Chlamydia trachomatis Infection Alters Host Cell Transcription in Diverse Cellular Pathways
Identifieur interne : 001D33 ( Istex/Corpus ); précédent : 001D32; suivant : 001D34Chlamydia trachomatis Infection Alters Host Cell Transcription in Diverse Cellular Pathways
Auteurs : Minsheng Xia ; Roger E. Bumgarner ; Mary F. Lampe ; Walter E. StammSource :
- The Journal of Infectious Diseases [ 0022-1899 ] ; 2003.
Abstract
To study the responses of the host cell to chlamydial infection, differentially transcribed genes of the host cells were examined. Complementary DNA (cDNA) probes were made from messenger RNAs of HeLa cells infected with Chlamydia trachomatis and were hybridized to a high-density human DNA microarray of 15,000 genes and expressed sequence tags. C. trachomatis alters host cell transcription at both the early and middle phases of its developmental cycle. At 2 h after infection, 13 host genes showed mean expression ratios ⩾2-fold. At 16 h after infection, 130 genes were differentially transcribed. These genes encoded factors inhibiting apoptosis and factors regulating cell differentiation, components of the cytoskeleton, transcription factors, and proinflammatory cytokines. This indicates that chlamydial infection, despite its intravacuolar location, alters the transcription of a broad range of host genes in diverse cellular pathways and provides a framework for future studies
Url:
DOI: 10.1086/367962
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ISTEX:107815330731AB44F26BF06CA7B7C580A248CC87Le document en format XML
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[6]</json:string></ref_bibl><bibl></bibl></unitex></namedEntities><ark><json:string>ark:/67375/HXZ-82VKJZX9-N</json:string></ark><categories><wos><json:string>1 - science</json:string><json:string>2 - microbiology</json:string><json:string>2 - infectious diseases</json:string><json:string>2 - immunology</json:string></wos><scienceMetrix><json:string>1 - health sciences</json:string><json:string>2 - biomedical research</json:string><json:string>3 - microbiology</json:string></scienceMetrix><scopus><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Infectious Diseases</json:string><json:string>1 - Health Sciences</json:string><json:string>2 - Medicine</json:string><json:string>3 - Immunology and Allergy</json:string></scopus><inist><json:string>1 - sciences appliquees, technologies et medecines</json:string><json:string>2 - sciences biologiques et medicales</json:string><json:string>3 - sciences biologiques fondamentales et appliquees. 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<journal-title>The Journal of Infectious Diseases</journal-title>
<abbrev-journal-title>The Journal of Infectious Diseases</abbrev-journal-title>
<issn pub-type="ppub">0022-1899</issn>
<issn pub-type="epub">1537-6613</issn>
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<subject>Bacteria</subject>
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<title-group>
<article-title><italic>Chlamydia trachomatis</italic> Infection Alters Host Cell Transcription in Diverse Cellular Pathways<xref ref-type="fn" rid="fn1"></xref></article-title></title-group>
<contrib-group>
<contrib contrib-type="author">
<name><surname>Xia</surname>
<given-names>Minsheng</given-names></name>
<xref ref-type="aff" rid="aff1">1</xref></contrib>
<contrib contrib-type="author">
<name><surname>Bumgarner</surname>
<given-names>Roger E.</given-names></name>
<xref ref-type="aff" rid="aff2">2</xref></contrib>
<contrib contrib-type="author">
<name><surname>Lampe</surname>
<given-names>Mary F.</given-names></name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="aff" rid="aff3">3</xref></contrib>
<contrib contrib-type="author" corresp="yes">
<name><surname>Stamm</surname>
<given-names>Walter E.</given-names></name>
<xref ref-type="aff" rid="aff1">1</xref></contrib>
<aff id="aff1">
<label>1</label>Division of Infectious Diseases, Department of Medicine,</aff>
<aff id="aff2">
<label>2</label>Center for Expression Arrays, and</aff>
<aff id="aff3">
<label>3</label>Department of Laboratory Medicine, University of Washington, Seattle</aff></contrib-group>
<author-notes>
<corresp id="cor1">Reprints or correspondence: Dr. Walter E. Stamm, 1959 NE Pacific St., University of Washington, Box 356523, Seattle, WA 98195 (<email>wes@u.washington.edu</email>)</corresp></author-notes>
<pub-date pub-type="ppub">
<day>1</day>
<month>2</month>
<year>2003</year></pub-date>
<volume>187</volume>
<issue>3</issue>
<fpage>424</fpage>
<lpage>434</lpage>
<history>
<date date-type="received">
<day>15</day>
<month>8</month>
<year>2002</year></date>
<date date-type="rev-recd">
<day>16</day>
<month>10</month>
<year>2002</year></date></history>
<copyright-statement>© 2003 by the Infectious Diseases Society of America</copyright-statement>
<copyright-year>2003</copyright-year>
<abstract>
