In recent years, various intervention strategies have reduced malaria morbidity and mortality, but further improvements likely depend upon development of a broadly protective vaccine. To better understand immune requirement for protection, we examined liver-stage immunity after vaccination with irradiated sporozoites, an effective though logistically difficult vaccine. We identified a population of memory CD8+ T cells that expressed the gene signature of tissue-resident memory (Trm) T cells and remained permanently within the liver, where they patrolled the sinusoids. Exploring the requirements for liver Trm cell induction, we showed that by combining dendritic cell-targeted priming with liver inflammation and antigen recognition on hepatocytes, high frequencies of Trm cells could be induced and these cells were essential for protection against malaria sporozoite challenge. Our study highlights the immune potential of liver Trm cells and provides approaches for their selective transfer, expansion or depletion, which may be harnessed to control liver infections or autoimmunity.
Liver-Resident Memory CD8<sup>+</sup> T Cells Form a Front-Line Defense against Malaria Liver-Stage Infection.
Specimen part
View SamplesRenal cell carcinomas with unclassified histology (uRCC) constitute a significant portion of aggressive non-clear cell RCC (nccRCC) that have no standard therapy. The oncogenic drivers in these tumors are unknown. We performed a molecular analysis of 62 high-grade primary uRCC, incorporating targeted cancer gene sequencing, RNA sequencing, Single Nucleotide Polymorphism array, fluorescence in-situ hybridization, immunohistochemistry, and cell-based assays. We identified recurrent somatic mutations in 29 genes, including NF2 (18%), SETD2 (18%), BAP1 (13%), KMT2C (10%), and MTOR (8%). Integrated analysis revealed distinct molecular subsets, including a subset of 26% uRCC characterized by NF2-loss, dysregulated Hippo-YAP pathway and worse survival. Overall design: Analysis of RNA from uRCC with or without NF2-loss
Molecular analysis of aggressive renal cell carcinoma with unclassified histology reveals distinct subsets.
Specimen part, Subject
View SamplesCD25+ regulatory T cells develop in the thymus (nTregs), but may also be generated in the periphery upon stimulation of naive CD4 T cells under appropriate conditions (iTregs). The mechanisms that regulate the generation of peripheral iTregs are largely unknown.
Analysis of the transcriptional program of developing induced regulatory T cells.
Specimen part, Treatment, Subject, Time
View SamplesIn the urinary tract, smooth muscle (SM) is present in the renal pelvis, the ureter, the bladder and the urethra and plays a crucial role in the functional and structural integrity of these organs. In Tshz3 mutant ureters the myogenic program is not activated in the proximal region due to the absence of expression of myocardin (Myocd), a key regulator of SM differentiation. We set out to characterize TSHZ3-dependent mechanisms that participate to the process of ureteric smooth muscle cells (SMC) differentiation.
The tiptop/teashirt genes regulate cell differentiation and renal physiology in Drosophila.
Specimen part
View SamplesTo study the function of BAF250 during ES cell self renewal and differentiation
ES cell pluripotency and germ-layer formation require the SWI/SNF chromatin remodeling component BAF250a.
No sample metadata fields
View SamplesSeasonal influenza outbreaks and recurrent influenza pandemics present major challenges to public health. By studying immunological responses to influenza in different host species, it may be possible to discover common mechanisms of susceptibility in response to various influenza strains. This could lead to novel therapeutic targets with wide clinical application. Using a mouse-adapted strain of influenza (A/HK/1/68-MA20 [H3N2]), we produced a mouse model of severe influenza (p-flu) that reproduces the hallmark high viral load and overexpression of cytokines associated with susceptibility to p-flu in humans. We mapped genetic determinants of the host response using a panel of 29 closely related mouse strains (AcB/BcA panel of recombinant congenic strains) created from influenza-susceptible A/J and influenza-resistant C57BL/6J (B6) mice. Combined clinical quantitative trait loci (cQTL) and lung expression QTL (eQTL) mapping identified candidate genes for two sex-specific QTLs on chromosomes 2 and 17. The former includes the previously described Hc gene, a deficit of which is associated with the susceptibility phenotype in females. The latter includes the phospholipase gene Pla2g7 and Tnfrsf21, a member of the tumor necrosis factor receptor superfamily. Confirmation of the gene underlying the chromosome 17 QTL may reveal new strategies for influenza treatment.
