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A spectrum of functional genes mobilized after Trichinella spiralis infection in skeletal muscle
Published online by Cambridge University Press: 16 December 2004
Abstract
Trichinella spiralis infection causes the transformation of infected muscle cells, which leads to nurse cell formation. To search for the candidate genes responsible for nurse cell formation, cDNA microarray analysis of muscle tissues was performed before and after Trichinella infection. The Atlas mouse 1.2 cDNA expression microarray revealed the expression profiles of 1176 known genes. Out of these, 311 gene expressions were detected in normal and/or infected muscles. After the infection, 184 out of the 311 genes increased in expression by more than 3-fold. These included genes responsible for cell differentiation, proliferation, cell cycle and apoptosis. Thus this study suggested candidate genes for further investigation to dissect the molecular mechanisms of nurse cell formation.
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- © 2005 Cambridge University Press
INTRODUCTION
Trichinella spiralis is an intracellular parasite of mammalian skeletal muscles. Infection by newborn larvae induces extensive changes of infected cells leading to prominent and unique cyst formation in infected muscle. The histopathological features have been well described by the previous authors (Despommier, 1975; Matsuo et al. 2000). Outside of the cyst wall, inflammatory cell accumulation and prominent angiogenesis occur (Baruch & Despommier, 1991; Despommier, 1993; Gabryel, Gustowska & Blotna-Filipiak, 1995; Liu et al. 1996; Polvere et al. 1997; Capo, Despommier & Polvere, 1998). Within the cyst wall, there are nurse cells that are not normal constituents of the host tissue. Of particular interest to Trichinella research is that the nurse cell is a transformed muscle cell. The question then arises “How are terminally differentiated cells transformed?” Based on this question, the processes of nurse cell formation have been intensively studied. The processes have been found to involve complex steps (see review by Despommier, 1998). The processes attempt to follow those seen during normal muscle cell repair, but are different in many respects. Infected muscle cells loose their integrity and transform to the nurse cell and undergo regeneration. Satellite cells proliferate but mis-differentiate to the nurse cell, not to the muscle cell (Matsuo et al. 2000; Wu et al. 2001; Boonmars et al. 2004a,b). These changes are thought to be triggered by parasite ES products (Despommier et al. 1990; Lee et al. 1991; Yao, Bohnet & Jasmer, 1998; Yao & Jasmer, 1998). In other words, muscle cells respond to the ES products in a different way from other causes of muscle cell damage, either overloading or drug-induced damage.
We have begun a series of molecular studies to determine the kinetics of certain genes that may play a key role in this unique transformation (Wu et al. 2001; Boonmars et al. 2004a,b). This cyst formation is, however, not simple because it involves numerous gene interactions. As such, the spectrum and kinetics of genes should be more extensively analysed. Recent genetic analysis techniques offer a powerful tool to match such a requirement. cDNA microarray assay is one of the methods that can examine the expression profile of thousands of genes simultaneously. In the present study, we adapted the Atlas mouse cDNA expression microarray (equipped with 1176 known genes) for analysing the gene expression in normal and T. spiralis-infected muscle tissues. The results provided fundamental knowledge for further understanding the mechanism of formation of the nurse cell and host–parasite relationship.
MATERIALS AND METHODS
Parasite and infection
Three nude mice (n=3) were orally infected with 600 larvae of T. spiralis (ISS413). The muscles of the hind limbs (containing about 1000 larvae per g of tissue) were collected at 23 days post-infection (p.i.) and subjected to RNA isolation (see next paragraph). Control samples were collected identically from uninfected nude mice (n=3).
RNA preparation
Total RNA was isolated from the muscle samples of the infected group and the normal mouse group using Trizol (GibcoBRL, Life Technologies, Inc., Carlsbad, CA, USA) according to the manufacturer's instructions. In brief, isolated total RNA was treated with 50 units/ml of DNase I (RQ1 RNase-free DNase, Promega Corporation, Madison, WI, USA) in the buffer (40 mM Tris-HCl, 10 mM MgSO4 and 1 mM CaCl2, pH 8·0) containing 400 units/ml ribonuclease inhibitor (Takara Bio INC. Shiga, Japan) at 37 °C for 30 min. The treated RNA was extracted with phenol/chloroform, precipitated with ethanol, and dissolved in RNase-free water.
cDNA microarray
The cDNA microarray assay was performed using Atlas™ mouse 1.2 Array (Clontech, Palo Alto, CA, USA), which contained 1176 different kinds of known genes dotted on 1 sheet of nylon membrane. The names and possible functions of the genes are listed in Table 1, according to the manufacturer's instructions.
