","authors":"Aditya K Gupta, Tong Wang, Avantika Mann, Vincent Piguet, Anuradha Chowdhary, Wayne L Bakotic","doi":"10.1371/journal.ppat.1012913","DOIUrl":"10.1371/journal.ppat.1012913","url":null,"abstract":"<p><p>The emergence of antifungal resistance calls for continued research efforts to better guide healthcare providers in treatment selection and outcomes. Unlike bacterial infections, treatment of superficial fungal infections is mainly limited to allylamines (terbinafine) and azoles (itraconazole). Here, we aim to update our current understanding of resistance mechanisms against allylamine and azole antifungals in the Trichophyton genus. Resistance development has been demonstrated in vitro by challenging Trichophyton isolates with allylamines or azoles at levels below the minimum inhibitory concentration (MIC), which corroborates the observation of clinical resistance. Frequently reported mechanisms of resistance include: (I) Alterations of the drug target by single-nucleotide variations (SNVs) of the SQLE/ERG1 and ERG11 genes; in particular, SQLE SNVs (Leu393Phe, Leu393Ser, and Phe397Leu) have been frequently reported in isolates with high terbinafine MICs; (II) overexpression of the target enzyme for azoles (ERG11) and downstream genes in the ergosterol biosynthesis pathway can decrease the effective drug concentration as well as prevent the depletion of ergosterol and the accumulation of toxic sterol intermediates; (III) the up-regulation of drug efflux channels-belonging to the ABC superfamily (PDR1, MDR2, MDR3, MDR4), MFS superfamily (MFS1), or Pma1 (plasma membrane ATPase 1)-can reduce the effective concentrations of terbinafine and azoles. The possibility of multidrug resistance has been shown in Trichophyton strains, of both human and animal origins, harboring multiple resistance mechanisms (e.g., target alteration/overexpression and drug efflux channels). Tackling the issue of antifungal resistance will require an integrated approach with multidisciplinary efforts including surveillance initiatives and antifungal stewardship programs. However, these efforts are hampered by the current limited accessibility of antifungal susceptibility testing as well as the limited choice of antifungals available in routine practice. A better understanding of resistance mechanisms could help develop targeted, molecular-based assays.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012913"},"PeriodicalIF":5.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813129/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400601","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Order among chaos: High throughput MYCroplanters can distinguish interacting drivers of host infection in a highly stochastic system.","authors":"Melissa Y Chen, Leah M Fulton, Ivie Huang, Aileen Liman, Sarzana S Hossain, Corri D Hamilton, Siyu Song, Quentin Geissmann, Kayla C King, Cara H Haney","doi":"10.1371/journal.ppat.1012894","DOIUrl":"10.1371/journal.ppat.1012894","url":null,"abstract":"<p><p>The likelihood that a host will be susceptible to infection is influenced by the interaction of diverse biotic and abiotic factors. As a result, substantial experimental replication and scalability are required to identify the contributions of and interactions between the host, the environment, and biotic factors such as the microbiome. For example, pathogen infection success is known to vary by host genotype, bacterial strain identity and dose, and pathogen dose. Elucidating the interactions between these factors in vivo has been challenging because testing combinations of these variables quickly becomes experimentally intractable. Here, we describe a novel high throughput plant growth system (MYCroplanters) to test how multiple host, non-pathogenic bacteria, and pathogen variables predict host health. Using an Arabidopsis-Pseudomonas host-microbe model, we found that host genotype and bacterial strain order of arrival predict host susceptibility to infection, but pathogen and non-pathogenic bacterial dose can overwhelm these effects. Host susceptibility to infection is therefore driven by complex interactions between multiple factors that can both mask and compensate for each other. However, regardless of host or inoculation conditions, the ratio of pathogen to non-pathogen emerged as a consistent correlate of disease. Our results demonstrate that high-throughput tools like MYCroplanters can isolate interacting drivers of host susceptibility to disease. Increasing the scale at which we can screen drivers of disease, such as microbiome community structure, will facilitate both disease predictions and treatments for medicine and agricultural applications.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012894"},"PeriodicalIF":5.