Microarray Analysis Reveals Previously Unknown Changes in Toxoplasma gondii-infected Human Cells

Blader, Ira J.; Manger, Ian D.; Boothroyd, John C.

doi:10.1074/jbc.m100951200

Cited by 248 publications

(308 citation statements)

References 42 publications

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“…Nevertheless, it is known that the (13) and that T. gondii is dependent on cholesterol derived from the host (3,5). It is well known that lower intracellular levels of cholesterol stimulate the endogenous synthesis of cholesterol and enhance expression of LDL (B/E) receptor expression and, consequently, lipoprotein endocytosis and internalization of blood VLDL and LDL cholesterol.…”

Section: Discussionmentioning

confidence: 99%

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Portugal¹,

Fernandes²,

César³

et al. 2004

Infect Immun

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Toxoplasma gondii is an intracellular protozoan that elicits a potent inflammatory response during the acute phase of infection. Herein, we evaluate whether T. gondii infection alters the natural course of aortic lesions. ApoE knockout mice were infected with T. gondii, and at 5 weeks of infection, serum, feces, and liver cholesterol; aortic lesion size, cellularity, and inflammatory cytokines; and levels of serum nitrite and gamma interferon (IFN-␥) were analyzed. Our results showed that serum cholesterol and atherogenic lipoproteins were reduced after T. gondii infection. The reduction of serum levels of total cholesterol and atherogenic lipoproteins was associated with increases in the aortic lesion area, numbers of inflammatory cells, and expression of monocyte chemoattractant protein 1 and inducible nitric oxide synthase mRNA in the site of lesions as well as elevated concentrations of IFN-␥ and nitrite in sera of T. gondii-infected animals. These results suggest that infection with T. gondii accelerates atherosclerotic development by stimulating the proinflammatory response and oxidative stress, thereby increasing the area of aortic lesion.Atherosclerotic lesions are characterized by progressive accumulation of lipids, macrophages, natural killer (NK) cells, T and B cells, smooth muscle cells, and fibroproliferative elements in the intima of arteries (30). However, hypercholesterolemia and, mainly, high serum levels of low-density lipoprotein (LDL) are considered an absolute prerequisite for lesion establishment. Several genetic and environmental risk factors have been found to contribute to the development of atherosclerosis (2,22,27,33). Among these factors, the immune system is one of the most important. Innate and adaptive immune responses modulate both the rate of lesion progression and composition of atherosclerotic lesions. ApoE knockout (KO) mice crossed into a recombination activating gene (Rag)-deficient background, which lack B and T lymphocytes, had an 80% decrease in the extension of atherosclerotic lesions (32). In addition, crosses of ApoE KO mice with different types of B-or T-cell-deficient mice also decreased atherosclerotic lesions (2,22,40). Inflammatory cytokines and chemokines, such as gamma interferon (IFN-␥), tumor necrosis factor alpha (TNF-␣), TNF-␤, interleukin-12 (IL-12), IL-1␤, and monocyte chemoattractant protein 1 (MCP-1), increase the influx of monocyte into the endothelium, an important step in fatty streak formation (21,24,39). Therefore, atherosclerosis is now considered a chronic inflammatory disease, and systemic infections are thought to play an important role in initiating and/or perpetuating the pathophysiology of aortic lesions. In fact, some studies indicate that bacterial and viral pathogens could be responsible for atherosclerotic development (35). Sunnemark et al. (37) have shown that the combination of an infection of the protozoan parasite Trypanosoma cruzi with an atherogenic diet induced atherosclerotic lesions in the aorta of atherosclerosis-resistant CBA/...

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Section: Discussionmentioning

confidence: 99%

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Portugal¹,

Fernandes²,

César³

et al. 2004

Infect Immun

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“…Early experience with small-scale arrays has demonstrated the potential value of this approach for studying gene expression in parasites [16][17][18][19]. We now report production and use of the first large-scale oligonucleotide microarray for a nematode parasite.…”

Section: Introductionmentioning

confidence: 95%

Profiling of gender-regulated gene transcripts in the filarial nematode Brugia malayi by cDNA oligonucleotide array analysis