Mapping of clinical and expression quantitative trait loci in a sex-dependent effect of host susceptibility to mouse-adapted influenza H3N2/HK/1/68.
Age, Specimen part
View SamplesMicroRNAs are 19 to 23 nt RNAs that post-transcriptionally regulate gene expression. Human cells express several hundred miRNAs which regulate important biological pathways such as development, proliferation, and apoptosis. Recently, 12 microRNA genes have been identified within the genome of Kaposis sarcoma-associated herpesvirus; however, their functions are still unknown. To identify host cellular genes that may be targeted by these novel viral regulators, we performed gene expression profiling in cells stably expressing KSHV-encoded miRNAs. Data analysis revealed a set of 81 genes whose expression was significantly changed in the presence of miRNAs. While the majority of changes were below 2-fold, eight genes were down-regulated between 4- and 20-fold. We confirmed miRNA-dependent regulation for three of these genes and found that protein levels of thrombospondin 1 (THBS1) were decreased >10-fold. THBS1 has previously been reported to be down-regulated in KS lesions and has known activity as a strong tumor suppressor and anti-angiogenic factor, exerting its anti-angiogenic effect in part by activating the latent form of TGF-b. We show that reduced THBS1 expression in the presence of viral miRNAs translates into decreased TGF-b activity. These data suggest that KSHV-encoded miRNAs may contribute directly to pathogenesis by down-regulation of THBS1, a major regulator of cell adhesion, migration, and angiogenesis.
Identification of cellular genes targeted by KSHV-encoded microRNAs.
No sample metadata fields
View SamplesMicroRNAs are small, non-coding RNAs that post-transcriptionally regulate gene expression by binding to 3UTRs of target mRNAs. Kaposis sarcoma-associated herpesvirus (KSHV), a virus linked to malignancies including primary effusion lymphoma (PEL), encodes 12 miRNA genes, but only a few regulatory targets are known. We found that KSHV-miR-K12-11 shares 100% seed-sequence homology with hsa-miR-155, a miRNA frequently found up-regulated in lymphomas and critically important for B cell development. Based on this seed-sequence homology, we hypothesized that both miRNAs regulate a common set of target genes and as a result, could have similar biological activities.
Kaposi's sarcoma-associated herpesvirus encodes an ortholog of miR-155.
No sample metadata fields
View SamplesThe fragile X mental retardation protein FMRP is an RNA binding protein that regulates translation of its bound mRNAs through incompletely defined mechanisms. FMRP has been linked to the microRNA pathway and we show here that it is associated with MOV10, a putative helicase that is also associated with the microRNA pathway. We show that FMRP associates with MOV10 in an RNA-dependent manner and facilitates MOV10-association with RNAs in brain. We identified the RNA sequences recognized by MOV10 using iCLIP and found an increased number of G-quadruplexes in the CLIP sites. We provide evidence that MOV10 facilitates microRNA-mediated translation regulation and also has the novel role of increasing the expression of a subset of RNAs by sterically hindering Argonaute2 association. In summary, we have identified a new mechanism for FMRP-mediated translational regulation through its association with MOV10. Overall design: Comparison of MOV10 siRNA knockdown, irrelevant siRNA control and MOV10 overexpression on total RNA levels
MOV10 and FMRP regulate AGO2 association with microRNA recognition elements.
Specimen part, Cell line, Treatment, Subject
View SamplesUsing the iCLIP protocol we have identified the cellular RNA entities that are bound by MOV10. We report the location and sequence of the MOV10 binding region on each RNA entity. Overall design: To identify the RNAs that bound MOV10, we UV-cross-linked HEK293F cells and immunoprecipitated with an irrelevant antibody (ir or "control") followed by a MOV10-specific antibody (MOV10) to isolate associated RNAs after stringent washing.
MOV10 and FMRP regulate AGO2 association with microRNA recognition elements.
No sample metadata fields
View Samples