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Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells. 异维A酸可促进消除CD4T细胞中具有翻译能力的艾滋病毒潜伏库。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-14 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012601
J Natalie Howard, Callie Levinger, Selase Deletsu, Rémi Fromentin, Nicolas Chomont, Alberto Bosque
{"title":"Isotretinoin promotes elimination of translation-competent HIV latent reservoirs in CD4T cells.","authors":"J Natalie Howard, Callie Levinger, Selase Deletsu, Rémi Fromentin, Nicolas Chomont, Alberto Bosque","doi":"10.1371/journal.ppat.1012601","DOIUrl":"10.1371/journal.ppat.1012601","url":null,"abstract":"<p><p>Development of novel therapeutic strategies that reactivate latent HIV and sensitize reactivated cells to apoptosis is crucial towards elimination of the latent viral reservoir. Among the clinically relevant latency reversing agents (LRA) under investigation, the γc-cytokine IL-15 and the superagonist N-803 have been shown to reactivate latent HIV ex vivo and in vivo. However, their clinical benefit can be hindered by IL-15 promoting survival of infected cells. We previously identified a small molecule, HODHBt, that sensitizes latently infected cells to death upon reactivation with γc-cytokines through a STAT-dependent pathway. In here, we aimed to identify and evaluate FDA-approved compounds that could also sensitize HIV-infected cells to apoptosis. Using the Connectivity Map (CMap), we identified the retinol derivative 13-cis-retinoic acid (Isotretinoin) causes similar transcriptional changes as HODHBt. Isotretinoin enhances IL-15-mediated latency reversal without inducing proliferation of memory CD4 T cells. Ex vivo analysis of PBMCs from ACTG A5325, where Isotretinoin was administered to ART-suppressed people with HIV, showed that Isotretinoin treatment enhances IL-15-mediated latency reversal. Furthermore, we showed that a combination of IL-15 with Isotretinoin promotes the reduction of translation-competent reservoirs ex vivo. Mechanistically, combination of IL-15 and Isotretinoin increases caspase-3 activation specifically in HIV-infected cells but not uninfected cells. Our results suggest that Isotretinoin can be a novel approach to target and eliminate translation-competent HIV reservoirs.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012601"},"PeriodicalIF":5.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11501018/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478579","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
Distinct chikungunya virus polymerase palm subdomains contribute to viral protein accumulation and virion production. 不同的基孔肯雅病毒聚合酶棕榈亚域有助于病毒蛋白质的积累和病毒的产生。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-14 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1011972
Marie-France Martin, Boris Bonaventure, Nia E McCray, Olve B Peersen, Kathryn Rozen-Gagnon, Kenneth A Stapleford
{"title":"Distinct chikungunya virus polymerase palm subdomains contribute to viral protein accumulation and virion production.","authors":"Marie-France Martin, Boris Bonaventure, Nia E McCray, Olve B Peersen, Kathryn Rozen-Gagnon, Kenneth A Stapleford","doi":"10.1371/journal.ppat.1011972","DOIUrl":"10.1371/journal.ppat.1011972","url":null,"abstract":"<p><p>Alphaviruses encode an error-prone RNA-dependent RNA polymerase (RdRp), nsP4, required for genome synthesis, yet how the RdRp functions in the complete alphavirus life cycle is not well-defined. Previous work using chikungunya virus has established the importance of the nsP4 residue cysteine 483 in replication. Given the location of residue C483 in the nsP4 palm domain, we hypothesized that other residues within this domain and surrounding subdomains would also contribute to polymerase function. To test this hypothesis, we designed a panel of nsP4 variants via homology modeling based on the coxsackievirus B3 3D polymerase. We rescued each variant in mammalian and mosquito cells and discovered that the palm domain and ring finger subdomain contribute to host-specific replication. In C6/36 cells, we found that while the nsP4 variants had replicase function similar to that of wild-type CHIKV, many variants presented changes in protein accumulation and virion production even when viral nonstructural and structural proteins were produced. Finally, we found that WT CHIKV and nsP4 variant replication and protein production could be enhanced in mammalian cells at 28°C, yet growing virus under these conditions led to changes in virus infectivity. Taken together, these studies highlight that distinct nsP4 subdomains are required for proper RNA transcription and translation, having major effects on virion production.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1011972"},"PeriodicalIF":5.5,"publicationDate":"2024-10-14","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11501042/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142478572","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
