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Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis. 嗜中性粒细胞中的脂肪酸代谢促进了肺结核期间的肺损伤和细菌复制。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-04 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012188
Poornima Sankar, Ramon Bossardi Ramos, Jamie Corro, Lokesh K Mishra, Tanvir Noor Nafiz, Gunapati Bhargavi, Mohd Saqib, Sibongiseni K L Poswayo, Suraj P Parihar, Yi Cai, Selvakumar Subbian, Anil K Ojha, Bibhuti B Mishra
{"title":"Fatty acid metabolism in neutrophils promotes lung damage and bacterial replication during tuberculosis.","authors":"Poornima Sankar, Ramon Bossardi Ramos, Jamie Corro, Lokesh K Mishra, Tanvir Noor Nafiz, Gunapati Bhargavi, Mohd Saqib, Sibongiseni K L Poswayo, Suraj P Parihar, Yi Cai, Selvakumar Subbian, Anil K Ojha, Bibhuti B Mishra","doi":"10.1371/journal.ppat.1012188","DOIUrl":"10.1371/journal.ppat.1012188","url":null,"abstract":"<p><p>Mycobacterium tuberculosis (Mtb) infection induces a marked influx of neutrophils into the lungs, which intensifies the severity of tuberculosis (TB). The metabolic state of neutrophils significantly influences their functional response during inflammation and interaction with bacterial pathogens. However, the effect of Mtb infection on neutrophil metabolism and its consequent role in TB pathogenesis remain unclear. In this study, we examined the contribution of glycolysis and fatty acid metabolism on neutrophil responses to Mtb HN878 infection using ex-vivo assays and murine infection models. We discover that blocking glycolysis aggravates TB pathology, whereas inhibiting fatty acid oxidation (FAO) yields protective outcomes, including reduced weight loss, immunopathology, and bacterial burden in lung. Intriguingly, FAO inhibition preferentially disrupts the recruitment of a pathogen-permissive immature neutrophil population (Ly6Glo/dim), known to accumulate during TB. Targeting carnitine palmitoyl transferase 1a (Cpt1a)-a crucial enzyme in mitochondrial β-oxidation-either through chemical or genetic methods impairs neutrophils' ability to migrate to infection sites while also enhancing their antimicrobial function. Our findings illuminate the critical influence of neutrophil immunometabolism in TB pathogenesis, suggesting that manipulating fatty acid metabolism presents a novel avenue for host-directed TB therapies by modulating neutrophil functions.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012188"},"PeriodicalIF":5.5,"publicationDate":"2024-10-04","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11482725/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142376198","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}
引用次数: 0
Tetraspanin-enriched microdomains play an important role in pathogenesis in the protozoan parasite Entamoeba histolytica. 富含四泛蛋白的微域在原生动物寄生虫组织溶解恩塔米巴虫的致病过程中发挥着重要作用。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012151
Han Jiang, Herbert J Santos, Tomoyoshi Nozaki
{"title":"Tetraspanin-enriched microdomains play an important role in pathogenesis in the protozoan parasite Entamoeba histolytica.","authors":"Han Jiang, Herbert J Santos, Tomoyoshi Nozaki","doi":"10.1371/journal.ppat.1012151","DOIUrl":"10.1371/journal.ppat.1012151","url":null,"abstract":"<p><p>Tetraspanins (TSPANs) are a family of highly conserved proteins present in a wide variety of eukaryotes. Although protein-protein interactions of TSPANs have been well established in eukaryotes including parasitic protists, the role they play in parasitism and pathogenesis remains largely unknown. In this study, we characterized three representative members of TSPANs, TSPAN4, TSPAN12, and TSPAN13 from the human intestinal protozoan Entamoeba histolytica. Co-immunoprecipitation assays demonstrated that TSPAN4, TSPAN12 and TSPAN13 are reciprocally pulled down together with several other TSPAN-interacting proteins including TSPAN binding protein of 55kDa (TBP55) and interaptin. Blue native-PAGE analysis showed that these TSPANs form several complexes of 120-250 kDa. Repression of tspan12 and tspan13 gene expression led to decreased secretion of cysteine proteases, while repression of tspan4 led to a four-fold increase in the activity of cysteine proteases in crude extracellular vesicles (EVs) fraction. Meanwhile, strains overexpressing HA-tagged TSPAN12 and TSPAN13 demonstrated reduced adhesion to collagen. Altogether, this study reveals that the TSPANs, especially TSPAN12 and TSPAN13, are engaged with complex protein-protein interactions and are involved in the pathogenicity-related biological functions such as protease secretion and adhesion, offering insights into the potential regulatory mechanisms of tetraspanins in protozoan parasites.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012151"},"PeriodicalIF":5.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11478834/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373338","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}
