scholarly journals Effect of the Leptin Receptor Q223R Polymorphism on the Host Transcriptome following Infection with Entamoeba histolytica

2013 ◽  
Vol 81 (5) ◽  
pp. 1460-1470 ◽  
Author(s):  
Nicole M. Mackey-Lawrence ◽  
Xiaoti Guo ◽  
Daniel E. Sturdevant ◽  
Kimmo Virtaneva ◽  
Matthew M. Hernandez ◽  
...  

ABSTRACTResistance to amebiasis is associated with a polymorphism in the leptin receptor. Previous studies demonstrated that humans with the ancestral Q223 leptin receptor allele were nearly four times less likely to be infected withEntamoeba histolyticathan those carrying the mutant R223 allele. We hypothesized that the Q223 allele protected againstE. histolyticavia STAT3-mediated transcription of genes required for mucosal immunity. To test this, mice containing the humanizedLEPRQ or R allele at codon 223 were intracecally infected withE. histolytica. Susceptibility to amebiasis was assessed, and cecal tissues were analyzed for changes in gene expression. By 72 h postchallenge, all Q223 mice had clearedE. histolytica, whereas 39% of 223R mice were infected. Thirty-seven genes were differentially expressed in response to infection at 72 h, including proinflammatory genes (CXCL2,S100A8/9,PLA2G7,ITBG2, andMMP9) and functions pertaining to the movement and activity of immune cells. A comparison at 12 h postchallenge of infected Q223 versus R223 mice identified a subset of differentially expressed genes, many of which were closely linked to leptin signaling. Further analyses indicated that the Q223 gene expression pattern was consistent with a suppressed apoptotic response to infection, while 223R showed increased cellular proliferation and recruitment. These studies are the first to illuminate the downstream effects of leptin receptor polymorphisms on intestinal infection byE. histolytica. As such, they are important for the insight that they provide into this previously uncharacterized mechanism of mucosal immunity.

2019 ◽  
Author(s):  
Adelaide Tovar ◽  
Gregory J. Smith ◽  
Joseph M. Thomas ◽  
Jack R. Harkema ◽  
Samir N. P. Kelada

AbstractExposure to ambient ozone (O3) pollution causes airway inflammation, epithelial injury, and decreased lung function. Long-term exposure is associated with increased mortality and exacerbations of respiratory conditions. While the adverse health effects of O3 exposure have been thoroughly described, less is known about the molecular processes that drive these outcomes. The aim of this study was to describe the cellular and molecular alterations observed in murine airways after exposure to either 1 or 2 ppm O3. After exposing adult, female C57BL/6J mice to filtered air, 1 or 2 ppm O3 for 3 hours, we assessed hallmark responses including airway inflammatory cell counts, epithelial permeability, cytokine secretion, and morphological alterations of the large airways. Further, we performed RNA-seq to profile gene expression in two critical tissues involved in O3 responses: conducting airways (CA) and airway macrophages (AM). We observed a concentration-dependent increase in airway inflammation and injury, and a large number of genes were differentially expressed in both target tissues at both concentrations of O3. Genes that were differentially expressed in CA were generally associated with barrier function, detoxification processes, and cellular proliferation. The differentially expressed genes in AM were associated with innate immune signaling, cytokine production, and extracellular matrix remodeling. Overall, our study has described transcriptional responses to acute O3 exposure, revealing both shared and unique gene expression patterns across multiple concentrations of O3 and in two important O3-responsive tissues. These profiles provide broad mechanistic insight into pulmonary O3 toxicity, and reveal a variety of targets for refined follow-up studies.


2012 ◽  
Vol 78 (6) ◽  
pp. 1865-1875 ◽  
Author(s):  
Anna E. Nikitkova ◽  
Elaine M. Haase ◽  
M. Margaret Vickerman ◽  
Steven R. Gill ◽  
Frank A. Scannapieco

