Abstract:
:Nonreplicating type I uracil auxotrophic mutants of Toxoplasma gondii possess a potent ability to activate therapeutic immunity to established solid tumors by reversing immune suppression in the tumor microenvironment. Here we engineered targeted deletions of parasite secreted effector proteins using a genetically tractable Δku80 vaccine strain to show that the secretion of specific rhoptry (ROP) and dense granule (GRA) proteins by uracil auxotrophic mutants of T. gondii in conjunction with host cell invasion activates antitumor immunity through host responses involving CD8α+ dendritic cells, the IL-12/interferon-gamma (IFN-γ) TH1 axis, as well as CD4+ and CD8+ T cells. Deletion of parasitophorous vacuole membrane (PVM) associated proteins ROP5, ROP17, ROP18, ROP35 or ROP38, intravacuolar network associated dense granule proteins GRA2 or GRA12, and GRA24 which traffics past the PVM to the host cell nucleus severely abrogated the antitumor response. In contrast, deletion of other secreted effector molecules such as GRA15, GRA16, or ROP16 that manipulate host cell signaling and transcriptional pathways, or deletion of PVM associated ROP21 or GRA3 molecules did not affect the antitumor activity. Association of ROP18 with the PVM was found to be essential for the development of the antitumor responses. Surprisingly, the ROP18 kinase activity required for resistance to IFN-γ activated host innate immunity related GTPases and virulence was not essential for the antitumor response. These data show that PVM functions of parasite secreted effector molecules, including ROP18, manipulate host cell responses through ROP18 kinase virulence independent mechanisms to activate potent antitumor responses. Our results demonstrate that PVM associated rhoptry effector proteins secreted prior to host cell invasion and dense granule effector proteins localized to the intravacuolar network and host nucleus that are secreted after host cell invasion coordinately control the development of host immune responses that provide effective antitumor immunity against established ovarian cancer.
journal_name
PLoS Genetjournal_title
PLoS geneticsauthors
Fox BA,Sanders KL,Rommereim LM,Guevara RB,Bzik DJdoi
10.1371/journal.pgen.1006189subject
Has Abstractpub_date
2016-07-22 00:00:00pages
e1006189issue
7eissn
1553-7390issn
1553-7404pii
PGENETICS-D-15-02588journal_volume
12pub_type
杂志文章相关文献
PLoS Genetics文献大全abstract::Skin pigment patterns of vertebrates are a classic system for understanding fundamental mechanisms of morphogenesis, differentiation, and pattern formation, and recent studies of zebrafish have started to elucidate the cellular interactions and molecular mechanisms underlying these processes. In this species, horizont...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003561
更新日期:2013-05-01 00:00:00
abstract::Cellulolytic fungi have evolved a complex regulatory network to maintain the precise balance of nutrients required for growth and hydrolytic enzyme production. When fungi are exposed to cellulose, the transcript levels of cellulase genes rapidly increase and then decline. However, the mechanisms underlying this bell-s...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008510
更新日期:2019-11-25 00:00:00
abstract::From genomic association studies, quantitative trait loci analysis, and epigenomic mapping, it is evident that significant efforts are necessary to define genetic-epigenetic interactions and understand their role in disease susceptibility and progression. For this reason, an analysis of the effects of genetic variatio...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007785
更新日期:2018-11-19 00:00:00
abstract::Recent studies of the HapMap lymphoblastoid cell lines have identified large numbers of quantitative trait loci for gene expression (eQTLs). Reanalyzing these data using a novel Bayesian hierarchical model, we were able to create a surprisingly high-resolution map of the typical locations of sites that affect mRNA lev...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000214
更新日期:2008-10-01 00:00:00
abstract::[This corrects the article DOI: 10.1371/journal.pgen.1006425.]. ...