The following pre-treatments (RNA purification, probe preparation, hybridization and signal visualization) were performed according to the manufacturer's user manual of Atlas™ mouse 1.2 Array (Clontech).
The probe was prepared using the Atlas™ Spotlight Labeling Kit (Clontech). In brief, 50 μg purified RNA was labelled by incubating with reaction buffer, labelling mixture and CDS (cDNA synthesis) primer mixture at 48 °C for 45 min, and then the labelled probe was purified by column chromatography.
Hybridization and signal detection were performed using the SpotLight™ Chemiluminescent Hybridization and Detection Kit (ClONTECH). In brief, the Atlas Array membrane was pre-hybridized in SpotHyb buffer containing 500 μg of sheared salmon testes DNA at 42 °C for 2 h, and hybridized with the probe at 42 °C overnight in a hybridization incubator. Then, the membrane was washed 3 times with 2X SSC (sodium citrate-sodium chloride) containing 1% SDS (sodium dodecyl sulfate) at 60 °C for 30 min, and twice with 0·1X SSC containing 0·1% SDS at 48 °C for 30 min. The membrane was incubated with block solution for 1 h and stabilized with streptavidin-HRP (horseradish peroxidase) conjugate for 15 min at room temperature. After washing with washing buffer, the membrane was incubated with substrate (a mixture of luminol/enhancer solution and stable peroxide solution) for 5 min at room temperature, and finally exposed to Biomax MS film (Kodak, Rochester, NY, USA).
Microarray data analysis
Microarray experiments were performed 3 times with 6 independent samples from normal (n=3) and infected mice (n=3). The results were analysed densitometrically using NIH Image 1.95 software (developed at the U.S. National Institute of Health and available on their website at http://rsb.info.nih.gov/nih-image/). To compare the infected muscle and normal muscle, expression data from 3 microarrays were averaged and normalized as following. First, the average pixel intensities of the spot of each gene (A) in infected muscle and normal muscle were determined. The background signal (B) was determined by measuring the signals of negative controls spots on the array membranes. The corrected signal (C) was obtained from C=A−B. Next, the housekeeping gene G3PD was used to normalize the corrected signals. The normalized signals in infected muscle were expressed as C X (C of infected muscle G3PD signal/C of normal muscle G3PD signal). Then the ratio was calculated as the ratio of normalized signal of infected muscle to that of normal muscle. These results were expressed as increased or decreased folds. The fold inductions in Tables are averages of 3 independent experiments. In the present study, the ratio threshold was set at 3·0. Only those genes that were 3·0-fold or greater were considered to be differentially expressed.
Because many genes showed extremely low or undetectable signals in normal muscle, the ratio cannot be calculated accurately. Therefore, the expression levels of these genes were judged according to the size and density of each spot and rated as negative (−), or positive (1+ to 12+). Only that the normal muscle was negative and the infected muscle was 2+ or greater were considered to be differentially expressed.
RESULTS
Table 1 lists the gene classification made by the manufacturer and the summary of the present microarray results, including total gene numbers, the numbers of signal detectable genes and the numbers of the genes of expression which increased more than that 3-fold or over 2+. Fig 1 shows the example results of the microarray membrane. In Table 2, we listed the genes with signals that were detectable. Although the hybridization results were highly reproducible, there was some variation in density among the 3 independent analyses. Therefore the results are depicted by mean values.
Fig. 1. The Atlas Mouse 1.2 Array images of cDNA hybridization. The upper panel and the lower panel represent gene expression in the hind limb muscles of normal mice and Trichinells spiralis-infected mice, respectively.
Among the 1176 plotted genes, 311 showed a detectable signal in the normal and/or infected muscles, and the remaining 865 genes were undetectable in both normal and infected muscle. Out of the 311 detectable genes, 184 genes exhibited a 3-fold or greater increase in the expression, while the remaining 131 genes exhibited unchanged or less than a 3-fold increase.