引用次数: 0
qsmR encoding an IclR-family transcriptional factor is a core pathogenic determinant of Burkholderia glumae beyond the acyl-homoserine lactone-mediated quorum-sensing system. 编码 IclR 家族转录因子的 qsmR 是一种超越酰基-高丝氨酸内酯介导的法定人数感应系统的伯克霍尔德菌核心致病决定因子。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1011862
Tiago De Paula Lelis, Jobelle Bruno, Jonas Padilla, Inderjit Barphagha, John Ontoy, Jong Hyun Ham
{"title":"qsmR encoding an IclR-family transcriptional factor is a core pathogenic determinant of Burkholderia glumae beyond the acyl-homoserine lactone-mediated quorum-sensing system.","authors":"Tiago De Paula Lelis, Jobelle Bruno, Jonas Padilla, Inderjit Barphagha, John Ontoy, Jong Hyun Ham","doi":"10.1371/journal.ppat.1011862","DOIUrl":"10.1371/journal.ppat.1011862","url":null,"abstract":"<p><p>The plant pathogenic bacterium Burkholderia glumae causes bacterial panicle blight (BPB) in rice-growing areas worldwide. It has been widely accepted that an acyl-homoserine lactone (AHL)-type quorum sensing (QS) system encoded by tofI and tofR genes (TofIR QS) is a key regulatory mechanism underlying the bacterial pathogenesis of B. glumae. In addition, qsmR, which encodes an IclR-family regulatory protein, has been considered an important part of TofIR QS. However, the present study with three strains of B. glumae representing different pathogenic strains revealed that this currently accepted paradigm should be modified. We characterized the regulatory function of TofIR QS and qsmR in three different strains of B. glumae, 336gr-1 (virulent), 411gr-6 (hypervirulent) and 257sh-1 (avirulent). In 336gr-1, both TofIR QS and qsmR were critical for the pathogenesis, being consistent with previous studies. However, in the hypervirulent strain 411gr-6, TofIR QS only partially contributes to the virulence, whereas qsmR was critical for pathogenesis like in 336gr-1. Furthermore, we found that a single nucleotide polymorphism causing T50K substitution in the qsmR coding sequence was the cause of the non-pathogenic trait of the naturally avirulent strain 257sh-1. Subsequent analyses of gene expression and transcriptome revealed that TofIR QS is partially controlled by qsmR at the transcriptional level in both virulent strains. Further genetic tests of additional B. glumae strains showed that 11 out of 20 virulent strains retained the ability to produce toxoflavin even after removing the tofI/tofM/tofR QS gene cluster like 411gr-6. In contrast, all the virulent strains tested lost the ability to produce toxoflavin almost completely upon deletion of the qsmR gene. Taking these results together, qsmR, rather than TofIR QS, is a master regulator that determines the pathogenic trait of B. glumae thus a more appropriate pathogen target for successful management of BPB.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1011862"},"PeriodicalIF":5.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11478832/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373337","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}
引用次数: 0
Mosaic and mixed HIV-1 glycoprotein nanoparticles elicit antibody responses to broadly neutralizing epitopes. 镶嵌式和混合式 HIV-1 糖蛋白纳米粒子可激发对广泛中和表位的抗体反应。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012558
Mitch Brinkkemper, Gius Kerster, Philip J M Brouwer, Andy S Tran, Jonathan L Torres, Roos A Ettema, Haye Nijhuis, Joel D Allen, Wenwen Zhu, Hongmei Gao, Wen-Hsin Lee, Tom P L Bijl, Jonne L Snitselaar, Judith A Burger, Ilja Bontjer, Wouter Olijhoek, Rashmi Ravichandran, Marielle J van Breemen, Iván Del Moral-Sánchez, Ronald Derking, Kwinten Sliepen, Gabriel Ozorowski, Max Crispin, David C Montefiori, Mathieu Claireaux, Andrew B Ward, Marit J van Gils, Neil P King, Rogier W Sanders