CD4+ T cell help during early acute hepacivirus infection is critical for viral clearance and the generation of a liver-homing CD103+CD49a+ effector CD8+ T cell subset. 在早期急性肝炎病毒感染期间,CD4+ T 细胞的帮助对病毒清除和肝脏归属 CD103+CD49a+ 效应 CD8+ T 细胞亚群的生成至关重要。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-11 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012615
Jarrett Lopez-Scarim, Dustyn Mendoza, Shashank M Nambiar, Eva Billerbeck
{"title":"CD4+ T cell help during early acute hepacivirus infection is critical for viral clearance and the generation of a liver-homing CD103+CD49a+ effector CD8+ T cell subset.","authors":"Jarrett Lopez-Scarim, Dustyn Mendoza, Shashank M Nambiar, Eva Billerbeck","doi":"10.1371/journal.ppat.1012615","DOIUrl":"10.1371/journal.ppat.1012615","url":null,"abstract":"<p><p>In hepatitis C virus (HCV) infection, CD4+ and CD8+ T cells are crucial for viral control. However, a detailed understanding of the kinetic of CD4+ T cell help and its role in the generation of different CD8+ T cell subsets during acute infection is lacking. The absence of a small HCV animal model has impeded mechanistic studies of hepatic antiviral T cell immunity and HCV vaccine development. In this study, we used a recently developed HCV-related rodent hepacivirus infection mouse model to investigate the impact of CD4+ T cell help on the hepatic CD8+ T cell response and viral clearance during hepacivirus infection in vivo. Our results revealed a specific kinetic of CD4+ T cell dependency during acute infection. Early CD4+ T cell help was essential for CD8+ T cell priming and viral clearance, while CD4+ T cells became dispensable during later stages of acute infection. Effector CD8+ T cells directly mediated timely hepacivirus clearance. An analysis of hepatic CD8+ T cells specific for two different viral epitopes revealed the induction of subsets of liver-homing CD103+CD49a+ and CD103-CD49a+ effector CD8+ T cells with elevated IFN-γ and TNF-α production. CD103+CD49a+ T cells further persisted as tissue-resident memory subsets. A lack of CD4+ T cell help and CD40L-CD40 interactions resulted in reduced effector functions and phenotypical changes in effector CD8+ T cells and a specific loss of the CD103+CD49a+ subset. In summary, our study shows that early CD4+ T cell help through CD40L signaling is essential for priming functional effector CD8+ T cell subsets, including unique liver-homing subsets, and hepacivirus clearance.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012615"},"PeriodicalIF":5.5,"publicationDate":"2024-10-11","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11498735/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142407085","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
Humoral and T-cell-mediated responses to an insect-specific flavivirus-based Zika virus vaccine candidate. 基于昆虫特异性黄病毒的寨卡病毒候选疫苗的体液和 T 细胞介导反应
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-10 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012566
Danielle L Porier, Awadalkareem Adam, Lin Kang, Pawel Michalak, Juselyn Tupik, Matthew A Santos, Manette Tanelus, Krisangel López, Dawn I Auguste, Christy Lee, Irving C Allen, Tian Wang, Albert J Auguste
{"title":"Humoral and T-cell-mediated responses to an insect-specific flavivirus-based Zika virus vaccine candidate.","authors":"Danielle L Porier, Awadalkareem Adam, Lin Kang, Pawel Michalak, Juselyn Tupik, Matthew A Santos, Manette Tanelus, Krisangel López, Dawn I Auguste, Christy Lee, Irving C Allen, Tian Wang, Albert J Auguste","doi":"10.1371/journal.ppat.1012566","DOIUrl":"10.1371/journal.ppat.1012566","url":null,"abstract":"<p><p>Flaviviruses represent a significant global health threat and relatively few licensed vaccines exist to protect against them. Insect-specific flaviviruses (ISFVs) are incapable of replication in humans and have emerged as a novel and promising tool for flavivirus vaccine development. ISFV-based flavivirus vaccines have shown exceptional safety, immunogenicity, and efficacy, however, a detailed assessment of the correlates of protection and immune responses induced by these vaccines are still needed for vaccine optimization. Here, we explore the mechanisms of protective immunity induced by a previously created pre-clinical Zika virus (ZIKV) vaccine candidate, called Aripo/Zika (ARPV/ZIKV). In brief, immunocompromised IFN-αβR-/- mice passively immunized with ARPV/ZIKV immune sera experienced protection after lethal ZIKV challenge, although this protection was incomplete. ARPV/ZIKV-vaccinated