Transcriptional profiling of Drosophila S2 cells in early response to Drosophila C virus
© Zhu et al.; licensee BioMed Central Ltd. 2013
Received: 18 April 2013
Accepted: 24 June 2013
Published: 27 June 2013
The innate immune response like phagocytosis, encapsulation and antimicrobial peptide (AMP) production often occur in the early stage of host-pathogen interactions in Drosophila melanogaster. To investigate the Drosophila early immune response to Drosophila C virus, we characterized the DCV infection-response transcriptome of Drosophila Schneider 2 (S2) cells at one hour post inoculation.
The total RNA was extracted from treated S2 cells by using Trizol reagent and then analyzed by CapitalBio Corp for Drosophila GeneChip (Affymetrix) assay. Then the results of signaling pathway and protein interaction about these genes were analyzed by MAS 3.0 software.
Most significantly affected genes (656 genes) by DCV infection were regulated as the same way in inactivated DCV treatment, but inactivated white spot syndrome virus (WSSV) showed a different transcriptome. DCV infection up-regulated the expression levels of 275 genes and down-regulated that of 442 genes significantly and some affected genes were related to phagocytosis. DCV infection activated the JAK/STAT pathway by 1 hour post incubation. The Imd pathway was activated and transcriptional induction of antimicrobial peptides (AMPs) from this pathway was enhanced by 1 hour post incubation. But the Toll pathway was not activated like Imd pathway and the expression levels of AMPs from this pathway was reduced. In addition, most pattern-recognition receptors were inhibited and the antiviral RNAi pathway was not activated in the early stage of DCV infection.
In conclusion, the present study demonstrates that DCV infection may activate phagocytosis, JAK/STAT pathway and Imd pathway in the early host-virus interactions. These results indicate that DCV is capable of activating or inhibiting some immune responses in the host cells and these changes would be vital for virus entry and replication.
KeywordsTranscriptional profiling Drosophila S2 cells Early response Drosophila C virus
The innate immune response of Drosophila is governed by numerous signaling pathways that trigger antimicrobial peptide (AMP) production, phagocytosis, melanization, and encapsulation to limit infection after exposure to microbes [1, 2]. Drosophila C virus (DCV) is a non-occluded isometric virus which containing a positive sense RNA genome [3, 4]. DCV is a natural pathogen of the model organism D. melanogaster, making it an ideal model system for studying invertebrate host-virus interactions . The mechanisms of antiviral defense in Drosophila highlight the potential of the D. melanogaster model for studying antiviral innate immunity . It is found that the Imd pathway is involved in the antiviral immune responses of Drosophila[7, 8]. The Toll pathway is required for efficient inhibition of Drosophila X virus replication in Drosophila and constitutive activation of the pathway resulted in decreased viral titer . Recently RNA interference (RNAi) was found to mediate innate antiviral immunity in Drosophila[10–12]. The JAK/STAT signaling pathway is reported to involve in the antiviral response of Drosophila[11–13]. However, many viruses always develop the ability of suppressing or evading host immune response. No evidence for the activation of the Toll, IMD or JAK/STAT pathways was found in D. melanogaster infected with the sigma virus (Rhabdoviridae) . And dengue virus (DENV) may suppress immune responses at early infection stages before activating them at later time points in Aedes aegypti. So it is very necessary to study the early immune response to pathogenic virus in host cells.
White spot syndrome virus (WSSV) is a bacilliform, enveloped double stranded DNA virus that causes viral diseases in shrimp . To investigate early immune responses against DCV, we exposed Drosophila S2 cells to DCV, inactivated DCV (inDCV), and inactivated WSSV (inWSSV). We selected inWSSV as a treatment but not WSSV because WSSV was not phagocytosed by S2 cells like DCV and inDCV and induced very complicated early response. We investigated the transcriptional profile of virus-challenged Drosophila S2 cells using oligonucleotide DNA microarrays to identify the Drosophila early immune response to DCV. This results of this study contribute to the understanding of early immunologic defense responses in invertebrate hosts to viral challenge, and this study paves the way for further experiments which investigate the roles of genes and pathways in antiviral immunity.