ABSTRACTStreptococcus gordonii, an important primary colonizer of dental plaque biofilm, specifically binds to salivary amylase via the surface-associated amylase-binding protein A (AbpA). We hypothesized that a function of amylase binding toS. gordoniimay be to modulate the expression of chromosomal genes, which could influence bacterial survival and persistence in the oral cavity. Gene expression profiling by microarray analysis was performed to detect genes inS. gordoniistrain CH1 that were differentially expressed in response to the binding of purified human salivary amylase versus exposure to purified heat-denatured amylase. Selected genes found to be differentially expressed were validated by quantitative reverse transcription-PCR (qRT-PCR). Five genes from the fatty acid synthesis (FAS) cluster were highly (10- to 35-fold) upregulated inS. gordoniiCH1 cells treated with native amylase relative to those treated with denatured amylase. AnabpA-deficient strain ofS. gordoniiexposed to amylase failed to show a response in FAS gene expression similar to that observed in the parental strain. Predicted phenotypic effects of amylase binding toS. gordoniistrain CH1 (associated with increased expression of FAS genes, leading to changes in fatty acid synthesis) were noted; these included increased bacterial growth, survival at low pH, and resistance to triclosan. These changes were not observed in the amylase-exposedabpA-deficient strain, suggesting a role for AbpA in the amylase-induced phenotype. These results provide evidence that the binding of salivary amylase elicits a differential gene response inS. gordonii, resulting in a phenotypic adjustment that is potentially advantageous for bacterial survival in the oral environment.


mSystems ◽  
2016 ◽  
Vol 1 (4) ◽  
Author(s):  
John D. Lippolis ◽  
Brian W. Brunelle ◽  
Timothy A. Reinhardt ◽  
Randy E. Sacco ◽  
Tyler C. Thacker ◽  
...  

ABSTRACT Bacteria can exhibit various types of motility. It is known that different types of motilities can be associated with virulence. In this work, we compare gene expression levels in bacteria that were grown under conditions that promoted three different types of E. coli motility. Better understanding of the mechanisms of how bacteria can cause an infection is an important first step to better diagnostics and therapeutics. Bacterial motility is thought to play an important role in virulence. We have previously shown that proficient bacterial swimming and swarming in vitro is correlated with the persistent intramammary infection phenotype observed in cattle. However, little is known about the gene regulation differences important for different motility phenotypes in Escherichia coli. In this work, three E. coli strains that cause persistent bovine mastitis infections were grown in three media that promote different types of motility (planktonic, swimming, and swarming). Using whole-transcriptome RNA sequencing, we identified a total of 935 genes (~21% of the total genome) that were differentially expressed in comparisons of the various motility-promoting conditions. We found that approximately 7% of the differentially expressed genes were associated with iron regulation. We show that motility assays using iron or iron chelators confirmed the importance of iron regulation to the observed motility phenotypes. Because of the observation that E. coli strains that cause persistent infections are more motile, we contend that better understanding of the genes that are differentially expressed due to the type of motility will yield important information about how bacteria can become established within a host. Elucidating the mechanisms that regulate bacterial motility may provide new approaches in the development of intervention strategies as well as facilitate the discovery of novel diagnostics and therapeutics. IMPORTANCE Bacteria can exhibit various types of motility. It is known that different types of motilities can be associated with virulence. In this work, we compare gene expression levels in bacteria that were grown under conditions that promoted three different types of E. coli motility. Better understanding of the mechanisms of how bacteria can cause an infection is an important first step to better diagnostics and therapeutics.


2010 ◽  
Vol 10 (3) ◽  
pp. 373-383 ◽  
Author(s):  
Kelly E. Caudle ◽  
Katherine S. Barker ◽  
Nathan P. Wiederhold ◽  
Lijing Xu ◽  
Ramin Homayouni ◽  
...  

ABSTRACTThe ABC transportersCandida glabrataCdr1 (CgCdr1), CgPdh1, and CgSnq2 are known to mediate azole resistance in the pathogenic fungusC. glabrata. Activating mutations inCgPDR1, a zinc cluster transcription factor, result in constitutive upregulation of these ABC transporter genes but to various degrees. We examined the genomewide gene expression profiles of two matched azole-susceptible and -resistantC. glabrataclinical isolate pairs. Of the differentially expressed genes identified in the gene expression profiles for these two matched pairs, there were 28 genes commonly upregulated withCgCDR1in both isolate sets includingYOR1,LCB5,RTA1,POG1,HFD1, and several members of theFLOgene family of flocculation genes. We then sequencedCgPDR1from each susceptible and resistant isolate and found two novel activating mutations that conferred increased resistance when they were expressed in a common background strain in whichCgPDR1had been disrupted. Microarray analysis comparing these reengineered strains to their respective parent strains identified a set of commonly differentially expressed genes, includingCgCDR1,YOR1, andYIM1, as well as genes uniquely regulated by specific mutations. Our results demonstrate that while CgPdr1 activates a broad repertoire of genes, specific activating mutations result in the activation of discrete subsets of this repertoire.