Rush

Crosby

et al. 2005

Molecular and Biochemical Parasitology

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Microarray technology permits high-throughput comparisons of gene expression in different parasite stages or sexes and has been used widely. We report the first use of this technology for analysis of gene expression in filarial male and female worms. The slide array (comprised of 65-mer oligos representing 3569 EST clusters) was spotted with sequences selected from the extensive Brugia malayi EST database (http://zeldia.cap.ed.ac.uk/fgn/brugia.php). Arrays were hybridized with Cy dye labeled male and female cDNA. The experimental design included both biological and technical (dye-flip) replicates. The data were normalized for background and probe intensity, and the relative abundance of hybridized cDNA for each spot was determined. Genes showing two-fold or greater differences with P < 0.05 were considered gender-regulated candidates. One thousand one hundred and seventy of 2443 clusters (48%) with signals above threshold in at least one sex were considered as gender-regulated gene candidates. This included 520 and 650 clusters up-regulated in male and female worms, respectively. Fifty of 53 (94%) gender-regulated candidate genes identified by microarray analysis were confirmed by real-time RT-PCR. Approximately 61% of gender-regulated genes had significant similarity to known genes in other organisms such as Caenorhabditis elegans. Many C. elegans homologues of these genes have been reported to have reproductive phenotypes (sterility or abnormal embryo development) by RNA interference. This study has provided the first broad view of gender-regulated gene expression in B. malayi; this should lead to improved understanding of reproduction in filarial nematodes. More generally, this approach holds great promise as a means of studying stage-specific or tissue-specific gene expression in parasitic nematodes.

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“…The recent application of oligonucleotide and cDNA microarray technologies toward the study of host-pathogen interactions has permitted rapid and unbiased examination of changes in expression of a large number of genes at the transcript level (2). Microarray analysis of host cell gene expression following infection with viral (3-7), bacterial (8 -12), fungal (13), and protozoan (14) pathogens has revealed complex and diverse transcriptional responses to these infectious agents. Data bases generated from these, and future, studies will provide an invaluable resource for the functional characterization of host cell pathways required to facilitate pathogen survival and for the further understanding of host defense mechanisms (1,15,16).…”

mentioning

confidence: 99%

Immediate/Early Response to Trypanosoma cruzi Infection Involves Minimal Modulation of Host Cell Transcription

Avalos¹,

Blader²,

Fisher³

et al. 2002

Journal of Biological Chemistry

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114

108

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Host cell infection by the intracellular pathogen, Trypanosoma cruzi, involves activation of signaling pathways, cytoskeletal reorganization, and targeted recruitment of host cell lysosomes. To determine the consequences of T. cruzi invasion on host cell gene expression, high density microarrays consisting of ϳ27,000 human cDNAs were hybridized with fluorescent probes generated from T. cruzi-infected human fibroblasts (HFF) at early time points following infection (2-24 h). Surprisingly, no genes were induced >2-fold in HFF between 2 and 6 h post-infection (hpi) in repeated experiments while immediate repression of six host cell transcripts was observed. A significant increase in transcript abundance for 106 host cell genes was observed at 24 hpi. Among the most highly induced is a set of interferon-stimulated genes, indicative of a type I interferon (IFN) response to T. cruzi. In support of this, T. cruzi-infected fibroblasts begin to secrete IFN␤ at 18 hpi following the induction of IFN␤ transcripts. As compared with global transcriptional responses evoked by other intracellular pathogens, T. cruzi is a stealth parasite that elicits few changes in host cell transcription during the initiation of infection.Global transcriptional responses elicited in mammalian cells by pathogenic organisms are predicted to provide a unique signature of the particular interaction (1). The recent application of oligonucleotide and cDNA microarray technologies toward the study of host-pathogen interactions has permitted rapid and unbiased examination of changes in expression of a large number of genes at the transcript level (2). Microarray analysis of host cell gene expression following infection with viral (3-7), bacterial (8 -12), fungal (13), and protozoan (14) pathogens has revealed complex and diverse transcriptional responses to these infectious agents. Data bases generated from these, and future, studies will provide an invaluable resource for the functional characterization of host cell pathways required to facilitate pathogen survival and for the further understanding of host defense mechanisms (1,15,16).Trypanosoma cruzi is a hemoflagellate protozoan parasite that causes Chagas' disease in humans. Key steps in the pathogenesis of disease include host cell penetration by T. cruzi and replication in the host cell cytoplasm. Host cell invasion, which is initiated following attachment of motile T. cruzi trypomastigotes to the host cell surface, is a slow, active process requiring ϳ5-10 min for completion (17). Parasite internalization coincides with the formation of a nascent parasitophorous vacuole, generated as a result of targeted fusion of host cell lysosomes with the plasma membrane (18). Signaling pathways that are rapidly activated in both the host cell and the parasite are known to regulate T. cruzi entry into mammalian cells. To further dissect the molecular events regulating early T. cruzi-host cell interactions, we have employed cDNA microarray hybridization to define the temporal host cell transcriptional respon...

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Microarray Analysis Reveals Previously Unknown Changes in Toxoplasma gondii-infected Human Cells

Cited by 248 publications

References 42 publications

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Infection withToxoplasma gondiiIncreases Atherosclerotic Lesion in ApoE-Deficient Mice

Profiling of gender-regulated gene transcripts in the filarial nematode Brugia malayi by cDNA oligonucleotide array analysis

Immediate/Early Response to Trypanosoma cruzi Infection Involves Minimal Modulation of Host Cell Transcription

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