Comparative DNA Microarray Analysis of Host Cell Transcriptional Responses to Infection by <i>Coxiella burnetii</i> or <i>Chlamydia trachomatis</i>

Ren, Qun; Robertson, Shelly J.; Howe, Dale; Barrows, Lorraine F.; Heinzen, Robert A.

doi:10.1111/j.1749-6632.2003.tb07447.x

Cited by 55 publications

(51 citation statements)

References 5 publications

(5 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Surprisingly, LM10 treatment also promoted better rejection of control clone P815B cl1, which does not express TDO. One explanation for this might be the expression of TDO by macrophages at the tumor site, as activation of macrophages by phorbol esters or intracellular infection was shown to induce TDO expression (18,19). We confirmed expression of TDO2 mRNA in F4/80 + macrophages isolated from the peritoneal cavity of both control mice and immunized mice carrying ascitic P815B cl1 tumor cells (Fig.…”

Section: Resultssupporting

confidence: 66%

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

Pilotte

Larrieu

Stroobant

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

506

532

View full text Add to dashboard Cite

Tryptophan catabolism mediated by indoleamine 2,3-dioxygenase (IDO1) is an important mechanism of peripheral immune tolerance contributing to tumoral immune resistance, and IDO1 inhibition is an active area of drug development. Tryptophan 2,3-dioxygenase (TDO) is an unrelated hepatic enzyme that also degrades tryptophan along the kynurenine pathway. Here, we show that enzymatically active TDO is expressed in a significant proportion of human tumors. In a preclinical model, TDO expression by tumors prevented their rejection by immunized mice. We developed a TDO inhibitor, which, upon systemic treatment, restored the ability of mice to reject TDO-expressing tumors. Our results describe a mechanism of tumoral immune resistance based on TDO expression and establish proof-of-concept for the use of TDO inhibitors in cancer therapy.T ryptophan 2,3-dioxygenase (TDO) is a homotetrameric hemecontaining cytosolic enzyme encoded by gene TDO2 and expressed at high levels in the liver. It catalyses the first and ratelimiting step of tryptophan degradation along the kynurenine pathway and thereby regulates systemic tryptophan levels. The same reaction can be catalyzed by another heme-containing cytosolic enzyme, named indoleamine 2,3-dioxygenase (IDO1), which has no sequence similarity with TDO, is not expressed in the liver, and is monomeric. IDO1 has been the focus of attention in recent years because of its immunosuppressive effects on T lymphocytes, resulting partly from tryptophan depletion and partly from direct effects of tryptophan catabolites (1-3). IDO1 is expressed constitutively in the placenta, where it plays a key role in feto-maternal tolerance (2), and in many tumors, where it contributes to tumoral resistance to immune rejection (4-7). IDO1 expression is also inducible in many cells, including dendritic cells, and appears to play a role in peripheral immune tolerance and the retro-control of immune responses (8). In contrast, little is known about the effect of TDO expression on the immune response. A recent report indicated that human cells transfected with TDO depleted tryptophan and thereby prevented both the growth of pathogens and the proliferation of allogeneic T lymphocytes (9). These results suggested that TDO might mediate immunosuppressive effects similar to those of IDO1. We set out to examine whether tumor cells express TDO and thereby inhibit T-cell-mediated immune responses. ResultsWe first observed that many human tumor samples expressed gene TDO2 as measured by real-time RT-PCR (Table 1). This was the case for 41% of bladder carcinomas, 50% of melanomas and 100% of hepatocarcinomas. To confirm the activity of TDO in tumor cells, we selected a series of human tumor cell lines that also expressed the TDO2 mRNA. We incubated cells for 24 h in medium containing a known concentration of tryptophan, and measured by HPLC in the supernatant the concentration of tryptophan and kynurenine, which is the main tryptophan catabolite (Table 2). HEK-293 cells transfected or not with human TDO2 were used as pos...

show abstract

Section: Resultssupporting

confidence: 66%

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

Pilotte

Larrieu

Stroobant

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

506

532

View full text Add to dashboard Cite

show abstract

“…Fractalkine (CX3CL1), a ␦-chemokine expressed by epithelial cells, DC, and some T cells, was upregulated, and its expression in response to chlamydial infection has not been described before. Induction of CXCR3, -4, and -6 was also observed and is consistent with the recruitment of T cells, NK cells, monocytes, macrophages, and neutrophils (7,47,66). The increased expression of CXCR6 in chlamydial infection has not been previously identified.…”