2018 ◽  
Vol 2018 ◽  
pp. 1-11 ◽  
Author(s):  
Qiyan Wang ◽  
Hui Meng ◽  
Qian Zhang ◽  
Tianjiao Shi ◽  
Xuefeng Zhang ◽  
...  

Danqi pill (DQP) is a widely prescribed traditional Chinese medicine (TCM) in the treatment of cardiovascular diseases. The objective of this study is to systematically characterize altered gene expression pattern induced by myocardial ischemia (MI) in a rat model and to investigate the effects of DQP on global gene expression. Global mRNA expression was measured. Differentially expressed genes among the sham group, model group, and DQP group were analyzed. The gene ontology enrichment analysis and pathway analysis of differentially expressed genes were carried out. We quantified 10,813 genes. Compared with the sham group, expressions of 339 genes were upregulated and 177 genes were downregulated in the model group. The upregulated genes were enriched in extracellular matrix organization, response to wounding, and defense response pathways. Downregulated genes were enriched in fatty acid metabolism, pyruvate metabolism, PPAR signaling pathways, and so forth. This indicated that energy metabolic disorders occurred in rats with MI. In the DQP group, expressions of genes in the altered pathways were regulated back towards normal levels. DQP reversed expression of 313 of the 516 differentially expressed genes in the model group. This study provides insight into the multitarget mechanism of TCM in the treatment of complex diseases.


PeerJ ◽  
2019 ◽  
Vol 7 ◽  
pp. e6388 ◽  
Author(s):  
Asanigari Saleembhasha ◽  
Seema Mishra

Despite years of research, we are still unraveling crucial stages of gene expression regulation in cancer. On the basis of major biological hallmarks, we hypothesized that there must be a uniform gene expression pattern and regulation across cancer types. Among non-coding genes, long non-coding RNAs (lncRNAs) are emerging as key gene regulators playing powerful roles in cancer. Using TCGA RNAseq data, we analyzed coding (mRNA) and non-coding (lncRNA) gene expression across 15 and 9 common cancer types, respectively. 70 significantly differentially expressed genes common to all 15 cancer types were enlisted. Correlating with protein expression levels from Human Protein Atlas, we observed 34 positively correlated gene sets which are enriched in gene expression, transcription from RNA Pol-II, regulation of transcription and mitotic cell cycle biological processes. Further, 24 lncRNAs were among common significantly differentially expressed non-coding genes. Using guilt-by-association method, we predicted lncRNAs to be involved in same biological processes. Combining RNA-RNA interaction prediction and transcription regulatory networks, we identified E2F1, FOXM1 and PVT1 regulatory path as recurring pan-cancer regulatory entity. PVT1 is predicted to interact with SYNE1 at 3′-UTR; DNAJC9, RNPS1 at 5′-UTR and ATXN2L, ALAD, FOXM1 and IRAK1 at CDS sites. The key findings are that through E2F1, FOXM1 and PVT1 regulatory axis and possible interactions with different coding genes, PVT1 may be playing a prominent role in pan-cancer development and progression.


2015 ◽  
Vol 27 (1) ◽  
pp. 117
Author(s):  
R. Cancian ◽  
M. Macelai ◽  
G. Tavares ◽  
R. S. Valente ◽  
E. S. Caixeta ◽  
...  