IFN-αβR-/- mice depleted of CD4+ or CD8+ T-cells at the time of ZIKV challenge showed no morbidity or mortality. However, the adoptive transfer of ARPV/ZIKV-primed T-cells into recipient IFN-αβR-/- mice resulted in a two-day median increase in survival time compared to controls. Altogether, these results suggest that ARPV/ZIKV-induced protection is primarily mediated by neutralizing antibodies at the time of challenge and that T-cells may play a comparatively minor but cumulative role in the protection observed. Lastly, ARPV/ZIKV-vaccinated Tcra KO mice, which are deficient in T-cell responses, experienced significant mortality post-challenge. These results suggest that ARPV/ZIKV-induced cell-mediated responses are critical for development of protective immune responses at vaccination. Despite the strong focus on neutralizing antibody responses to novel flavivirus vaccine candidates, these results suggest that cell-mediated responses induced by ISFV-based vaccines remain important to overall protective responses.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012566"},"PeriodicalIF":5.5,"publicationDate":"2024-10-10","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11495591/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142401704","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
Virus stealth technology: Tools to study virus cell-to-cell transmission. 病毒隐形技术:研究病毒细胞间传播的工具。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-09 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012590
Peiqi Yin, Caroline K Martin, Margaret Kielian
{"title":"Virus stealth technology: Tools to study virus cell-to-cell transmission.","authors":"Peiqi Yin, Caroline K Martin, Margaret Kielian","doi":"10.1371/journal.ppat.1012590","DOIUrl":"10.1371/journal.ppat.1012590","url":null,"abstract":"","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012590"},"PeriodicalIF":5.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463765/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394522","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
Molecular and microbiological methods for the identification of nonreplicating Mycobacterium tuberculosis. 鉴定非复制结核分枝杆菌的分子和微生物学方法。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-09 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012595
Jansy Passiflora Sarathy
{"title":"Molecular and microbiological methods for the identification of nonreplicating Mycobacterium tuberculosis.","authors":"Jansy Passiflora Sarathy","doi":"10.1371/journal.ppat.1012595","DOIUrl":"10.1371/journal.ppat.1012595","url":null,"abstract":"<p><p>Chronic tuberculosis (TB) disease, which requires months-long chemotherapy with multiple antibiotics, is defined by diverse pathological manifestations and bacterial phenotypes. Targeting drug-tolerant bacteria in the host is critical to achieving a faster and durable cure for TB. In order to facilitate this field of research, we need to consider the physiology of persistent MTB during infection, which is often associated with the nonreplicating (NR) state. However, the traditional approach to quantifying bacterial burden through colony enumeration alone only informs on the abundance of live bacilli at the time of sampling, and provides an incomplete picture of the replicative state of the pathogen and the extent to which bacterial replication is balanced by ongoing cell death. Modern approaches to profiling bacterial replication status provide a better understanding of inter- and intra-population dynamics under different culture conditions and in distinct host microenvironments. While some methods use molecular markers of DNA replication and cell division, other approaches take advantage of advances in the field of microfluidics and live-cell microscopy. Considerable effort has been made over the past few decades to develop preclinical in vivo models of TB infection and some are recognized for more closely recapitulating clinical disease pathology than others. Unique lesion compartments presenting different environmental conditions produce significant heterogeneity between Mycobacterium tuberculosis populations within the host. While cellular lesion compartments appear to be more permissive of ongoing bacterial replication, caseous foci are associated with the maintenance of M. tuberculosis in a state of static equilibrium. The accurate identification of nonreplicators and where they hide within the host have significant implications for the way novel chemotherapeutic agents and regimens are designed for persistent infections.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012595"},"PeriodicalIF":5.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463790/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394518","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