<p>To study the responses of the host cell to chlamydial infection, differentially transcribed genes of the host cells were examined. Complementary DNA (cDNA) probes were made from messenger RNAs of HeLa cells infected with <italic>Chlamydia trachomatis</italic> and were hybridized to a high-density human DNA microarray of 15,000 genes and expressed sequence tags. <italic>C. trachomatis</italic> alters host cell transcription at both the early and middle phases of its developmental cycle. At 2 h after infection, 13 host genes showed mean expression ratios ⩾2-fold. At 16 h after infection, 130 genes were differentially transcribed. These genes encoded factors inhibiting apoptosis and factors regulating cell differentiation, components of the cytoskeleton, transcription factors, and proinflammatory cytokines. This indicates that chlamydial infection, despite its intravacuolar location, alters the transcription of a broad range of host genes in diverse cellular pathways and provides a framework for future studies</p></abstract></article-meta></front>
<body>
<p>Chlamydiae are obligate intracellular bacteria capable of infecting a wide range of eukaryotic cells, propagating through a unique biphasic developmental cycle that alternates between the infectious extracellular metabolically inert elementary body (EB) and the noninfectious intracellular metabolically active reticulate body (RB). Clinically, <italic>Chlamydia trachomatis</italic> causes a variety of ocular, respiratory, and genitourinary infections in humans. The organism infects mucosal epithelial cells of the eyes, causing trachoma, a major cause of preventable blindness in much of the developing world. It also is the most common bacterial sexually transmitted disease in both industrialized and developing countries and often leads to significant sequelae in women, including pelvic inflammatory disease, ectopic pregnancy, and infertility. It has been hypothesized that chlamydial diseases result primarily from host-derived inflammation, tissue damage, and subsequent immunopathologic processes. Pathologically, the infection site is first infiltrated by polymorphonuclear neutrophils and later by aggregations of mononuclear cells [<xref ref-type="bibr" rid="ref1">1</xref>, <xref ref-type="bibr" rid="ref2">2</xref>]. However, the role of the primarily infected host cells in initiating this pathologic process has not been well defined. Previous studies examining host responses have focused on cytokines and have indicated that cytokine expression is an important part of the host reaction [<xref ref-type="bibr" rid="ref3">3</xref><xref ref-type="bibr" rid="ref4"></xref>–<xref ref-type="bibr" rid="ref5">5</xref>]. To expand the scope of host gene responses examined, a recent study by Hess et al. [<xref ref-type="bibr" rid="ref6">6</xref>] that used 1176 microarray-screened genes found altered gene expression of cytokines, transcription factors, and antiapoptotic genes. To more fully define altered gene expression in <italic>C. trachomatis</italic>–infected cells, we performed a microarray study screening 15,000 host genes to define the extent and magnitude of transcriptional changes at the early and middle stages of infection. Specifically, we determined host cell transcriptional changes during the early (2 h after infection) and the middle (16 h after infection) stages of the <italic>C. trachomatis</italic> developmental cycle by use of a high-density cDNA microarray that carried the <italic>Homo sapiens</italic> 15K sequence verified set derived from the human cDNA Integrated Molecular Analysis of Genomes and Expression (I.M.A.G.E.) collection [<xref ref-type="bibr" rid="ref7">7</xref>] from Research Genetics. The gene list can be found at the University of Washington Center for Expression Arrays Web site (<ext-link ext-link-type="uri" xlink:href="http://ra.microslu.washington.edu/Website/index.html">http://ra.microslu.washington.edu/Website/index.html</ext-link>). This array was used to hybridize with fluorescence-labeled probes generated from <italic>C. trachomatis</italic>–infected HeLa cells. We found that the profiles of altered host cell transcription in the early and middle stages of the infection were distinctive in both quantitative and qualitative terms. Chlamydia-induced differentially transcribed host genes fell into several functional categories, including transcription, signal transduction, immunity, inflammation, cell structure/cytoskeleton, cell proliferation/differentiation, and apoptosis. In addition, several previously described cancer-related genes also were found to be up-regulated. Further analysis of host transcriptional responses to <italic>C. trachomatis</italic> infection by microarray hybridization will provide insights into chlamydial pathogenesis</p>
<sec id="S1">
<title>Materials and Methods</title>
<p><bold><italic>Bacterial strain, cell lines, and time course of infection</italic></bold><italic>C. trachomatis</italic> biovar LGV L2/434/Bu was cultured in McCoy cells and were purified as described elsewhere [<xref ref-type="bibr" rid="ref8">8</xref>]. To ensure consistency in inoculation quantity and organism viability, we prepared large batches of purified <italic>C. trachomatis</italic> EBs of L2 serovar (L2/434/Bu) frozen at −70°C in a 5×10<sup>7</sup> inclusion-forming units/mL concentration in 1-mL aliquot as stock. Only freshly thawed EBs in sucrose phosphate glutamate buffer (SPG) were used for inoculation, and leftovers were not frozen and reused. HeLa 229 cells at 85% confluence in culture flasks were statically infected with purified <italic>C. trachomatis</italic> L2. A control plate was set up for each time course inoculation, to ensure that >90% infectivity was achieved. After 1 h of absorption at a 37°C in a 5% CO<sub>2</sub> environment, minimal essential medium supplemented with Earle’s salts, 10% fetal bovine serum, and 2 m<italic>M</italic><sc>l</sc>-glutamine was added to the culture flask. The culture was incubated at 37°C in a 5% CO<sub>2</sub> atmosphere and was terminated at 2 or 16 h after infection by decanting the flask. Control HeLa cells were mock infected with SPG in the absence of EB. To screen for differentially transcribed genes, mRNAs extracted from the samples at 2 or 16 h after infection were compared with mRNAs extracted from the mock-infected controls at the same time points</p>