{"title":"Mosaic and mixed HIV-1 glycoprotein nanoparticles elicit antibody responses to broadly neutralizing epitopes.","authors":"Mitch Brinkkemper, Gius Kerster, Philip J M Brouwer, Andy S Tran, Jonathan L Torres, Roos A Ettema, Haye Nijhuis, Joel D Allen, Wenwen Zhu, Hongmei Gao, Wen-Hsin Lee, Tom P L Bijl, Jonne L Snitselaar, Judith A Burger, Ilja Bontjer, Wouter Olijhoek, Rashmi Ravichandran, Marielle J van Breemen, Iván Del Moral-Sánchez, Ronald Derking, Kwinten Sliepen, Gabriel Ozorowski, Max Crispin, David C Montefiori, Mathieu Claireaux, Andrew B Ward, Marit J van Gils, Neil P King, Rogier W Sanders","doi":"10.1371/journal.ppat.1012558","DOIUrl":"10.1371/journal.ppat.1012558","url":null,"abstract":"<p><p>An effective human immunodeficiency virus 1 (HIV-1) vaccine will most likely have to elicit broadly neutralizing antibodies (bNAbs) to overcome the sequence diversity of the envelope glycoprotein (Env). So far, stabilized versions of Env, such as SOSIP trimers, have been able to induce neutralizing antibody (NAb) responses, but those responses are mainly strain-specific. Here we attempted to broaden NAb responses by using a multivalent vaccine and applying a number of design improvements. First, we used highly stabilized SOSIP.v9 trimers. Second, we removed any holes in the glycan shields and optimized glycan occupancy to avoid strain-specific glycan hole responses. Third, we selected five sequences from the same clade (B), as we observed previously that combining Env trimers from clade A, B and C did not improve cross-reactive responses, as they might have been too diverse. Fourth, to improve antibody (Ab) responses, the Env trimers were displayed on two-component I53-50 nanoparticles (NPs). Fifth, to favor activation of cross-reactive B cells, the five Env trimers were co-displayed on mosaic NPs. Sixth, we immunized rabbits four times with long intervals between vaccinations. These efforts led to the induction of cross-reactive B cells and cross-reactive binding Ab responses, but we only sporadically detected cross-neutralizing responses. We conclude that stabilized HIV-1 Env trimers that are not modified specifically for priming naive B cells are unable to elicit strong bNAb responses, and infer that sequential immunization regimens, most likely starting with specific germline-targeting immunogens, will be necessary to overcome Env's defenses against the induction of NAbs. The antigens described here could be excellent boosting immunogens in a sequential immunization regimen, as responses to bNAb epitopes were induced.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012558"},"PeriodicalIF":5.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11449375/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373336","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}
引用次数: 0
The five homologous CiaR-controlled Ccn sRNAs of Streptococcus pneumoniae modulate Zn-resistance. 肺炎链球菌的五种同源 CiaR 控制 Ccn sRNA 可调节 Zn 抗性。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-03 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012165
Nicholas R De Lay, Nidhi Verma, Dhriti Sinha, Abigail Garrett, Maximillian K Osterberg, Daisy Porter, Spencer Reiling, David P Giedroc, Malcolm E Winkler
{"title":"The five homologous CiaR-controlled Ccn sRNAs of Streptococcus pneumoniae modulate Zn-resistance.","authors":"Nicholas R De Lay, Nidhi Verma, Dhriti Sinha, Abigail Garrett, Maximillian K Osterberg, Daisy Porter, Spencer Reiling, David P Giedroc, Malcolm E Winkler","doi":"10.1371/journal.ppat.1012165","DOIUrl":"10.1371/journal.ppat.1012165","url":null,"abstract":"<p><p>Zinc is a vital transition metal for all bacteria; however, elevated intracellular free Zn levels can result in mis-metalation of Mn-dependent enzymes. For Mn-centric bacteria such as Streptococcus pneumoniae that primarily use Mn instead of Fe as an enzyme cofactor, Zn is particularly toxic at high concentrations. Here, we report our identification and characterization of the function of the five homologous, CiaRH-regulated Ccn sRNAs in controlling S. pneumoniae virulence and metal homeostasis. We show that deletion of all five ccn genes (ccnA, ccnB, ccnC, ccnD, and ccnE) from S. pneumoniae strains D39 (serotype 2) and TIGR4 (serotype 4) causes Zn hypersensitivity and an attenuation of virulence in a murine invasive pneumonia model. We provide