Results and discussion
Genome-wide analysis of the Drosophila early immune response to DCV
The list of DCV infection affected genes
The number of affected genes
275 up-regulated genes
18w, a, Ald, alpha-Adaptin, alpha-Est1, alphaPS4, alphaPS5, AnnIX, alphaTub84D, aPKC, Asator, Ast, Atpalpha, AttA, AttC, AttD, b, B52, Best1, bnl, brp, bves, CaMKII, Ccn, Cct1, Cdk5, CecB, CecC, CG10011, CG10103, CG10337, CG10581, CG10630, CG10641, CG10657, CG10702, CG10962, CG1124, CG11353, CG11671, CG11779, CG11790, CG11791, CG11825, CG11897, CG12014, CG12054, CG12112, CG12290, CG12418, CG12477, CG12883, CG12896, CG13078, CG13196, CG13248, CG13335, CG1340, CG13482, CG14015, CG14085, CG14322, CG14340, CG14545, CG14567, CG14801, CG14879, CG15097, CG15308, CG15543, CG15673, CG1600, CG16717, CG16718, CG16833, CG17599, CG17660, CG17681, CG18528, CG18557, CG18643, CG18769, CG30108, CG30115, CG30281, CG30421, CG30466, CG30502, CG31012, CG31323, CG31324, CG31431, CG31522, CG31523, CG3168, CG31778, CG32048, CG32066, CG32170, CG32206, CG32207, CG32313, CG32512, CG32982, CG33099, CG3348, CG34330, CG34349, CG34360, CG34383, CG34404, CG3788, CG3884, CG42327, CG42348, CG4455, CG4570, CG4629, CG4726, CG5174, CG5246, CG5346, CG5535, CG5758, CG5919, CG6051, CG6125, CG6231, CG6330, CG6357, CG6498, CG6767, CG7056, CG7251, CG7510, CG7720, CG7778, CG7794, CG7816, CG7841, CG7888, CG8008, CG8046, CG8177, CG9119, CG9222, CG9238, CG9312, CG9626, CG9641, CG9663, CG9812, CG9932, cher, chn, chrb, Cortactin, Cpr67Fa1, Csk, Cyp4g1, DAAM, dally, Dhap-at, drl, Ets21C, ewg, fra, Gadd45, GlcAT-S, Gli, Gp150, Gr94a, gsb, h, Hip1, Hsp22, Hsp70Aa, Hsp70Ba, Hsp70Bc, ifc, ImpL2, ImpL3, insc, inx2, Irk3, jar, JhI-21, Jupiter, kay, kel, KP78b, KrT95D, lcs, Lerp, Lis-1, Lmpt, loco, LpR2, Luna, Mctp, Mf, Mmp1, moody, Mpk2, mthl2, Mtk, MtnA, Myo28B1, Myo31DF, mys, nahoda, nau, nes, Nhe3, nkd, Nrt, Oatp30B, Obp44a, Or19a, ovo, Pabp2, pain, Pak, path, Pde8, Phk-3, pirk, Pka-C3, PKD, pot, ppk10, Prx2540-2, puc, Pvf2, Rel, Rep, Rgn, RhoGEF3, RhoL, RN-tre, rogdi, RpS5b, rtGEF, scarface, sdk, shn, SIP3, slgA, Socs36E, Sox14, spir, Stam, stv, Su(dx), tamo, Thor, tmod, Tom34, Trc8, Tsp, Tsp42Eg, tty, Ugt36Bb, upd2, upd3, vfl, viaf, vir-1, Vrp1, WASp, wun, wun2, yellow-b, zfh1, zpg
442 down-regulated genes
Ac13E, Ac76E, Acer, Acox57D-d, Act79B, Adk3, Amph, Ance-5, arg, armi, Atet, att-ORFA, aub, Bc, Best4, betaTub97EF, bgm, bmm, bt, by, Cad96Ca, CG10026, CG10073, CG10126, CG10131, CG10184, CG10205, CG10249, CG10336, CG10469, CG10479, CG10512, CG10550, CG10660, CG10764, CG10863, CG11063, CG11134, CG11147, CG11151, CG11319, CG11347, CG11395, CG11400, CG11638, CG11668, CG11686, CG11739, CG11943, CG12140, CG12262, CG12340, CG12512, CG12702, CG12744, CG12825, CG12970, CG13085, CG13116, CG13377, CG13559, CG13631, CG13641, CG13654, CG13707, CG13794, CG13822, CG13877, CG13897, CG14033, CG14141, CG14215, CG14216, CG14225, CG14511, CG14615, CG14619, CG14629, CG14741, CG14787, CG14803, CG14806, CG14856, CG14872, CG14933, CG14990, CG1503, CG15043, CG15161, CG15202, CG15333, CG15658, CG15739, CG15818, CG15820, CG15917, CG1607, CG1623, CG1628, CG1637, CG1648, CG16700, CG16712, CG16713, CG1674, CG16947, CG1702, CG17029, CG17032, CG17167, CG17270, CG17322, CG17323, CG17350, CG17549, CG17597, CG17839, CG17928, CG18446, CG18522, CG18549, CG18563, CG18622, CG2003, CG2052, CG2444, Cg25C, CG2893, CG30017, CG30069, CG30085, CG30090, CG30104, CG30148, CG30217, CG30269, CG30273, CG30345, CG30359, CG3036, CG30377, CG30460, CG30463, CG30479, CG30492, CG31048, CG31075, CG31145, CG31274, CG31313, CG31326, CG31454, CG31477, CG31601, CG31607, CG31674, CG31675, CG3184, CG31886, CG3191, CG31974, CG31