<p><bold><italic>Total RNA and Poly(A)</italic></bold><sup><bold><italic>+</italic></bold></sup><bold><italic> purification</italic></bold> Total RNA was extracted from both samples and control samples by use of Trizol (Gibco) and RNeasy Kit (Qiagen), according to the manufacturers’ instructions. Cell lysate was homogenized by passing a 21-gauge needle 10 times. The total RNA was treated with RNase-free DNase and was purified further by use of RNeasy column. The integrity of total RNA preparations were assessed by means of the Bioanalyzer 2100 instrument (Agilent), and only RNA that passed Bioanalyzer analysis was used to proceed to poly(A)<sup>+</sup> eukaryotic RNA purification. Poly(A)<sup>+</sup> RNA was extracted from total RNA by use of the Oligotex kits (Qiagen), according to the manufacturer’s instructions. The poly(A)<sup>+</sup> RNA was further precipitated with linear acrylamide (Ambion) in 0.2 <italic>M</italic> LiCl and ethanol at −20°C overnight. After centrifugation at 4°C and 16,000 <italic>g</italic> for 30 min, the pellet was washed with 75% ethanol, air dried, and resuspended to 1.0 μg/μL in RNase-free water. The purified poly(A)<sup>+</sup> RNA preparations were further checked with the Bioanalyzer 2100 for possible mRNA degradation</p>
<p><bold><italic>Microarray, fluorescence-labeled probe, and hybridization</italic></bold> A high-density human cDNA microarray was constructed at the University of Washington Center for Expression Arrays. This array contains the 15,000 known <italic>Homo sapiens</italic> genes and expressed sequence tags (ESTs), as well as nonhuman genes as negative controls. PCR-amplified DNA were deposited in duplicate on two 7.5×2.5–cm type VII mirrored glass slides (Amersham Biosciences) by use of a Molecular Dynamics Generation III Arrayer. Cy3-dCTP– and Cy5-dCTP–labeled cDNA probes were synthesized through reverse transcription. Two micrograms of mRNA from <italic>C. trachomatis</italic> L2–infected HeLa cells, primed by 8 pmol of anchored dT primer and 1 μg of random 9-mer, were mixed in a 10.5-μL reaction volume. The reaction mix was incubated at 70°C for 10 min, briefly chilled on ice, and centrifuged. Reverse transcription was carried out in a 20-μL reaction volume with final concentration of 1× first-strand buffer (Life Technologies), 10 m<italic>M</italic> Cy3-dCTP or Cy5-dCTP, and 0.5 U of Rnasin (Promega). Subsequently, 200 U reverse transcriptase (Life Technologies) were added to the reaction mix and incubated at 42°C for 2 h. The resulting RNA-cDNAs were hydrolyzed by sodium hydroxide and were neutralized by 4-morpholine-propanesulfonic acid. Purified cDNAs were analyzed for Cy3-dCTP or Cy5-dCTP labeling by scanning the probe from wavelength 210 to 700 nm with Shimadzu UV/Vis spectrophotometer. Labeled cDNAs were quantified by absorption at 260 nm, and the dye incorporation rate was quantified by absorption at 550 (for Cy3) and 649 nm (for Cy5). These probes were purified further by use of the G-50 ProbeQuant columns, according to the manufacturer’s instructions (AP Biotech), and were dried in SpeedVac. Probes were resuspended in 40 μL, combined, applied to the microarrays, and hybridized in 50% formamide for 14 h at 42°C under a glass cover slip. RT-PCR was used to confirm data on selected genes from the microarray analysis</p>
<p><bold><italic>Data analysis and criteria for selecting differentially expressed genes</italic></bold>To control bias due to differences in labeling efficiencies of Cy3 and Cy5, for each experiment, <italic>C. trachomatis</italic>–infected HeLa mRNA and control HeLa mRNA were labeled with reversed Cy dye and by using 2 sets of slides. The first set was hybridized to Cy-3–labeled experimental cDNA and Cy-5–labeled control cDNA; the second set was hybridized to Cy-5–labeled experimental cDNA and Cy-3–labeled control cDNA. Because each DNA element was spotted in duplicate, the hybridization intensity of each gene was thus measured 4 times per experiment. The Cy3:Cy5 ratios were calculated by use of a computer program developed at the Center for Expression Array [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref10">10</xref>]. The program normalizes the data, rejects outliers, and calculates the mean and SDs for replicate measurements. Nonlinearities in the Cy3:Cy5 ratio as a function of signal intensity were taken into account. A normalization factor was used for expression ratios so that the median Cy3:Cy5 ratio is 1 over all intensity ranges. Only those spots with a hybridization signal intensity >500 fluorescence units for both Cy3 and Cy5 were used for calculating expression ratios, because signals below this level are not reliably quantified [<xref ref-type="bibr" rid="ref9">9</xref>, <xref ref-type="bibr" rid="ref10">10</xref>]. Genes of expression ratio ⩾2-fold at the P<.05 significance level were regarded as differentially transcribed genes. The <italic>P</italic> value was calculated by assuming a normal distribution of the logarithmically transformed expression ratios</p>