journal_title:PLoS genetics
pub_type: 杂志文章,已发布勘误
doi:10.1371/journal.pgen.1006831
更新日期:2017-06-07 00:00:00
abstract::The ratio of forced expiratory volume in one second to forced vital capacity (FEV(1)/FVC) is a measure used to diagnose airflow obstruction and is highly heritable. We performed a genome-wide association study in 7,691 Framingham Heart Study participants to identify single-nucleotide polymorphisms (SNPs) associated wi...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000429
更新日期:2009-03-01 00:00:00
abstract::Mitotic and cytokinetic processes harness cell machinery to drive chromosomal segregation and the physical separation of dividing cells. Here, we investigate the functional requirements for exocyst complex function during cell division in vivo, and demonstrate a common mechanism that directs anaphase cell elongation a...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005632
更新日期:2015-11-03 00:00:00
abstract::The nuclear lamina is the structural scaffold of the nuclear envelope and is well known for its central role in nuclear organization and maintaining nuclear stability and shape. In the past, a number of severe human disorders have been identified to be associated with mutations in lamins. Extensive research on this to...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003261
更新日期:2013-01-01 00:00:00
abstract::High-throughput genetic screens are powerful methods to identify genes linked to a given phenotype. The catalytic null mutant of the Cas9 RNA-guided nuclease (dCas9) can be conveniently used to silence genes of interest in a method also known as CRISPRi. Here, we report a genome-wide CRISPR-dCas9 screen using a starti...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1007749
更新日期:2018-11-07 00:00:00
abstract::Controlling infectious disease without inducing unwanted inflammatory disease requires proper regulation of the innate immune response. Thus, innate immunity needs to be activated when needed during an infection, but must be limited to prevent damage. To accomplish this, negative regulators of innate immunity limit th...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003855
更新日期:2013-10-01 00:00:00
abstract::The Structural Maintenance of Chromosome (SMC) complex, termed cohesin, is essential for sister chromatid cohesion. Cohesin is also important for chromosome condensation, DNA repair, and gene expression. Cohesin is comprised of Scc3, Mcd1, Smc1, and Smc3. Scc3 also binds Pds5 and Wpl1, cohesin-associated proteins that...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005036
更新日期:2015-03-06 00:00:00
abstract::Understanding buffering mechanisms for various perturbations is essential for understanding robustness in cellular systems. Protein-level dosage compensation, which arises when changes in gene copy number do not translate linearly into protein level, is one mechanism for buffering against genetic perturbations. Here, ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006554
更新日期:2017-01-25 00:00:00
abstract::Global climate change, increasingly erratic weather and a burgeoning global population are significant threats to the sustainability of future crop production. There is an urgent need for the development of robust measures that enable crops to withstand the uncertainty of climate change whilst still producing maximum ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005705
更新日期:2015-12-03 00:00:00
abstract::The rate at which genomes adapt to environmental changes and the prevalence of adaptive processes in molecular evolution are two controversial issues in current evolutionary genetics. Previous attempts to quantify the genome-wide rate of adaptation through amino-acid substitution have revealed a surprising diversity o...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005774
更新日期:2016-01-11 00:00:00
abstract::Undifferentiated embryonal sarcoma of the liver (UESL) is a rare and aggressive malignancy. Though the molecular underpinnings of this cancer have been largely unexplored, recurrent chromosomal breakpoints affecting a noncoding region on chr19q13, which includes the chromosome 19 microRNA cluster (C19MC), have been re...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008642
更新日期:2020-04-20 00:00:00
abstract::Abeta peptide accumulation is thought to be the primary event in the pathogenesis of Alzheimer's disease (AD), with downstream neurotoxic effects including the hyperphosphorylation of tau protein. Glycogen synthase kinase-3 (GSK-3) is increasingly implicated as playing a pivotal role in this amyloid cascade. We have d...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1001087
更新日期:2010-09-02 00:00:00
abstract::Microtubule-microfilament interactions are important for cytokinesis and subcellular localization of proteins and mRNAs. In the early zebrafish embryo, astral microtubule-microfilament interactions also facilitate a stereotypic segregation pattern of germ plasm ribonucleoparticles (GP RNPs), which is critical for thei...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003448
更新日期:2013-04-01 00:00:00