Atlas 1.2 array contains 171 basic transcription factor genes, 37 of which produced detectable signals. Out of 37 genes, 22 showed more than a 3-fold increase expression in infected muscle. The highest increased expression was seen in the nuclear factor of activated T cells (NFAT1) (10+), which is a gene relative to cell differentiation and growth. The expressions of 7 homeobox genes were increased.
In 117 genes of transcription activators and repressors, 41 genes gave detectable signals. Out of the 41 genes, 16 genes showed more than a 3-fold or 2+ increase of expression, including 4 homeobox genes.
Out of 45 cyclins and cell cycle related protein, 16 genes gave detectable signals. Out of the 16 genes, 13 genes showed more than a 3-fold or 2+ up-regulatory expression. These genes included the cyclins that function mainly during G1 and G1-S phases, such as cyclin D2, cyclin D3, cyclin C, cyclin E1 and cyclin B2. The cyclin dependent kinase 4 (CDK4), a protein that forms a complex with cyclin D family and regulates cell cycle progression during G1/S phase, showed an up-regulatory expression in infected muscle. While some cyclin-dependent kinase inhibitors (P57 and P27), which are mitotic inhibitors inducing cell cycle arrest in G1 and G2/M, showed an up-regulatory expression.
The expression of many heat shock protein genes was upregulated in infected muscle. Within 11 heat shock protein genes, 5 genes showed more than a 3-fold increase in expression, including oxidative stress-induced protein (OSI) and heat shock proteins (HSP84, HSP86 and HSP105).
Of 58 apoptosis-associated protein genes, expression of 14 genes was upregulated. The most prominently upregulated gene was tumour necrosis factor receptor 1 (TNF-R1), which showed a 12+ increase in expression, compared with it being undetectable in normal muscle. The expression of activator of apoptosis hara-kiri (HRK) and Bcl2-associated X protein (BAX) was increased.
The expressions of many growth factors were increased, for example, 5 insulin-like growth factors (IGF) (IGF I, IGF I receptor, IGF binding protein 5, IFG binding protein 4, and IGF binding protein 2), 3 fibroblast growth factors (FGF) (FGF6, FGF12, and FGF7), and 4 bone morphogenetic proteins (BMP) (BMP4, BMP1, BMP3, and BMP8).
Out of 19 protease and 13 protease inhibitor genes, the expression of 5 proteases and 5 protease inhibitors increased more than 3-fold or 2+, for example, the proteases cathepsin B, cathepsin D, cathepsin L, and protease inhibitor plasminogen activator inhibitor 1 (PAI1), tissue inhibitor of metalloproteinase 2 (TIMP2), TIMP3, and 2 serine proteinase inhibitors (SPI) (SPIJ6 and SPI4).
The expression of some genes was downregulated after infection. Such examples included homeobox A13, nuclear receptor 1H2, and some cytoskeleton and motility proteins (myosin heavy chain, myosin light chain, myomesin 1 and keratin complex 2).
DISCUSSION
In this study we revealed the expressions profile of as many as 1176 genes in muscle tissues before and after Trichinella infection. In total, 311 of the 1176 genes were detected by the present microarray analysis. The expression of 184 genes out of the 311 genes was increased after the infection. Although the 184 genes may have been expressed in the process of inflammatory reactions and/or angiogenesis seen near the cyst, at least some of them must have been directly involved in nurse cell formation.
An urgent need is the identification of such genes in these processes. Towards this goal, we paid careful attention to some important genes such as cell differentiation, apoptosis, cell cycle, homeobox and growth factors, because Trichinella infection causes permanent phenotypic (morphology, metabolism) changes of host muscle cell, including re-entry into the cell cycle, and arresting in G2/M of the cell cycle (Despommier, 1975; Jasmer, 1993).
Our unpublished preliminary data, however, showed that cDNA of T. spiralis muscle larvae hybridize the two genes on the Atlas 1.2 array (eyes absent 2 and nerve growth factor alpha). As such, these two genes should be excluded from further analysis.