evidence that bioavailable Zn disproportionately increases in S. pneumoniae strains lacking the five ccn genes. Consistent with a response to Zn intoxication or relatively high intracellular free Zn levels, expression of genes encoding the CzcD Zn exporter and the Mn-independent ribonucleotide reductase, NrdD-NrdG, were increased in the ΔccnABCDE mutant relative to its isogenic ccn+ parent strain. The growth inhibition by Zn that occurs as the result of loss of the ccn genes is rescued by supplementation with Mn or Oxyrase, a reagent that removes dissolved oxygen. Lastly, we found that the Zn-dependent growth inhibition of the ΔccnABCDE strain was not altered by deletion of sodA, whereas the ccn+ ΔsodA strain phenocopied the ΔccnABCDE strain. Overall, our results indicate that the Ccn sRNAs have a crucial role in preventing Zn intoxication in S. pneumoniae.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012165"},"PeriodicalIF":5.5,"publicationDate":"2024-10-03","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11478796/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142373339","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}
引用次数: 0
2'-O-methyltransferase-deficient yellow fever virus: Restricted replication in the midgut and secondary tissues of Aedes aegypti mosquitoes severely limits dissemination. 2'-O-甲基转移酶缺陷型黄热病病毒:埃及伊蚊中肠和次级组织中的复制受限严重限制了传播。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-02 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012607
Anja Vom Hemdt, Alexandra L Thienel, Katrin Ciupka, Janett Wieseler, Hannah M Proksch, Martin Schlee, Beate M Kümmerer
{"title":"2'-O-methyltransferase-deficient yellow fever virus: Restricted replication in the midgut and secondary tissues of Aedes aegypti mosquitoes severely limits dissemination.","authors":"Anja Vom Hemdt, Alexandra L Thienel, Katrin Ciupka, Janett Wieseler, Hannah M Proksch, Martin Schlee, Beate M Kümmerer","doi":"10.1371/journal.ppat.1012607","DOIUrl":"10.1371/journal.ppat.1012607","url":null,"abstract":"<p><p>The RNA genome of orthoflaviviruses encodes a methyltransferase within the non-structural protein NS5, which is involved in 2'-O-methylation of the 5'-terminal nucleotide of the viral genome resulting in a cap1 structure. While a 2'-O-unmethylated cap0 structure is recognized in vertebrates by the RNA sensor RIG-I, the cap1 structure allows orthoflaviviruses to evade the vertebrate innate immune system. Here, we analyzed whether the cap0 structure is also recognized in mosquitoes. Replication analyses of 2'-O-methyltransferase deficient yellow fever virus mutants (YFV NS5-E218A) of the vaccine 17D and the wild-type Asibi strain in mosquito cells revealed a distinct downregulation of the cap0 viruses. Interestingly, the level of inhibition differed for various mosquito cells. The most striking difference was found in Aedes albopictus-derived C6/36 cells with YFV-17D cap0 replication being completely blocked. Replication of YFV-Asibi cap0 was also suppressed in mosquito cells but to a lower extent. Analyses using chimeras between YFV-17D and YFV-Asibi suggest that a synergistic effect of several mutations across the viral genome accompanied by a faster initial growth rate of YFV-Asibi cap1 correlates with the lower level of YFV-Asibi cap0 attenuation. Viral growth analyses in Dicer-2 knockout cells demonstrated that Dicer-2 is entirely dispensable for attenuating the YFV cap0 viruses. Translation of a replication-incompetent cap0 reporter YFV-17D genome was reduced in mosquito cells, indicating a cap0 sensing translation regulation mechanism. Further, oral infection of Aedes aegypti mosquitoes resulted in lower infection rates for YFV-Asibi cap0. The latter is related to lower viral loads found in the midguts, which largely diminished dissemination to secondary tissues. After intrathoracic infection, YFV-Asibi cap0 replicated slower and to decreased amounts in secondary tissues compared to YFV-Asibi cap1. These results suggest the existence of an ubiquitously expressed innate antiviral protein recognizing 5'-terminal RNA cap-modifications in mosquitoes, both in the midgut as well as in secondary tissues.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012607"},"PeriodicalIF":5.5,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472933/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367129","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}