Saurian-associated Leishmania tarentolae in dogs: Infectivity and immunogenicity evaluation in the canine model. 狗体内与金牛星相关的透明利什曼原虫:犬模型的感染性和免疫原性评估。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-09 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012598
Jairo Alfonso Mendoza-Roldan, Ilaria Varotto-Boccazzi, Viviane Noll Louzada-Flores, Alec Evans, Imad Bouzaidi Cheikhi, Mariaelisa Carbonara, Andrea Zatelli, Sara Epis, Claudio Bandi, Frédéric Beugnet, Domenico Otranto
{"title":"Saurian-associated Leishmania tarentolae in dogs: Infectivity and immunogenicity evaluation in the canine model.","authors":"Jairo Alfonso Mendoza-Roldan, Ilaria Varotto-Boccazzi, Viviane Noll Louzada-Flores, Alec Evans, Imad Bouzaidi Cheikhi, Mariaelisa Carbonara, Andrea Zatelli, Sara Epis, Claudio Bandi, Frédéric Beugnet, Domenico Otranto","doi":"10.1371/journal.ppat.1012598","DOIUrl":"10.1371/journal.ppat.1012598","url":null,"abstract":"<p><p>In canine leishmaniosis endemic areas, Leishmania infantum may occur in sympatry with the non-pathogenic Leishmania tarentolae, which is associated to reptiles. The potential infectivity of L. tarentolae for mammals raises questions about the interactions between the two Leishmania species, and the potential cross-immune protection in dogs. This study aimed to assess the outcome of experimental L. tarentolae infection in dogs, determining: i) the anti-L. tarentolae antibody production, ii) the duration of the immunity and cytokine expression, and iii) the possible pathogenic effect in the canine host. Twelve purpose-bred beagle dogs were randomly allocated to three groups (intravenous inoculation, G1; intradermal inoculation, G2; negative control, G3). G1 and G2 dogs were inoculated twice (day 0, day 28) with 108 promastigotes of L. tarentolae strain (RTAR/IT/21/RI-325) isolated from a Tarentola mauritanica gecko. The animals were followed until day 206. Blood, serum, conjunctival swabs and lymph node aspirate samples were collected monthly and bone marrow, liver and spleen biopsies on day 91. Hematological and biochemical parameters were assessed monthly, as well as serology (IFAT and ELISA) and molecular identification of L. tarentolae. Mononuclear cells (PBMC) were obtained to assess the cytokine expression through in vitro stimulation or (re-) infection. Data from this study demonstrated that DNA from L. tarentolae is detectable up to 3 months post-infection, with seroconversion after day 28. Moreover, the non-pathogenic nature of L. tarentolae was confirmed, with a neutral Th1/Th2 polarization, and a possible shift to Th1 phenotype after derived macrophages (re-) infection, as demonstrated by the expression of IFN-gamma. Therefore, L. tarentolae demonstrated a great potential as a surrogate pathogen and/or immune-prophylaxis/immune-therapy against Leishmania infections in dogs and humans.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012598"},"PeriodicalIF":5.5,"publicationDate":"2024-10-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11463833/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394520","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
Functional plasticity shapes neutrophil response to Leishmania major infection in susceptible and resistant strains of mice. 功能可塑性决定了小鼠易感株和抗感株中性粒细胞对大利什曼原虫感染的反应。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-08 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012592
Thiago DeSouza-Vieira, Marco Antônio M Pretti, Phillipe Souza Lima Gomes, Heitor A Paula-Neto, Amy Goundry, Michelle T Nascimento, Sundar Ganesan, Triciana Gonçalves da Silva, Olena Kamenyeva, Juraj Kabat, Javier Manzella-Lapeira, Fábio B Canto, Vanderlei da Silva Fraga-Junior, Mateus Eustáquio Lopes, Leonardo Gomes Vaz, Gabriela Pessenda, Andrea Paun, Anita L Freitas-Mesquita, José Roberto Meyer-Fernandes, Mariana Boroni, Maria Bellio, Gustavo Batista Menezes, Joseph Brzostowski, Jeremy Mottram, David Sacks, Ana Paula C A Lima, Elvira M Saraiva
{"title":"Functional plasticity shapes neutrophil response to Leishmania major infection in susceptible and resistant strains of mice.","authors":"Thiago DeSouza-Vieira, Marco Antônio M Pretti, Phillipe Souza Lima Gomes, Heitor A Paula-Neto, Amy Goundry, Michelle T Nascimento, Sundar Ganesan, Triciana Gonçalves da Silva, Olena Kamenyeva, Juraj Kabat, Javier Manzella-Lapeira, Fábio B Canto, Vanderlei da Silva Fraga-Junior, Mateus Eustáquio Lopes, Leonardo Gomes Vaz, Gabriela Pessenda, Andrea Paun, Anita L Freitas-Mesquita, José Roberto Meyer-Fernandes, Mariana Boroni, Maria Bellio, Gustavo Batista Menezes, Joseph Brzostowski, Jeremy Mottram, David Sacks, Ana Paula C A Lima, Elvira M