The cryopreservation of in vitro-produced (IVP) bovine embryos is one of the most challenging areas of the assisted reproductive biotechnologies. The aim of the present study was to evaluate the global gene expression pattern of Bos indicus (Nellore) and Bos taurus (Simmental) IVP embryos after vitrification. Follicular aspiration was performed on Nellore (n = 14) and Simmental (n = 14) cows, and oocytes (n = 840 and 450; respectively) were submitted to in vitro maturation and in vitro fertilization. Presumptive zygotes were denuded and cultured in SOFaa with 0.5% BSA and 2.5% FCS during 7 days under standard culture conditions. Blastocysts (grade 1 and 2) were vitrified, warmed, and cultured for an additional 12 h under the same conditions. Nellore (n = 8) and Simmental (n = 8) IVP blastocysts considered viable after vitrification, with re-expanded blastocoel, were submitted to total RNA extraction (PicoPure, Arcturus, Applied Biosystems®, Foster Dity, CA, USA), DNAse I treatment (Qiagen®, Valencia, CA, USA), and amplification (RiboAmp, Applied Biosystems®). Fragmented cRNA were obtained through 3′IVT Express Kit (Affymetrix®, Santa Clara, CA, USA) to perform the hybridization using GeneChip Bovine Genome Array (Affymetrix®). Microarray data analysis was performed using the FlexArray 1.6.1.1 software. Genes with at least a 1.5-fold change and a P-value of less than 0.05 were considered differentially expressed. Of the 1278 genes differentially expressed between Bos taurus and Bos indicus vitrified embryos, 1108 were annotated, with 1193 genes up-regulated and 85 genes down-regulated in Bos taurus compared with Bos indicus IVP vitrified embryos. Differentially expressed genes were associated with the functional networks of cell cycle, cellular movement and DNA replication, recombination and repair; RNA post-transcriptional modifications; gene expression, protein synthesis; RNA damage and repair; cellular function and maintenance; and cell death and survival. The top 6 canonical pathways generated by Ingenuity Pathway Analysis® with the differentially expressed genes were ELF2 signalling, oxidative phosphorylation, tricarboxylic acid cycle, protein ubiquitination pathway, mTOR signalling, and IGF-1 signalling. In conclusion, Bos taurus IVP embryos seem to trigger different cellular response mechanisms to the vitrification stress in comparison with Bos indicus IVP embryos. Differential response is mainly represented by different expression profiles of genes regulating important canonical pathways involved in cellular response to stress that could be related with the higher post-cryopreservation survival capacity observed in Bos taurus embryos.Research was supported by FAPESP, CNPq, FAPERGS, and LNBio – National Laboratory of Biosciences/MCT.


Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2863-2863
Author(s):  
Ralf Kronenwett ◽  
Elena Diaz-Blanco ◽  
Thorsten Graef ◽  
Ulrich Steidl ◽  
Slawomir Kliszewski ◽  
...  

Abstract In this study, we examined gene expression profiles of immunomagnetically enriched CD34+ cells from bone marrow (BM) of 9 patients with untreated CML in chronic phase and from 8 healthy volunteers using Affymetrix GeneChips. Additionally, in 3 patients CD34+ from peripheral blood (PB) were compared with those from BM. Differential expression of 12 candidate genes was corroborated by quantitative real-time RT-PCR. Following hybridization of labelled cRNA to Affymetrix GeneChips covering 8793 genes we used the statistical scripting language “R” for data analysis. For normalization a method of variance stabilization transformations was used. To identify significantly differentially expressed genes we used the Significance Analysis of Microarrays (SAM) algorithm. The intraindividual comparison of CD34+ cells from BM and PB in CML showed no differentially expressed genes which is different to normal CD34+ cells which had distinct gene expression patterns comparing circulating and sedentary CD34+ cells (Steidl et al., Blood, 2002). Comparing malignant BM CD34+ cells from CML with normal BM CD34+ cells 792 genes were significantly differentially expressed (fold change: >1.3; q-value: <0.03). 735 genes had a higher and 57 genes a lower expression in CML. Gene expression patterns reflected BCR-ABL-induced functional alterations such as increased cell-cycle and proteasome activity as well as decreased apoptosis. Downregulation of several genes involved in DNA repair and detoxification in CML might be the basis for DNA instability and progression to blast crisis. An interesting finding was an upregulation of fetal hemoglobin (Hb) components such as Hb gamma A and G in leukemic progenitor cells whereas no difference in adult Hb expression was observed suggesting an induction of fetal Hb synthesis in CML. Looking at genes involved in stem cell maintenance we found an upregulation of GATA2 and a reduced expression of proteins from the Wnt signalling pathway suggesting an increased self-renewal of CML hematopoietic stem cells compared to the normal counterpart. Moreover, several genes playing a role in ubiquitin-dependent protein catabolism and in fatty acid biosynthesis such as fatty acid synthase (FAS) were stronger expressed in CML. The functional role of FAS for leukemic cell growth was assessed in cell culture experiments. Incubation of the leukemic cell line K562 with the FAS inhibitor cerulenin (10 μg/ml) for 3 days resulted in death of 99% of cells suggesting that survival of leukemic cells depends upon endogenous fatty acid synthesis. In an attempt to find a specific gene expression pattern associated with response to imatinib therapy we divided the patients included in this study into two groups: maximal reduction of BCR-ABL transcript level <3-log vs. >3-log (major molecular remission) during therapy. Comparing pretherapeutic gene expression profiles of both groups we could not identify a pattern predictive for major molecular response. In conclusion, malignant CD34+ cells in CML have a specific gene expression pattern which seems not to be predictive for response to imatinib therapy.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1892-1892
Author(s):  
Alicia Baez ◽  
Jose Ignacio Piruat ◽  
Teresa Caballero-Velazquez ◽  
María Victoria Barbado ◽  
Isabel Alvarez-Laderas ◽  
...  