<p><bold><italic>Confirmation of microarray results by use of RT-PCR</italic></bold> To verify the microarray results, RT-PCR was carried out on 6 host genes that were up-regulated at 16 h after infection. Total RNA was prepared as described above. cDNAs were made from a single-round reverse transcription process. The reverse-transcription reactions were carried out at 42°C for 1 h with 1 μg total RNAs with 1 μg random 9-mers, 1 μg oligo(dT)<sub>25</sub> 5 m<italic>M</italic> dNTPs, 10 m<italic>M</italic> dithiothreitol, 50 U of Rnasin (Promega), and 200 U of Superscript II in 20 mL of 1× first-strand buffer (Life Technologies). Subsequent PCR was carried out in a 50-μL reaction volume that contained 1 μL of the reverse-transcription reaction mixture, 10 pmol each of the gene-specific primers, 0.5 m<italic>M</italic> QuantumRNA 18S internal control (Ambion), 5% dimethyl sulfoxide, 1.5 m<italic>M</italic> MgCl<sub>2</sub>, and 1 U <italic>Taq</italic> DNA polymerase (Life Technologies) in 1× buffer. The 6 host genes and their PCR primer sequences (in 5′→3′ order) are as follows: (1) B cell translocation gene forward, CTGTTCAGGCTTCTCCCAAG; reverse, TCGTTCTGCCCAAGAGAAGT; (2) early-growth response protein forward, GTTATGAAGGCAAAGAAAATGAGG; reverse, TGTTCAGAGAGATGTCAGGAAAAG; (3) interleukin (IL)–1β forward, GATTCTCTTCAGCCAATCTTCATT; reverse, GGAAGGAGCACTTCATCTGTTTAG; (4) immediate-early response 3 forward, TGCAGGTCTCTTGGTATTTATTGA; reverse, ACACAGTAGACAGACGGAGTTGAG; (5) insulin-like growth factor binding protein forward, AAGTAATTGCATTTCTGCTCTTCC; reverse, CTTTCCCTACACATGTACATCCAA; and (6) induced myeloid leukemia cell differentiation protein forward, CATCTTTGGATTTCAGTCTTGATG; reverse, AGTTGAAAAGATACCAGTCCAAGG. DNA products were amplified for 12–24 cycles, depending on the linear range of the amplification of the target cDNA. Each cycle consisted of 90 s at 93°C, 60 s at 55°C, and 90 s at 72°C. The resulting PCR products were separated by electrophoresis on 2% agarose gels, stained with ethidium bromide, and normalized to the 18S internal control coamplified with each gene product. The densitometry of PCR products and controls was measured with the Kodak Digital Science molecular analysis software</p></sec>
<sec id="S2">
<title>Results</title>
<p><bold><italic>RNA quality</italic></bold> To perform a valid cDNA microarray assessment of transcriptional analysis, it is important to determine the RNA integrity before doing further experiments. When the chlamydial infection proceeded to the designated time point, cell monolayers were lysed and homogenized immediately, to avoid RNA degradation. On average, ∼600 μg of total RNA with an A260:A280 ratio of ∼1.9 were extracted from each 225-cm<sup>2</sup> cell culture flask. The integrity of purified total RNA was analyzed further by use of the Bioanalyzer 2100 (Agilent), with respect to the rRNA peaks. <xref ref-type="fig" rid="Fig1">Figure 1<italic>A</italic></xref> shows that the total RNA from 16 h after infection contained both prokaryotic and eukaryotic RNAs on the basis of the rRNA compositions, thus indicating multiplication of the organism in the host, despite the fact that chlamydia inclusions were not yet readily visible by microscopy. Subsequently, purified poly(A)<sup>+</sup> RNAs also were examined through the Bioanalyzer, as shown in <xref ref-type="fig" rid="Fig1">figure 1<italic>B</italic></xref></p>
<p><bold><italic>Differential transcription of host genes at 2 and 16 h after infection</italic></bold> We measured changes in mRNA abundance of <italic>C. trachomatis</italic>–infected host cells by use of the mean ratios of the hybridization signal strength between experimental and control samples. A representative pseudo color image of hybridization results is shown in <xref ref-type="fig" rid="Fig2">figure 2</xref>. At both time points, we identified differentially transcribed genes that were induced or suppressed by >2-fold. Only 2 genes, the chromosome 8 open-reading frame–4 of unknown function and B cell translocation gene 1, were shown to be up-regulated at both time points. All other differentially transcribed genes were observed at only 1 of 2 time points. This suggests that these 2 time points represent essentially completely different phases of the host response to the chlamydial infection</p>
<p>At 2 h, 13 known genes and 5 uncharacterized ESTs (not shown) were identified as differentially transcribed (<xref ref-type="fig" rid="tb1">table 1</xref>). To our knowledge, these differentially transcribed genes encode factors that have not been specifically studied in the context of chlamydial infection. <italic>C. trachomatis</italic>–infected host cell genes induced at 2 h after infection included 2 cancer-related genes, the jun B proto-oncogene and the gene encoding tumor-associated antigen L6. Previous studies have found that antigen L6 was highly expressed in lung, breast, colon, and ovarian cancer [<xref ref-type="bibr" rid="ref11">11</xref>, <xref ref-type="bibr" rid="ref12">12</xref>]. Host transcription factors YY1/NF-E1 and ESE-1b were up-regulated during the early phase of the