Section: Vol 78 2010supporting

confidence: 55%

“…Gene expression profiling studies have used a variety of array platforms to study the host response to chlamydial infection (2,18,32,43,44,47,64,66,70,86,89,93). With the exception of two recent studies (43,64), each has described the in vitro response in experimentally infected cell lines or cells isolated from tissue.…”

mentioning

confidence: 99%

Human Conjunctival Transcriptome Analysis Reveals the Prominence of Innate Defense inChlamydia trachomatisInfection

et al. 2010

View full text Add to dashboard Cite

Trachoma is the leading infectious cause of blindness and is endemic in 52 countries. There is a critical need to further our understanding of the host response during disease and infection, as millions of individuals are still at risk of developing blinding sequelae. Infection of the conjunctival epithelial cells by the causative bacterium, Chlamydia trachomatis, stimulates an acute host response. The main clinical feature is a follicular conjunctivitis that is incompletely defined at the tissue-specific gene expression and molecular levels. To explore the features of disease and the response to infection, we measured host gene expression in conjunctival samples from Gambian children with active trachoma and healthy controls. Genome-wide expression and transcription network analysis identified signatures characteristic of the expected infiltrating immune cell populations, such as neutrophils and T/B lymphocytes. The expression signatures were also significantly enriched for genes in pathways which regulate NK cell activation and cytotoxicity, antigen processing and presentation, chemokines, cytokines, and cytokine receptors. The data suggest that in addition to polymorph and adaptive cellular responses, NK cells may contribute to a significant component of the conjunctival inflammatory response to chlamydial infection.

show abstract

“…However, as intracellular pathogens have been shown to subvert many host cell functions (64), an alternative approach for understanding the pathogenic strategies utilized by these organisms would be to look at changes in the host cell gene expression profile following infection. In the case of A. phagocytophilum, we have previously shown by use of macroarray analysis that the bacterium causes repression of rac2 mRNA expression in human promyelocytic HL-60 cells, with a resulting influence on the host cell capacity to generate a respiratory burst (12).…”

mentioning

confidence: 99%

Early Transcriptional Response of Human Neutrophils toAnaplasma phagocytophilumInfection

et al. 2005

View full text Add to dashboard Cite

Anaplasma phagocytophilum, an unusual obligate intracellular pathogen that persists within neutrophils, causes human anaplasmosis (previously known as human granulocytic ehrlichiosis). To study the effects of this pathogen on the transcriptional profile of its host cell, we performed a comprehensive DNA microarray analysis of the early (4-h) transcriptional response of human neutrophils to A. phagocytophilum infection. A. phagocytophilum infection resulted in the up-and down-regulation of 177 and 67 neutrophil genes, respectively. These data were verified by quantitative reverse transcription-PCR of selected genes. Notably, the up-regulation of many antiapoptotic genes, including the BCL2A1, BIRC3, and CFLAR genes, and the down-regulation of the proapoptotic TNFSF10 gene were observed. Genes involved in inflammation, innate immunity, cytoskeletal remodeling, and vesicular transport also exhibited differential expression. Vascular endothelial growth factor was also induced. These data suggest that A. phagocytophilum may alter selected host pathways in order to facilitate its survival within human neutrophils. To gain further insight into the bacterium's influence on host cell gene expression, this report presents a detailed comparative analysis of our data and other gene expression profiling studies of A. phagocytophilum-infected neutrophils and promyelocytic cell lines.

show abstract

Comparative DNA Microarray Analysis of Host Cell Transcriptional Responses to Infection by Coxiella burnetii or Chlamydia trachomatis

Cited by 55 publications

References 5 publications

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

Reversal of tumoral immune resistance by inhibition of tryptophan 2,3-dioxygenase

Human Conjunctival Transcriptome Analysis Reveals the Prominence of Innate Defense inChlamydia trachomatisInfection

Early Transcriptional Response of Human Neutrophils toAnaplasma phagocytophilumInfection

Contact Info

Product

Resources

About