Abstract Introduction Memory B cells (MBCs) remain viable in a non-proliferative state for years. These cells express genes involved in cell survival and anti-apoptotic factors, while repress the expression of cell cycle regulatory genes. During their differentiation into plasma cells (PCs), these cells develop an opposite gene expression pattern, with a higher expression of genes implicated in cell proliferation and activation, and a lower expression of survival genes. In multiple myeloma (MM) the PCs accumulate into the bone marrow due, at least in part, to failure of pro-apoptotic mechanisms normally expressed in PCs. In the present study we analyzed the gene expression patterns of MBCs and PCs from healthy donors and patients with MM, in order to determine whether or not myelomatous PCs share characteristics of MBCs and/or normal PCs, and to identify possible genes related to the pathophysiology of the disease. Methods MBCs were obtained by immunomagnetic separation from buffy coats of 5 aged healthy donors. Likewise, PCs were isolated from bone marrow of 6 healthy donors and of 5 patients with MM. Using microarray techniques we analyzed the expression of 45000 genes in all samples. We performed unsupervised hierarchical cluster of gene expression data using the average linkage and the Euclidean distance. To identify differentially expressed genes among experimental groups we applied non-parametric Kruskal Wallis test. The differences in expression with a p value < 0.05 were considered significant. All analyses were performed using the Multi-experiment Viewer 4.7.1 software. Results From the hierarchical cluster obtained we clearly identified two groups, one which included normal PCs samples and the other one containing myelomatous PCs and MBCs. Interestingly, myelomatous PCs displayed intermediate features between MBCs and normal PCs (Figure 1). We found 5159 genes differentially expressed between normal and myelomatous PCs. Among these, we identified 3455 genes which displayed a similar expression pattern between MBCs and myelomatous PCs, including caspases inhibitors, MAP kinases, ubiquitins, transcription and translation factors. Conclusion Myelomatous PCs display an intermediate gene expression pattern between normal PCs and MBCs. These cells display high expression of genes involved in cell survival that should be normally inactivated in the transit of MBC to a normal PC, so that its expression pattern is closer to a MBC than a normal PC. Disclosures: No relevant conflicts of interest to declare.


2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Min Li ◽  
Wenye Zhu ◽  
Chu Wang ◽  
Yuanyuan Zheng ◽  
Shibo Sun ◽  
...  

Abstract Background Asthma is a heterogeneous disease that can be divided into four inflammatory phenotypes: eosinophilic asthma (EA), neutrophilic asthma (NA), mixed granulocytic asthma (MGA), and paucigranulocytic asthma (PGA). While research has mainly focused on EA and NA, the understanding of PGA is limited. In this study, we aimed to identify underlying mechanisms and hub genes of PGA. Methods Based on the dataset from Gene Expression Omnibus(GEO), weighted gene coexpression network analysis (WGCNA), differentially expressed genes (DEGs) analysis and protein–protein interaction (PPI) network analysis were conducted to construct a gene network and to identify key gene modules and hub genes. Functional enrichment analyses were performed to investigate the biological process, pathways and immune status of PGA. The hub genes were validated in a separate dataset. Results Compared to non-PGA, PGA had a different gene expression pattern, in which 449 genes were differentially expressed. One gene module significantly associated with PGA was identified. Intersection between the differentially expressed genes (DEGs) and the genes from the module that were most relevant to PGA were mainly enriched in inflammation and immune response regulation. The single sample Gene Set Enrichment Analysis (ssGSEA) suggested a decreased immune infiltration and function in PGA. Finally six hub genes of PGA were identified, including ADCY2, CXCL1, FPRL1, GPR109B, GPR109A and ADCY3, which were validated in a separate dataset of GSE137268. Conclusions Our study characterized distinct gene expression patterns, biological processes and immune status of PGA and identified hub genes, which may improve the understanding of underlying mechanism and provide potential therapeutic targets for PGA.


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