引用次数: 0
Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination. 生命早期的连续病毒感染会调节微生物群以及对全身和粘膜疫苗接种的适应性免疫反应。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-02 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012557
Yuhao Li, Jerome M Molleston, Crystal Lovato, Jasmine Wright, Isabel Erickson, Duyen Bui, Andrew H Kim, Harshad Ingle, Somya Aggarwal, Lila S Nolan, Ahmed O Hassan, Lynne Foster, Michael S Diamond, Megan T Baldridge
{"title":"Sequential early-life viral infections modulate the microbiota and adaptive immune responses to systemic and mucosal vaccination.","authors":"Yuhao Li, Jerome M Molleston, Crystal Lovato, Jasmine Wright, Isabel Erickson, Duyen Bui, Andrew H Kim, Harshad Ingle, Somya Aggarwal, Lila S Nolan, Ahmed O Hassan, Lynne Foster, Michael S Diamond, Megan T Baldridge","doi":"10.1371/journal.ppat.1012557","DOIUrl":"10.1371/journal.ppat.1012557","url":null,"abstract":"<p><p>Increasing evidence points to the microbial exposome as a critical factor in maturing and shaping the host immune system, thereby influencing responses to immune challenges such as infections or vaccines. To investigate the effect of early-life viral exposures on immune development and vaccine responses, we inoculated mice with six distinct viral pathogens in sequence beginning in the neonatal period, and then evaluated their immune signatures before and after intramuscular or intranasal vaccination against SARS-CoV-2. Sequential viral infection drove profound changes in all aspects of the immune system, including increasing circulating leukocytes, altering innate and adaptive immune cell lineages in tissues, and markedly influencing serum cytokine and total antibody levels. Beyond changes in the immune responses, these exposures also modulated the composition of the endogenous intestinal microbiota. Although sequentially-infected mice exhibited increased systemic immune activation and T cell responses after intramuscular and intranasal SARS-CoV-2 immunization, we observed decreased vaccine-induced antibody responses in these animals. These results suggest that early-life viral exposures are sufficient to diminish antibody responses to vaccination in mice, and highlight the potential importance of considering prior microbial exposures when investigating vaccine responses.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012557"},"PeriodicalIF":5.5,"publicationDate":"2024-10-02","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11472911/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367130","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}
引用次数: 0
The importance of IFNα2A (Roferon-A) in HSV-1 latency and T cell exhaustion in ocularly infected mice. IFNα2A(Roferon-A)在眼部感染小鼠的 HSV-1 潜伏期和 T 细胞衰竭中的重要性。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-01 DOI: 10.1371/journal.ppat.1012612
Shaohui Wang, Ujjaldeep Jaggi, Makoto Katsumata, Homayon Ghiasi
{"title":"The importance of IFNα2A (Roferon-A) in HSV-1 latency and T cell exhaustion in ocularly infected mice.","authors":"Shaohui Wang, Ujjaldeep Jaggi, Makoto Katsumata, Homayon Ghiasi","doi":"10.1371/journal.ppat.1012612","DOIUrl":"10.1371/journal.ppat.1012612","url":null,"abstract":"<p><p>Published studies have generated compelling results indicating that type I IFN modulates function of HSV-1 latency-associated transcript (LAT). One member of type I IFN is IFNα2A also called Roferon-A). IFNα2A has been used in monotherapy or in combination therapy with other drugs to treat viral infections and different kinds of cancer in humans. The goal of this study was to determine whether the absence of IFNα2A affects primary and latent infections in ocularly infected mice. Therefore, we generated a mouse strain lacking IFNα2A expression (IFNα2A-/-). Ocular HSV-1 replication, IFN and immune cell expressions on days 3 and 5 post infection (PI), as well as eye disease, survival, latency-reactivation, and T cell exhaustion were evaluated in ocularly infected IFNα2A-/- and wild type (WT) control mice. Absence of IFNα2A did not affect other members of the IFNα family but it affected IFNβ and IFNγ expressions as well as some immune cells on day 5 PI compared to WT mice. Viral replication in the eye, eye disease, and survival amongst ocularly infected IFNα2A-/- mice were similar to that of WT infected mice. The absence of IFNα2A significantly reduced the levels of latency and T cell exhaustion but not time of reactivation compared with control mice. Our results suggest that blocking IFNα2A expression may be a useful tool in reducing latency and the subsequent side effects associated with higher levels of latency.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012612"},"PeriodicalIF":5.5,"publicationDate":"2024-10-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11469491/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142367131","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}