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11813117/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143399367","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"A guanidine-based coronavirus replication inhibitor which targets the nsp15 endoribonuclease and selects for interferon-susceptible mutant viruses.","authors":"Benjamin Van Loy, Eugènia Pujol, Kenichi Kamata, Xiao Yin Lee, Nikolai Bakirtzoglou, Ria Van Berwaer, Julie Vandeput, Cato Mestdagh, Leentje Persoons, Brent De Wijngaert, Quinten Goovaerts, Sam Noppen, Maarten Jacquemyn, Kourosh Ahmadzadeh, Eline Bernaerts, Juan Martín-López, Celia Escriche, Bert Vanmechelen, Besir Krasniqi, Abhimanyu K Singh, Dirk Daelemans, Piet Maes, Patrick Matthys, Wim Dehaen, Jef Rozenski, Kalyan Das, Arnout Voet, Santiago Vázquez, Lieve Naesens, Annelies Stevaert","doi":"10.1371/journal.ppat.1012571","DOIUrl":"10.1371/journal.ppat.1012571","url":null,"abstract":"<p><p>The approval of COVID-19 vaccines and antiviral drugs has been crucial to end the global health crisis caused by SARS-CoV-2. However, to prepare for future outbreaks from drug-resistant variants and novel zoonotic coronaviruses (CoVs), additional therapeutics with a distinct antiviral mechanism are needed. Here, we report a novel guanidine-substituted diphenylurea compound that suppresses CoV replication by interfering with the uridine-specific endoribonuclease (EndoU) activity of the viral non-structural protein-15 (nsp15). This compound, designated EPB-113, exhibits strong and selective cell culture activity against human coronavirus 229E (HCoV-229E) and also suppresses the replication of SARS-CoV-2. Viruses, selected under EPB-113 pressure, carried resistance sites at or near the catalytic His250 residue of the nsp15-EndoU domain. Although the best-known function of EndoU is to avoid induction of type I interferon (IFN-I) by lowering the levels of viral dsRNA, EPB-113 was found to mainly act via an IFN-independent mechanism, situated during viral RNA synthesis. Using a combination of biophysical and enzymatic assays with the recombinant nsp15 proteins from HCoV-229E and SARS-CoV-2, we discovered that EPB-113 enhances the EndoU cleavage activity of hexameric nsp15, while reducing its thermal stability. This mechanism explains why the virus escapes EPB-113 by acquiring catalytic site mutations which impair compound binding to nsp15 and abolish the EndoU activity. Since the EPB-113-resistant mutant viruses induce high levels of IFN-I and its effectors, they proved unable to replicate in human macrophages and were readily outcompeted by the wild-type virus upon co-infection of human fibroblast cells. Our findings suggest that antiviral targeting of nsp15 can be achieved with a molecule that induces a conformational change in this protein, resulting in higher EndoU activity and impairment of viral RNA synthesis. Based on the appealing mechanism and resistance profile of EPB-113, we conclude that nsp15 is a challenging but highly relevant drug target.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012571"},"PeriodicalIF":5.5,"publicationDate":"2025-02-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11856660/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143400599","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Repression of varicella zoster virus gene expression during quiescent infection in the absence of detectable histone deposition.","authors":"Jiayi Wang, Nadine Brückner, Simon Weissmann, Thomas Günther, Shuyong Zhu, Carolin Vogt, Guorong Sun, Rongrong Guo, Renzo Bruno, Birgit Ritter, Lars Steinbrück, Benedikt B Kaufer, Daniel P Depledge, Adam Grundhoff, Abel Viejo-Borbolla","doi":"10.1371/journal.ppat.1012367","DOIUrl":"10.1371/journal.ppat.1012367","url":null,"abstract":"<p><p>Varicella zoster virus (VZV) is a human-specific herpesvirus that establishes latency in peripheral neurons. The only transcripts detected in infected human trigeminal ganglia (TG) obtained shortly after death correspond to the VZV latency-associated transcript (VLT) and associated VLT-ORF63 splice variants. In vitro studies showed that VLT-ORF63 is translated into a protein (pVLT-ORF63) that induces VZV transcription. The mechanisms that lead to this restricted gene expression and the transition to lytic replication remain unknown, partly due to the difficulty of working with human neurons. In this study, we addressed whether the neuroblastoma-derived cell line SH-SY5Y could serve as a model to investigate the mechanisms that lead to repression of VZV gene expression followed by reactivation. VZV productively infected differentiated SH-SY5Y (dSH-SY5Y) whereas incubation with acyclovir (ACV) inhibited virus replication and induced a progressive repression of the virus. Upon removal of ACV there was production of viral particles in a subset of cells, while others contained non-replicating VZV genomes and VLT-containing transcripts for at least 20 days post-infection (dpi). Exogenous expression of VLT-ORF63 induced productive infection, suggesting that the non-replicating and repressed genomes remained functional. Interestingly, histone deposition was undetectable at VZV genomes in quiescently infected dSH-SY5Y cells, pointing to a potential novel mechanism leading to VZV repression in this neuronal setting.