Saraiva","doi":"10.1371/journal.ppat.1012592","DOIUrl":"10.1371/journal.ppat.1012592","url":null,"abstract":"<p><p>Neutrophils rapidly infiltrate sites of infection and possess several microbicidal strategies, such as neutrophil extracellular traps release and phagocytosis. Enhanced neutrophil infiltration is associated with higher susceptibility to Leishmania infection, but neutrophil effector response contribution to this phenotype is uncertain. Here, we show that neutrophils from susceptible BALB/c mice (B/c) produce more NETs in response to Leishmania major than those from resistant C57BL/6 mice (B6), which are more phagocytic. The absence of neutrophil elastase contributes to phagocytosis regulation. Microarray analysis shows enrichment of genes involved in NET formation (mpo, pi3kcg, il1b) in B/c, while B6 shows upregulation of genes involved in phagocytosis and cell death (Arhgap12, casp9, mlkl, FasL). scRNA-seq in L. major-infected B6 showed heterogeneity in the pool of intralesional neutrophils, and we identified the N1 subset as the putative subpopulation involved with phagocytosis. In vivo, imaging validates NET formation in infected B/c ears where NETing neutrophils were mainly uninfected cells. NET digestion in vivo augmented parasite lymphatic drainage. Hence, a balance between NET formation and phagocytosis in neutrophils may contribute to the divergent phenotype observed in these mice.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012592"},"PeriodicalIF":5.5,"publicationDate":"2024-10-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11488723/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394517","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
Myosin A and F-Actin play a critical role in mitochondrial dynamics and inheritance in Toxoplasma gondii. 肌球蛋白 A 和 F-肌动蛋白在弓形虫线粒体动力学和遗传中发挥着关键作用。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-07 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012127
Rodolpho Ornitz Oliveira Souza, Chunlin Yang, Gustavo Arrizabalaga
{"title":"Myosin A and F-Actin play a critical role in mitochondrial dynamics and inheritance in Toxoplasma gondii.","authors":"Rodolpho Ornitz Oliveira Souza, Chunlin Yang, Gustavo Arrizabalaga","doi":"10.1371/journal.ppat.1012127","DOIUrl":"10.1371/journal.ppat.1012127","url":null,"abstract":"<p><p>The single mitochondrion of the obligate intracellular parasite Toxoplasma gondii is highly dynamic. Toxoplasma's mitochondrion changes morphology as the parasite moves from the intracellular to the extracellular environment and during division. Toxoplasma's mitochondrial dynamic is dependent on an outer mitochondrion membrane-associated protein LMF1 and its interaction with IMC10, a protein localized at the inner membrane complex (IMC). In the absence of either LMF1 or IMC10, parasites have defective mitochondrial morphology and inheritance defects. As little is known about mitochondrial inheritance in Toxoplasma, we have used the LMF1/IMC10 tethering complex as an entry point to dissect the machinery behind this process. Using a yeast two-hybrid screen, we previously identified Myosin A (MyoA) as a putative interactor of LMF1. Although MyoA is known to be located at the parasite's pellicle, we now show through ultrastructure expansion microscopy (U-ExM) that this protein accumulates around the mitochondrion in the late stages of parasite division. Parasites lacking MyoA show defective mitochondrial morphology and a delay in mitochondrion delivery to the daughter parasite buds during division, indicating that this protein is involved in organellar inheritance. Disruption of the parasite's actin network also affects mitochondrion morphology. We also show that parasite-extracted mitochondrion vesicles interact with actin filaments. Interestingly, mitochondrion vesicles extracted out of parasites lacking LMF1 pulled down less actin, showing that LMF1 might be important for mitochondrion and actin interaction. Accordingly, we are showing for the first time that actin and Myosin A are important for Toxoplasma mitochondrial morphology and inheritance.</p>","PeriodicalId":48999,"journal":{"name":"PLoS Pathogens","volume":"20 10","pages":"e1012127"},"PeriodicalIF":5.5,"publicationDate":"2024-10-07","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11486366/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142394519","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 HSV-1 encoded CCCTC-binding factor, CTRL2, impacts the nature of viral chromatin during HSV-1 lytic infection. HSV-1 编码的 CCCTC 结合因子 CTRL2 在 HSV-1 裂解感染过程中影响病毒染色质的性质。
IF 5.5 1区 医学
PLoS Pathogens Pub Date : 2024-10-07 eCollection Date: 2024-10-01 DOI: 10.1371/journal.ppat.1012621
Pankaj Singh, Liqian Zhu, Mason A Shipley, Ziyun A Ye, Donna M Neumann
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