infection, which suggests a possible role in the initiation of a cascade of activation of transcription. B cell translocation gene 1 is a member of the antiproliferative factor family that is expressed in response to factors that induce growth arrest and subsequent differentiation and may inhibit macrophage proliferation through the prostaglandin E2–mediated pathway [<xref ref-type="bibr" rid="ref13">13</xref>, <xref ref-type="bibr" rid="ref14">14</xref>]. The up-regulation of these antiproliferative factors in response to growth stimuli suggests that host cells modify their growth cycle beginning at an early time point after infection. In addition, the gene encoding the tryptophanyl-tRNA synthetase was shown to be up-regulated at 2 h after infection. This observation suggests that tryptophan is essential to chlamydial development even in the very early stages [<xref ref-type="bibr" rid="ref15">15</xref>]. The only down-regulated gene was nuclear factor 90 (NF90), which binds to double-stranded RNA and has been shown to induce an interferon response that inhibits viral infections [<xref ref-type="bibr" rid="ref16">16</xref>, <xref ref-type="bibr" rid="ref17">17</xref>]</p>
<p>The time point at 16 h after infection represents a period of active metabolism and binary fission of <italic>C. trachomatis</italic> reticulate bodies within the host cell. At this time point, 130 known genes and 125 ESTs (not shown) from the 15,000 array elements were differentially transcribed (table 2). Of the 130 differentially transcribed genes, 26 (20%) are transcription factors and translation regulators, 14 (11%) involve cell signaling, 21 (16%) are immunity and inflammation related, 20 (15%) relate to cell proliferation, differentiation, and apoptosis, 9 (7%) are metabolism related, 14 (11%) relate to cytoskeleton and the extracellular matrix, and 10 (8%) are cancer related. The remaining 16 (12%) involve a variety of cellular functions such as injury repair, intracellular vesicle trafficking, ribosome biogenesis, and protein degradation. However, such groupings of particular genes into specific functional classes is arbitrary to a certain degree, because some genes may be involved in several cellular functions and pathways. In addition, because these observations were made at a given time point, it is difficult to determine whether the induction or suppression of these genes results from the primary response to the infection or from secondary responses to the primary changes in transcription</p>
<p><bold><italic>Confirmation using RT-PCR</italic></bold> To verify the microarray data through a second method, we used RT-PCR to amplify 6 differentially transcribed genes and to compare the results with that of microarray. The PCR cDNA templates were reverse transcribed from RNAs extracted from <italic>C. trachomatis</italic>–infected HeLa cells at 16 h after infection and from uninfected control samples, as prepared for the microarray experiment. In each RT-PCR set, products amplified from experimental and control samples were standardized to the 18S rRNA band that was coamplified. Fold changes in up-regulation assessed by microarray versus RT-PCR were as follows (mean of fold change±SE): (1) B cell translocation gene, 3.2±1.1 versus 5.8±2.7; (2) early-growth response protein, 16.4±1.3 versus 9.3±3.3; (3) IL-1β, 6.8±1.3 versus 8.2±2.4; (4) immediate-early response 3, 6.5±1.4 versus 3.3±0.7; (5) insulin-like growth factor binding protein 1, 10.7±1.2 versus 5.5±0.8; and (6) induced myeloid leukemia cell differentiation protein, 7.0±2.4 versus 8.5±1.9</p></sec>
<sec id="S3">
<title>Discussion</title>
<p>The present study provides a cross-sectional view of differentially expressed genes within HeLa cells 2 and 16 h after infection with the human pathogen <italic>C. trachomatis</italic> L2 serovar. The study shows that <italic>C. trachomatis</italic> infection alters transcription of a wide range of genes across the host genome, despite the fact that chlamydia develops exclusively inside a membrane bound inclusion within the host cytosol. Considering the nature and scope of these differentially transcribed genes, interactions between the chlamydia and host cell is far more complex than simply fulfilling the metabolic needs of chlamydia. It would be interesting to examine whether chlamydial type III secretion proteins were implicated in the process of some or all of the induction of differentially transcribed genes, given that this mechanism has been proposed as the central pathway in the chlamydia-host interaction [<xref ref-type="bibr" rid="ref18">18</xref>, <xref ref-type="bibr" rid="ref19">19</xref>]</p>