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012367"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11838886/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Discovery of bimodal hepatitis B virus ribonuclease H and capsid assembly inhibitors.","authors":"Daniel P Bradley, Caleb J Valkner, Qilan Li, Makafui Gasonoo, Marvin J Meyers, Georgia-Myrto Prifti, Dimitrios Moianos, Grigoris Zoidis, Adam Zlotnick, John E Tavis","doi":"10.1371/journal.ppat.1012920","DOIUrl":"10.1371/journal.ppat.1012920","url":null,"abstract":"<p><p>Hepatitis B virus (HBV) ribonuclease H (RNaseH) inhibitors are a potent class of antivirals that prevent degradation of the viral pregenomic RNA during reverse transcription and block formation of mature HBV DNAs. Development of HBV RNaseH inhibitors is entering advanced preclinical analyses. To ensure the mechanism of action was fully understood, we defined the effects of RNaseH inhibitors on other steps of HBV replication. Some N-hydroxypyridinedione (HPD) HBV RNaseH inhibitors significantly reduced accumulation of capsids in HBV-replicating cells. A representative HPD 1466, with a 50% effective concentration against HBV replication of 0.25 µM, decreased capsid and core protein accumulation by 50-90% in HepDES19 and HepG2.2.15 cells. Surprisingly, 1466 did not affect pregenomic RNA encapsidation, demonstrating a specific effect on empty capsids. HBV genomic replication was not necessary for 1466's inhibitory effect as it decreased capsid accumulation in cells transfected with replication-deficient mutants blocking pgRNA encapsidation (Δ-bulge), DNA synthesis (YMHA), and RNaseH (D702A) activities. 1466 also decreased capsid and core protein accumulation in cells transfected with a core protein expression plasmid, indicating that other HBV products are unneeded. 1466 reduced initial capsid assembly rates in biochemical assembly reactions employing purified core protein (Cp149), demonstrating a specific effect on HBV core protein. We conclude that the bimodal HPD HBV RNaseH inhibitor 1466 is the prototypic member of a new class of capsid assembly modulators (CAM) that inhibits capsid assembly rather than accelerating it, as all other CAM classes do. We propose that this class be called CAM-I, for CAM-inhibitor. These results lay the foundation for identifying bimodal HBV antivirals targeting the RNaseH and capsid assembly.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012920"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828405/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392210","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Moving beyond multi-triazole to multi-fungicide resistance: Broader selection of drug resistance in the human fungal pathogen Aspergillus fumigatus.","authors":"Spyros G Kanellopoulos, Eveline Snelders","doi":"10.1371/journal.ppat.1012851","DOIUrl":"10.1371/journal.ppat.1012851","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012851"},"PeriodicalIF":5.5,"publicationDate":"2025-02-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11809870/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143392212","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"E6AP is essential for the proliferation of HPV-positive cancer cells by preventing senescence.","authors":"Alicia Avenhaus, Milica Velimirović, Julia Bulkescher, Martin Scheffner, Felix Hoppe-Seyler, Karin Hoppe-Seyler","doi":"10.1371/journal.ppat.1012914","DOIUrl":"10.1371/journal.ppat.1012914","url":null,"abstract":"<p><p>Oncogenic types of human papillomaviruses (HPVs) are major human carcinogens. The formation of a trimeric complex between the HPV E6 oncoprotein, the cellular ubiquitin ligase E6AP and the p53 tumor suppressor protein leads to proteolytic p53 degradation and plays a central role for HPV-induced cell transformation. We here uncover that E6AP silencing in HPV-positive cancer cells ultimately leads to efficient induction of cellular senescence, revealing that E6AP acts as a potent anti-senescent factor in these cells. Thus, although the downregulation of either E6 or E6AP expression also acts partially pro-apoptotic, HPV-positive cancer cells surviving E6 repression proliferate further, whereas they become irreversibly growth-arrested upon E6AP repression. We moreover show that the senescence induction following E6AP downregulation is mechanistically highly dependent on induction of the p53/p21 axis, other than the known pro-senescent response of HPV-positive cancer cells following combined downregulation of the viral E6 and E7 oncoproteins. Of further note, repression of E6AP allows senescence induction in the presence of the anti-senescent HPV E7 protein. Yet, despite these mechanistic differences, the pathways underlying the pro-senescent effects of E6AP or E6/E7 repression ultimately converge by being both dependent on the cellular pocket proteins pRb and p130. Taken together, our results uncover a hitherto unrecognized and potent anti-senescent function of the E6AP protein in HPV-positive cancer cells, which is essential for their sustained proliferation. Our results further indicate that interfering with E6AP expression or function could result in therapeutically desired effects in HPV-positive cancer cells by efficiently inducing an irreversible growth arrest. Since the critical role of the E6/E6AP/p53 complex for viral transformation is conserved between different oncogenic HPV types, this approach could provide a therapeutic strategy, which is not HPV type-specific.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012914"},"PeriodicalIF":5.