abstract::Intraflagellar transport (IFT) particles or trains are composed of IFT-A and IFT-B complexes. To assess the working mechanism of the IFT-A complex in IFT and ciliogenesis, we have analyzed ift43 mutants of Chlamydomnonas in conjunction with mutants of the other IFT-A subunits. An ift43 null mutant or a mutant with a p...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006627
更新日期:2017-02-16 00:00:00
abstract::Epigenetic mechanisms suppress the transcription of transposons and DNA repeats; however, this suppression can be transiently released under prolonged heat stress. Here we show that the Arabidopsis thaliana imprinted gene SDC, which is silent during vegetative growth due to DNA methylation, is activated by heat and co...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004806
更新日期:2014-11-20 00:00:00
abstract::Aneuploidy refers to losses and/or gains of individual chromosomes from the normal chromosome set. The resulting gene dosage imbalance has a noticeable affect on the phenotype, as illustrated by aneuploid syndromes, including Down syndrome in humans, and by human solid tumor cells, which are highly aneuploid. Although...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000226
更新日期:2008-10-01 00:00:00
abstract::The presence of 5-methylcytidine (m(5)C) in tRNA and rRNA molecules of a wide variety of organisms was first observed more than 40 years ago. However, detection of this modification was limited to specific, abundant, RNA species, due to the usage of low-throughput methods. To obtain a high resolution, systematic, and ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1003602
更新日期:2013-06-01 00:00:00
abstract::Escherichia coli translation initiation factor 2 (IF2) performs the unexpected function of promoting transition from recombination to replication during bacteriophage Mu transposition in vitro, leading to initiation by replication restart proteins. This function has suggested a role of IF2 in engaging cellular restart...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1002648
更新日期:2012-01-01 00:00:00
abstract::We have exploited the high selectivity of the homing endonuclease I-PpoI for the X-linked Anopheles gambiae 28S ribosomal genes to selectively target X chromosome carrying spermatozoa. Our data demonstrated that in heterozygous males, the expression of I-PpoI in the testes induced a strong bias toward Y chromosome-car...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1000291
更新日期:2008-12-01 00:00:00
abstract::Nervous systems have the ability to select appropriate actions and action sequences in response to sensory cues. The circuit mechanisms by which nervous systems achieve choice, stability and transitions between behaviors are still incompletely understood. To identify neurons and brain areas involved in controlling the...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008589
更新日期:2020-02-14 00:00:00
abstract::Inter-individual variation in gene regulatory elements is hypothesized to play a causative role in adverse drug reactions and reduced drug activity. However, relatively little is known about the location and function of drug-dependent elements. To uncover drug-associated elements in a genome-wide manner, we performed ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004648
更新日期:2014-10-02 00:00:00
abstract::The molecular clock of neutral mutations, which represents linear mutation fixation over generations, is theoretically explained by genetic drift in fitness-steady evolution or hitchhiking in adaptive evolution. The present study is the first experimental demonstration for the molecular clock of neutral mutations in a...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1005392
更新日期:2015-07-15 00:00:00
abstract::In flowering plants, gene expression in the haploid male gametophyte (pollen) is essential for sperm delivery and double fertilization. Pollen also undergoes dynamic epigenetic regulation of expression from transposable elements (TEs), but how this process interacts with gene expression is not clearly understood. To e...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1008462
更新日期:2020-04-01 00:00:00
abstract::Race, specifically African ancestry, and obesity are important risk factors for uterine fibroids, and likely interact to provide the right conditions for fibroid growth. However, existing studies largely focus on the main-effects rather than their interaction. Here, we firstly provide evidence for interaction between ...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006871
更新日期:2017-07-17 00:00:00
abstract::Opportunistic infections caused by Pseudomonas aeruginosa can be acute or chronic. While acute infections often spread rapidly and can cause tissue damage and sepsis with high mortality rates, chronic infections can persist for weeks, months, or years in the face of intensive clinical intervention. Remarkably, this di...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1004518
更新日期:2014-07-24 00:00:00
abstract::In nature, microbes often need to "decide" which of several available nutrients to utilize, a choice that depends on a cell's inherent preference and external nutrient levels. While natural environments can have mixtures of different nutrients, phenotypic variation in microbes' decisions of which nutrient to utilize i...
journal_title:PLoS genetics
pub_type: 杂志文章
doi:10.1371/journal.pgen.1006766
更新日期:2017-05-24 00:00:00