<p>At the early and middle stages of the <italic>C. trachomatis</italic> developmental cycle, the organisms are relatively more synchronized than at a later stage, during which both RBs and newly converted EBs are present in the host cells. The internalized organisms are beginning to differentiate but are still primarily in the form of EBs at 2 h after infection, whereas they are completely converted to RBs at 16 h after infection. Therefore, differentially transcribed genes at 2 and 16 h after infection should primarily reflect host responses to the EB and RB phases, respectively. The findings listed in <xref ref-type="fig" rid="tb1">tables 1</xref> and <xref ref-type="fig" rid="tb2">2</xref> indicate that the host response in terms of transcription at these 2 phases are distinctive. At the earlier time point, the organism-host interaction was surprisingly quiescent—only 0.1% (18 of 15,000 genes) overall host transcription changes were noted. It is possible that genes early in a phase of up-regulation might not have been detected because of insufficient RNA generated at 2 h after infection. Of interest, there was no up-regulation in cytokine genes detected. The absence of induction of proinflammatory cytokines by chlamydiae at the early stage of the infection is in contrast with other invasive intracellular bacteria that often induce rapid proinflammatory cytokine expression. This also confirms the previous study by Rasmussen et al. [<xref ref-type="bibr" rid="ref3">3</xref>] that observed no host cell cytokine expression in the first few hours after infection with <italic>C. trachomatis</italic>. Cytokine expression was therefore not among the earliest consequences of the organism-host interaction</p>
<p>However, up-regulation of transcription factors, including YY1 and the epithelial-specific transcription factor ESE-1b, were noted. Transcription factor YY1 is a 65-kDa sequence-specific DNA-binding protein with zinc-finger motifs. It functions both as a transcriptional activator and as a repressor of a number of genes, and it modifies chromatin structures, allowing for accessibility to DNA binding proteins during active gene transcription [<xref ref-type="bibr" rid="ref20">20</xref>]. In addition, another transcription factor ESE-1, a member of the <italic>ets</italic> family of transcription factors, was induced early in the infection. Previous studies have demonstrated that ESE-1 was expressed exclusively in epithelial cells and promoted epithelial cell differentiation [<xref ref-type="bibr" rid="ref21">21</xref>, <xref ref-type="bibr" rid="ref22">22</xref>]. The up-regulation of factors influencing cell differentiation and expression of keratin indicate that <italic>C. trachomatis</italic>–infected cells embark on differentiation soon after being infected and that this precedes the expression of proinflammation cytokines. The induction of tryptophanyl-tRNA synthetase may indicate an increased tryptophan metabolism in the early stages of chlamydial infection</p>
<p>The only down-regulated gene at the early time point was the NF90, a double-stranded RNA–binding protein that can serve as either a positive or negative regulator of gene expression, depending on the promoter [<xref ref-type="bibr" rid="ref23">23</xref>]. NF90 also was found to be down-regulated in a model of influenza virus infection of HeLa cells in a previous study [<xref ref-type="bibr" rid="ref10">10</xref>]. Therefore, down-regulation of NF90 probably is a shared mechanism of host response to diverse infections</p>
<p>Data demonstrate a completely different host transcriptional profile at 16 h after infection than that seen 2 h after infection. At the later stage of the infection, the proportion of differentially expressed genes increased to 1.7%, and the magnitude of differential transcription also is apparently increased (<xref ref-type="fig" rid="tb2">table 2</xref>table 2). Most important, at 16 h after infection, the altered host transcriptional response involved a much greater range of cellular activities. These widespread modifications in transcription probably resulted from changes in host transcription regulatory and signaling pathways, because one-third of the differentially transcribed genes represented transcription factors and cell signaling molecules. It is likely that changes in some of these host genes are shared by other infecting pathogens; however, it is difficult to define a set of host genes that specifically indicate response to chlamydial infection until other pathogens have been similarly studied</p>
<p>Although it is difficult to be certain of the precise consequences of these alterations in transcription, several major features of the transcriptional profile at 16 h after infection can be deduced. First, chlamydial infection affects apoptosis and differentiation of the host cells. The up-regulation of inhibitors of apoptosis—namely, inhibitor of apoptosis (IAP) homolog B/MIHB, IAP homolog C/MIHC, and apoptosis antigen–1—demonstrate that chlamydiae begin to restrain host cell apoptosis at least from the middle of the developmental cycle. Fan et al. [<xref ref-type="bibr" rid="ref24">24</xref>] proposed that chlamydiae interfered with the host apoptosis process by inhibiting mitochondrial cytochrome c release as a key antiapoptotic mechanism. However, whether this mechanism links to the up-regulation of apoptosis inhibitors observed in our study is uncertain. Chlamydia’s apparent ability to alter host differentiation is manifested by the induction of growth factors—including insulin-like growth factor binding proteins 1, 5, and 6, vascular endothelial growth factor and its related protein, cell cycle progression restoration protein 8, platelet-derived growth factor receptor, fibroblast growth factor 1 and 3, and the connective tissue growth factor—and the suppression of the Ras-like estrogen-regulated growth inhibitor</p>