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805377/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371308","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Wnt/β-catenin signalling underpins juvenile Fasciola hepatica growth and development.","authors":"Rebecca Armstrong, Nikki J Marks, Timothy G Geary, John Harrington, Paul M Selzer, Aaron G Maule","doi":"10.1371/journal.ppat.1012562","DOIUrl":"10.1371/journal.ppat.1012562","url":null,"abstract":"<p><p>Infection by the liver fluke, Fasciola hepatica, places a substantial burden on the global agri-food industry and poses a significant threat to human health in endemic regions. Widespread resistance to a limited arsenal of chemotherapeutics, including the frontline flukicide triclabendazole (TCBZ), renders F. hepatica control unsustainable and accentuates the need for novel therapeutic target discovery. A key facet of F. hepatica biology is a population of specialised stem cells which drive growth and development - their dysregulation is hypothesised to represent an appealing avenue for control. The exploitation of this system as a therapeutic target is impeded by a lack of understanding of the molecular mechanisms underpinning F. hepatica growth and development. Wnt signalling pathways govern a myriad of stem cell processes during embryogenesis and drive tumorigenesis in adult tissues in animals. Here, we identify five putative Wnt ligands and five Frizzled receptors in liver fluke transcriptomic datasets and find that Wnt/β-catenin signalling is most active in juveniles, the most pathogenic life stage. FISH-mediated transcript localisation revealed partitioning of the five Wnt ligands, with each displaying a distinct expression pattern, consistent with each Wnt regulating the development of different cell/tissue types. The silencing of each individual Wnt or Frizzled gene yielded significant reductions in juvenile worm growth and, in select cases, blunted the proliferation of neoblast-like cells. Notably, silencing FhCTNNB1, the key effector of the Wnt/β-catenin signal cascade led to aberrant development of the neuromuscular system which ultimately proved lethal - the first report of a lethal RNAi-induced phenotype in F. hepatica. The absence of any discernible phenotypes following the silencing of the inhibitory Wnt/β-catenin destruction complex components is consistent with low destruction complex activity in rapidly developing juvenile worms, corroborates transcriptomic expression profiles and underscores the importance of Wnt signalling as a key molecular driver of growth and development in early-stage juvenile fluke. The putative pharmacological inhibition of Wnt/β-catenin signalling using commercially available inhibitors phenocopied RNAi results and provides impetus for drug repurposing. Taken together, these data functionally and chemically validate the targeting of Wnt signalling as a novel strategy to undermine the pathogenicity of juvenile F. hepatica.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012562"},"PeriodicalIF":5.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11805424/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371312","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Asymptomatic neonatal herpes simplex virus infection in mice leads to persistent CNS infection and long-term cognitive impairment.","authors":"Abigail J Dutton, Evelyn M Turnbaugh, Chaya D Patel, Callaghan R Garland, Sean A Taylor, Roberto Alers-Velazquez, David M Knipe, Katherine M Nautiyal, David A Leib","doi":"10.1371/journal.ppat.1012935","DOIUrl":"10.1371/journal.ppat.1012935","url":null,"abstract":"<p><p>Neonatal herpes simplex virus (nHSV) is a devastating infection impacting approximately 14,000 newborns globally each year. nHSV infection is associated with high neurologic morbidity and mortality, making early intervention critical. Clinical outcomes of symptomatic nHSV infections are well-studied, but little is known about the frequency of, or outcomes following, subclinical or asymptomatic nHSV. Given the ubiquitous nature of HSV infection and frequency of asymptomatic shedding in adults, subclinical infections are underreported and could contribute to long-term neurological damage. To assess potential neurological morbidity associated with subclinical nHSV infection, we developed a low-dose (100 PFU) intranasal HSV infection model in neonatal wild-type C57BL/6 mice. At this dose, HSV DNA was detected in the brain by quantitative PCR (qPCR) but was not associated with acute clinical signs of infection. However, months after neonatal inoculation with this low dose of HSV, we observed impaired mouse performance on a range of cognitive and memory tests. Memory impairment was induced by infection with either HSV-1 or HSV-2 wild-type viruses, indicating that the cognitive impairment associated with neonatal infection was not strain-specific. Maternal immunization reduced neonate central nervous system (CNS) viral burden and prevented offspring from developing neurological sequelae following nHSV infection. Altogether, these results support the idea that subclinical neonatal infections may lead to cognitive decline in adulthood and that maternal vaccination is an effective strategy for reducing neurological sequelae in infected offspring. These findings may have profound implications for understanding and modeling the etiology of human neurodegenerative disorders such as Alzheimer's Disease.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"21 2","pages":"e1012935"},"PeriodicalIF":5.5,"publicationDate":"2025-02-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11828378/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"143371247","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}