引用次数: 0
N4-Hydroxycytidine/molnupiravir inhibits RNA virus-induced encephalitis by producing less fit mutated viruses. N4-Hydroxycytidine/molnupiravir 能抑制 RNA 病毒诱发的脑炎,因为它能产生更少的适合变异病毒。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-09-30 eCollection Date: 2024-09-01 DOI: 10.1371/journal.ppat.1012574
Durbadal Ojha, Collin S Hill, Shuntai Zhou, Alyssa Evans, Jacqueline M Leung, Christine A Schneider, Franck Amblard, Tyson A Woods, Raymond F Schinazi, Ralph S Baric, Karin E Peterson, Ronald Swanstrom
{"title":"N4-Hydroxycytidine/molnupiravir inhibits RNA virus-induced encephalitis by producing less fit mutated viruses.","authors":"Durbadal Ojha, Collin S Hill, Shuntai Zhou, Alyssa Evans, Jacqueline M Leung, Christine A Schneider, Franck Amblard, Tyson A Woods, Raymond F Schinazi, Ralph S Baric, Karin E Peterson, Ronald Swanstrom","doi":"10.1371/journal.ppat.1012574","DOIUrl":"10.1371/journal.ppat.1012574","url":null,"abstract":"<p><p>A diverse group of RNA viruses have the ability to gain access to the central nervous system (CNS) and cause severe neurological disease. Current treatment for people with this type of infection is generally limited to supportive care. To address the need for reliable antivirals, we utilized a strategy of lethal mutagenesis to limit virus replication. We evaluated ribavirin (RBV), favipiravir (FAV) and N4-hydroxycytidine (NHC) against La Crosse virus (LACV), which is one of the most common causes of pediatric arboviral encephalitis cases in North America and serves as a model for viral CNS invasion during acute infection. NHC was approximately 3 to 170 times more potent than RBV or FAV in neuronal cells. Oral administration of molnupiravir (MOV), the prodrug of NHC, decreased neurological disease development (assessed as limb paralysis, ataxia and weakness, repeated seizures, or death) by 31% (4 mice survived out of 13) when treatment was started on the day of infection. MOV also reduced disease by 23% when virus was administered intranasally (IN). NHC and MOV produced less fit viruses by incorporating predominantly G to A or C to U mutations. Furthermore, NHC also inhibited virus production of two other orthobunyaviruses, Jamestown Canyon virus and Cache Valley virus. Collectively, these studies indicate that NHC/MOV has therapeutic potential to inhibit viral replication and subsequent neurological disease caused by orthobunyaviruses and potentially as a generalizable strategy for treating acute viral encephalitis.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 9","pages":"e1012574"},"PeriodicalIF":5.5,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11493283/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330619","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}
引用次数: 0
Put a little doxy-PEP in your step: Using doxycycline to prevent chlamydia, syphilis, and gonorrhea infections. 在你的生活中加入一点强力霉素-PEP:使用强力霉素预防衣原体、梅毒和淋病感染。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-09-30 eCollection Date: 2024-09-01 DOI: 10.1371/journal.ppat.1012575
Eric A Meyerowitz, Rina Liang, Derek Bishop, Caroline E Mullis
{"title":"Put a little doxy-PEP in your step: Using doxycycline to prevent chlamydia, syphilis, and gonorrhea infections.","authors":"Eric A Meyerowitz, Rina Liang, Derek Bishop, Caroline E Mullis","doi":"10.1371/journal.ppat.1012575","DOIUrl":"10.1371/journal.ppat.1012575","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 9","pages":"e1012575"},"PeriodicalIF":5.5,"publicationDate":"2024-09-30","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11441668/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142330624","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}
引用次数: 0
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