<p>Second, chlamydiae apparently modify the host cell structure and cytoskeletal components. The up-regulation of several cell structure related molecules (e.g., spectrin, integrin, and tubulin components) and increased expression of myosin may have a role in modifying the host cell structure to accommodate chlamydial growth. It is amazing to observe at the late stage of the chlamydial developmental cycle that the chlamydia inclusion occupies the vast majority of the cell’s volume yet host cell integrity is maintained until eventual lysis of the host cell. Perhaps this is achieved through antiapoptosis and extensive host cytoskeleton remodeling</p>
<p>Third, innate host cell defense mechanisms have clearly been mobilized by 16 h after infection. Cytokines, including IL-1β, IL-6, and IL-16, as well as interferon (IFN)–induced proteins and IFN regulatory factors, were up-regulated. Previous studies have documented that chlamydial infection induces host expression of IL-1β and IL-6 [<xref ref-type="bibr" rid="ref3">3</xref><xref ref-type="bibr" rid="ref4"></xref><xref ref-type="bibr" rid="ref5"></xref>–<xref ref-type="bibr" rid="ref6">6</xref>, <xref ref-type="bibr" rid="ref25">25</xref>]. However, in addition to IL-1 and IL-6, a modest up-regulation of IL-16 from the chlamydia-infected host was observed in our study and has not been reported. IL-16, a chemoattractant factor, can be expressed by epithelial cells under inflammatory conditions [<xref ref-type="bibr" rid="ref26">26</xref>] and serves to chemoattract CD4<sup>+</sup> T cells, monocytes, and eosinophils to the infection site [<xref ref-type="bibr" rid="ref27">27</xref>, <xref ref-type="bibr" rid="ref28">28</xref>]. Furthermore, the significant up-regulation of intercellular adhesion molecule 3 (ICAM-3) by chlamydia-infected epithelial cells may be a novel finding. ICAM-3 belongs to the immunoglobulin superfamily and binds to leukocyte function–associated antigen. When exposed to proinflammatory cytokines, ICAM-3 is expressed on leukocytes and endothelial cells [<xref ref-type="bibr" rid="ref29">29</xref>, <xref ref-type="bibr" rid="ref30">30</xref>]. Like ICAM-1, ICAM-3 may play a crucial role in host immunity in early recruitment and activation of CD4<sup>+</sup> and CD8<sup>+</sup> T cells [<xref ref-type="bibr" rid="ref31">31</xref>]</p>
<p>Finally, the observation that some cancer-related or proto-oncogenes have elevated transcript levels is intriguing. Although epidemiological studies have associated cervical cancer with chlamydial infection [<xref ref-type="bibr" rid="ref32">32</xref>, <xref ref-type="bibr" rid="ref33">33</xref>], the actual role played by <italic>C. trachomatis</italic> in causing cervical cancer is certainly debatable, considering the confounding effect of human papillomavirus infection. However, accumulation of multiple mutations in proto-oncogenes promotes carcinogenesis, and whether chlamydia infection–mediated up-regulation of proto-oncogenes (especially under conditions of persistent infection) represents an increased hazard are unknown</p>
<p>In summary, we have demonstrated that <italic>C. trachomatis</italic> infection alters host gene transcription globally. These differentially transcribed genes involve many cellular processes, and most have not previously been examined in the context of chlamydial infection. Methodologically, we have shown that high-throughput DNA microarray analysis is an efficient tool for examining host response to this obligate intracellular bacterium. Although regulation of gene expression in eukaryotes is a multistep process, and we cannot immediately interpret the functional consequences of some of the differentially transcribed genes, the present study certainly expands our investigational scope in terms of the host genes and cellular pathways that are affected by chlamydial infection</p></sec></body>
<back>
<ack>
<title>Acknowledgements</title>
<p>We appreciate useful discussions with Dr. Stephen Lory of the Harvard Medical School in utilizing the microarray method. We thank Dr. Mette Peters and the staff of the Center for Expression Arrays for producing the microarrays used in our study, providing the RNA analysis services, and assisting array analysis</p></ack>
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<sec sec-type="display-objects">
<title>Figures and Tables</title>
<fig id="Fig1" position="float">
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<p>Analysis of total RNA and poly(A)<sup>+</sup> RNA integrity using the Agilent Bioanalyzer 2100. <italic>A</italic> Analysis of total RNA extracted from HeLa cell monolayers infected with <italic>Chlamydia trachomatis</italic> L2 serovar at 16 h after infection and the total RNA from infected HeLa cells. As indicated by multiple fluorescence absorption peaks of rRNA, the total RNA contained both eukaryotic and prokaryotic RNA. <italic>B</italic> HeLa poly(A)<sup>+</sup> RNA purified from total RNA extracted at 16 h after infection with <italic>C. trachomatis</italic> serovar L2</p></caption>
<graphic mimetype="image" xlink:href="187-3-424-fig001.tif"></graphic></fig>
<fig id="Fig2" position="float">
<label>Figure 2</label>
<caption>