After larvae enter the muscle cell, the cell exhibits prominent changes such as hypertrophy and enlarged nuclei, and satellite cells are activated (Despommier, 1975; Wu et al. 2001). These features are similar to those seen during muscle differentiation (Smith, Janney & Allen, 1994; Seale & Rudnicki, 2000; Hawke & Garry, 2001). In our study, as expected, cell differentiation genes were upregulated. Examples were given by myocyte-specific enhancer factor 2C (MEF2), Lbx 1 transcription factor and NFAT. MEF2 is involved in the activation of muscle-specific gene expression (Naya & Olson, 1999), and acts in concert with myogenic regulatory factors (MRFs) in muscle cell differentiation (Parker, Seale & Rudnicki, 2003). NFAT plays a role in regulating the expression of MRFs in satellite cells (Friday & Pavlath, 2001). Prominent angiogenesis seen around the cysts (Baruch & Despommier, 1991; Capo et al. 1998) is another candidate that may account for the increased expression of at least some cell differentiation genes.
After T. spiralis infection, the expression of 11 homeobox genes was upregulated, as shown in Table 3. Homeobox genes are regulatory genes encoding nuclear proteins that act as transcription factors, regulating aspects of morphogenesis and cell differentiation during normal embryonic development (see review by Abate-Shen, 2002) and muscle cell differentiation (see review by Olson & Rosenthal, 1994).
The expression of all 3 homeobox MSX family genes (MSX1, MSX2 and MSX3) was increased after infection. Interestingly, MSX genes inhibit the differentiation of many cell types. For example, MSX1 is known to regulate proliferation and prevent differentiation of cells (Song, Wang & Sassoon, 1992; Hu et al. 2001). This homeobox transcription factor down-regulates the expression of MRFs and inhibits differentiation (Woloshin et al. 1995; Bendall et al. 1999; Odelberg, Kollhoff & Keating, 2000). Moreover, MSX1 is known to trigger the de-differentiation of multinucleate myotubes into monocleated cells which are then able to re-enter the cell cycle and re-differentiate into myogenic cells (Woloshin et al. 1995; Odelberg et al. 2000). Therefore the unusual phenomenon of Trichinella-infected muscle cells, mis-differentiation of satellite cells, should be discussed in light of the increased expression of MSX1 genes.
Trichinella-infected muscle cells exit from G0 and re-enter the cell cycle (Jasmer, 1993). Therefore cell cycle regulation genes are of particular interest. Out of 45 cell cycle related genes, 13 genes were upregulated. For example, cyclin C, B2, D2 and D3 were increased in expression.
The mammalian cell cycle is regulated by a series of cell cycle regulatory molecules, including cyclin, cyclin-dependent kinase (CDK) and CDK inhibitor. Different cyclins bind specifically to different CDKs to form distinct complexes at specific phases of the cell cycle and thereby drive the cell from one stage of cycle to another. Upon stimulation, D-type cyclins assemble CDK4 and CDK6 to form complexes, which facilitate cells to exit from G0 phase and re-enter the cell cycle of G1 (Reed et al. 1994; Weinberg, 1996; Wuarain & Nurse, 1996). Our present data showed that genes of these proteins (cyclin D2, cyclin D3 and CDK4) were increased after infection, which supports the thesis that the infected cells re-enter the cell cycle.
Of particular interest is that the expression of retinoblastoma (Rb), p27 and p57 is increased. These proteins are known to play an important role in the growth arrest of differentiating cells, because they specifically inhibit CDKs, which leads to the withdrawal of cells from cycle and differentiation (Liu et al. 1996; Jacks & Weinberg, 1996; Pines 1997; Matushansky, Radparvar & Skoultchi, 2000). This implies that the increased expression of cycle inhibitor genes may be responsible for the arrest in G2/M of infected cells.
During the process of cystogenesis, apoptosis plays an important role in remodeling the host tissue (Boonmars et al. 2004b). The present microarray analysis revealed that out of 58 apoptosis related genes, expression of 14 genes was upregulated after the infection. The examples include tumour necrosis factor receptor I (TNFRI), Bcl2-associated X protein (BAX), activator of apoptosis hara-kiri (HRK) and protein kinase B (PKB). Our previous study showed that expressions of mitochondrial apoptosis related genes (BAX and PKB) were elevated in the T. spiralis-infected muscle cells during cyst formation (Boonmars et al. 2004b), which is reconfirmed by the present microarray results.