<p>Pseudo color image of microarray hybridization pattern from <italic>Chlamydia trachomatis</italic>–infected HeLa cells at 16 h after infection and mock-infected controls. poly(A)<sup>+</sup> mRNA extracted from experimental and control samples were used to synthesize cDNAs with incorporation of either Cy3-dCTP <italic>(green)</italic> or Cy5-dCTP<italic> (red)</italic>. Subsequent purified cDNA probes were combined and applied to a microarray slide. After hybridization, washing, and drying, slides were scanned with a confocal dual-laser microscope at 532 and 633 nm. There are 15,360 spots (DNA elements) on each slide. The 2 panels represent the same set of spotted DNAs on 2 identical slides with a reverse-color (Cy dye) labeling scheme. <italic>Left</italic> Infected HeLa cell cDNA labeled with Cy3-dCTP and mock-infected HeLa cell cDNA labeled with Cy5-dCTP; <italic>right</italic> infected HeLa cell cDNA labeled with Cy5-dCTP and mock-infected HeLa cell cDNA labeled with Cy3-dCTP</p></caption>
<graphic mimetype="image" xlink:href="187-3-424-fig002.tif"></graphic></fig>
<fig id="tb1" position="float">
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<p>Differentially transcribed genes of HeLa cells at 2 h after infection by Chlamydia trachomatis L2</p></caption>
<graphic mimetype="image" xlink:href="187-3-424-tab001.tif"></graphic></fig>
<fig id="tb2" position="float">
<label>Table 2</label>
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<p>Differentially transcribed genes of HeLa cells at 16 h after infection by Chlamydia trachomatis L2</p></caption>
<graphic mimetype="image" xlink:href="187-3-424-tab002.tif"></graphic></fig>
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<p>Financial support: National Institutes of Health (grants AI 48769 and AI 31448 to W.E.S.)</p></fn></fn-group></back></article></istex:document></istex:metadataXml><mods version="3.6"><titleInfo><title>Chlamydia trachomatis Infection Alters Host Cell Transcription in Diverse Cellular Pathways</title></titleInfo><titleInfo type="alternative" contentType="CDATA"><title>Chlamydia trachomatis Infection Alters Host Cell Transcription in Diverse Cellular Pathways</title></titleInfo><name type="personal"><namePart type="given">Minsheng</namePart><namePart type="family">Xia</namePart><affiliation>Division of Infectious Diseases, Department of Medicine,</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Roger E.</namePart><namePart type="family">Bumgarner</namePart><affiliation>Center for Expression Arrays, and</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal"><namePart type="given">Mary F.</namePart><namePart type="family">Lampe</namePart><affiliation>Division of Infectious Diseases, Department of Medicine,</affiliation><affiliation>Department of Laboratory Medicine, University of Washington, Seattle</affiliation><role><roleTerm type="text">author</roleTerm></role></name><name type="personal" displayLabel="corresp"><namePart type="given">Walter E.</namePart><namePart type="family">Stamm</namePart><affiliation>Division of Infectious Diseases, Department of Medicine,</affiliation><affiliation>E-mail: wes@u.washington.edu</affiliation><role><roleTerm type="text">author</roleTerm></role></name><typeOfResource>text</typeOfResource><genre type="research-article" displayLabel="research-article" authority="ISTEX" authorityURI="https://content-type.data.istex.fr" valueURI="https://content-type.data.istex.fr/ark:/67375/XTP-1JC4F85T-7">research-article</genre><originInfo><publisher>The University of Chicago Press</publisher><dateIssued encoding="w3cdtf">2003-02-01</dateIssued><copyrightDate encoding="w3cdtf">2003</copyrightDate></originInfo><abstract>To study the responses of the host cell to chlamydial infection, differentially transcribed genes of the host cells were examined. Complementary DNA (cDNA) probes were made from messenger RNAs of HeLa cells infected with Chlamydia trachomatis and were hybridized to a high-density human DNA microarray of 15,000 genes and expressed sequence tags. C. trachomatis alters host cell transcription at both the early and middle phases of its developmental cycle. At 2 h after infection, 13 host genes showed mean expression ratios ⩾2-fold. At 16 h after infection, 130 genes were differentially transcribed. These genes encoded factors inhibiting apoptosis and factors regulating cell differentiation, components of the cytoskeleton, transcription factors, and proinflammatory cytokines. This indicates that chlamydial infection, despite its intravacuolar location, alters the transcription of a broad range of host genes in diverse cellular pathways and provides a framework for future studies</abstract><relatedItem type="host"><titleInfo><title>The Journal of Infectious Diseases</title></titleInfo><titleInfo type="abbreviated"><title>The Journal of Infectious Diseases</title></titleInfo><genre type="journal" authority="ISTEX" authorityURI="https://publication-type.data.istex.fr" valueURI="https://publication-type.data.istex.fr/ark:/67375/JMC-0GLKJH51-B">journal</genre><identifier type="ISSN">0022-1899</identifier><identifier type="eISSN">1537-6613</identifier><identifier type="PublisherID">jid</identifier><identifier type="PublisherID-hwp">jinfdis</identifier><part><date>2003</date><detail type="volume"><caption>vol.</caption><number>187</number></detail><detail type="issue"><caption>no.</caption><number>3</number></detail><extent unit="pages"><start>424</start><end>434</end></extent></part></relatedItem><relatedItem type="references" displayLabel="b1"><titleInfo><title>Cytologic manifestations of cervical and vaginal infections. 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