After T. spiralis infection, the expression of many growth factors was elevated. These upregulated growth factors are likely to be associated with satellite cell activation, re-entry to the cell cycle, muscle hypertrophy and regulation of differentiation and proliferation. Satellite cells are known to modulate their cell cycle state in response to growth factors (Hawke & Garry, 2001; Stamler & Meissner, 2001). In fact, many reports have indicated that growth factors (HGF, FGFs and IGFs) regulate the satellite cell activation (Doumit, Cook & Merkel, 1993; Coleman et al. 1995; Tatsumi et al. 2001). Of particular interest is FGF-6, which is muscle specific and upregulated during muscle regeneration (Floss, Arnold & Braun, 1997; Kastner et al. 2000).
The IGF family plays a crucial role in regulating cell proliferation and differentiation, and has mitogenic and anti-apoptosis effects on normal and transformed cells. IGF-I and IGF-II levels are upregulated in skeletal muscle undergoing regeneration (Levinovitz et al. 1992; Krishan & Dhoot, 1996). Both factors are able to alter MRFs expression and promote both the proliferation and differentiation of myoblasts (Coleman et al. 1995; Engert, Berglund & Rosenthal, 1996). IGF can induce skeletal muscle hypertrophy that resembles the pathological changes seen in Trichinella-infected muscle cells. The hypertrophic effects of IGF I are attributed to the activation of satellite cells. On the other hand, IGFBP-5 can inhibit both proliferation and differentiation. Therefore, the elevated expression of IGFs may be related to the muscle hypertrophy induced by the infection, and to regulation of proliferation and differentiation of infected cells during nurse cell formation.
BMPs are a large subgroup within the transforming growth factor-beta (TGF-beta) family. They are involved in growth and differentiation and are crucial regulators of early embryogenesis and subsequent organogenesis as well as tissue homeostasis in adults (Wozney, 2002). For example, BMP-4 inhibits myogenesis (Reshef, Maroto & Lassar, 1998). BMPs elicit their effects through activation of type I and type II kinase receptors, which initiate the signal transmission of Smad proteins to the nucleus. Activated Smads were transported into the nucleus and play a direct role in gene transcription, which is also regulated by other molecules such as Id, c-Ski. The expression of c-ski in infected muscle was highly upregulated (12+). This gene was identified as a transcriptional co-repressor of Smad2 and Smad3 in a TGF-beta dependent manner. High expression of c-ski may suppress TGF signal transcription, leading to withdrawal of infected muscle cells from differentiation.
All of the detectable BMP genes showed increased expression after the infection, as shown in Table 5. The upregulation of these genes is very likely due to many types of cell growth and differentiation during completion of cyst formation.
Thus, the present cDNA microarray analysis showed kinetics of the genes mobilized in response to Trichinella infection, and gave hints about key genes in muscle transformation. The usefulness of the present microarray results are now being confirmed by more quantitative analysis whereby the cyst components are separated by laser-capture microdissection and subjected to RT-PCR for gene expression. Such examples included tumour necrosis factor receptor 1, insulin-like growth factor, ski proto-oncogene, smad 1, cyclin D3 and osteopontin, which provided more direct and precise data about functional involvement of examined genes (to be published elsewhere).
This study was partially supported by a Grant-in-Aid for Scientific Research (15590366) from the Ministry of Education, Culture, Sports, Science and Technology of Japan.
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Table 1. Summary of microarray analysis
Fig. 1. The Atlas Mouse 1.2 Array images of cDNA hybridization. The upper panel and the lower panel represent gene expression in the hind limb muscles of normal mice and Trichinells spiralis-infected mice, respectively.
Table 2. Differentially expressed genes between normal and Trichinella spiralis-infected muscles
Table 3. Expression of homeobox genes after Trichinella spiralis infection
Table 4. Expression of IGF and FGF genes after Trichinella spiralis infection
Table 5. Expression of BMP and associated genes after Trichinella spiralis infection
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