999, CG32017, CG32085, CG32091, CG3224, CG32306, CG32320, CG32354, CG32364, CG3246, CG32582, CG3259, CG32613, CG32647, CG32700, CG32812, CG33225, CG33252, CG33275, CG33465, CG3402, CG34331, CG34398, CG34436, CG3505, CG3635, CG3829, CG3831, CG3857, CG3902, CG40160, CG4019, CG40244, CG41265, CG42259, CG42296, CG42345, CG42358, CG42369, CG42394, CG4250, CG42611, CG4325, CG4351, CG4389, CG4398, CG4484, CG4576, CG4598, CG4615, CG4666, CG4733, CG4928, CG4949, CG5080, CG5167, CG5191, CG5322, CG5381, CG5397, CG5455, CG5707, CG5731, CG5853, CG5895, CG5955, CG5958, CG5973, CG6045, CG6188, CG6199, CG6208, CG6232, CG6289, CG6410, CG6426, CG6639, CG6687, CG6812, CG6836, CG6951, CG7059, CG7083, CG7091, CG7120, CG7149, CG7255, CG7280, CG7320, CG7322, CG7358, CG7458, CG7607, CG7777, CG7781, CG7966, CG7985, CG7995, CG7997, CG8066, CG8080, CG8097, CG8112, CG8157, CG8211, CG8213, CG8353, CG8398, CG8399, CG8451, CG8501, CG8586, CG8668, CG8788, CG9008, CG9098, CG9117, CG9232, CG9331, CG9338 , CG9416, CG9463, CG9505, CG9541, CG9577, CG9616, CG9624, CG9691, CG9973, CG9989, cpo, Cpr49Ac, Cpr65Au, Cpr97Eb, CPTI, CREG, Cyp12c1, Cyp12d1-d, Cyp18a1, Cyp28a5, Cyp28d1, Cyp4ac1, Cyp4d2, Cyp4s3, Cyp6a13, Cyp6a14, Cyp6a21, Cyp9f2, Cyp9h1, Cys, Dh, dj-1beta, DNApol-alpha50, DNaseII, dpp, dpr17, drpr, eater, edl, egr, Ela, fan, fbp, fng, fru, fz2, GLaz, glob1, Glt, grh, GstD4, GstD5, GstD6, GstD7, He, Hil, hoe1, Hr51, Hsp60B, htl, if, ine, Invadolysin, inx3, Irp-1B, Jheh3, Kap-alpha3, l(3)neo38, lectin-24A, lectin-28C, lin-28, Lip4, Lkr, lox, mAcR-60C, mav, mbc, Mcm6, mew, mex1, mspo, Myd88, MYPT-75D, nAcRalpha-30D, Nep4, NetB, Nha2, nimB2, nimB3, nimB4, nimB5, nimC1, nimC2, Oat, Oatp33Ea, Obp18a, Obp99a, Obp99c, obst-A, olf186-M, out, Pde6, Pdk, PGRP-LE, Pka-R2, PNUTS, prc, Prestin, Pxn, pyd, pyd3, qtc, r-cup, rdgB, rg, Rgk1, Rph, Rpt3R, ry, scpr-A, scu, shf, Sip1, Sk1, skpB, sls, sn, snk, Sp212, sqz, Sr-CI, Sry-alpha, stnA, Strn-Mlck, su(r), Sucb, Sur, sut1, Taf12L, TepI, topi, TotA, troll, Tsp29Fa, Tsp2A, Tsp5D, TwdlE, twi, Ubc84D, Ugt35a, Ugt36Bc, Ugt86Dd, Vago, veil, vkg, W, wnd, y, yellow-f2, yellow-h, yip2
Expression profiles of selected important immune genes revolved in early immune response to DCV, inDCV and inWSSV
Gene (GenBank accession number)
Immunity signal transduction
JAK/STAT pathway is involved in antiviral immunity in Drosophila
Toll pathway is involved in early response to Drosophila C virus
Imd pathway is involved in early response to Drosophila C virus
RNAi pathway was not activated in early response to Drosophila C virus
Previous studies have shown that RNA interference played a critical role in the control of viral infections in Drosophila and Ago2, Ars2, Dcr-2 and R2D2 as the core antiviral RNAi machinery [10, 35, 36]. However, the relative expression of Ago1, Ago2, Ars2, Dcr-1, Dcr-2, R2D2 and Drosha, which are important to antiviral RNAi pathway in Drosophila, remained stable in all three experimental groups (data not shown). The antiviral RNAi pathway was not activated in S2 cells by 1 hour post incubation with DCV or inWSSV. Virus infection in Drosophila initiates a specific transcriptional response, including the induction of Vago, a recently identified antiviral molecule that is required to restrict viral replication in flies . In this study, Vago was significantly down-regulated (P<0.01) in all three treatments (Table 2). The data indicate that the antiviral RNAi pathway was not induced in S2 cells at 1 hour post incubation with DCV or inWSSV. Previous studies also showed that DCV encodes a dsRNA-binding protein, DCV-1A, which suppresses RNA silencing in Drosophila[38, 39].
Materials and methods
Maintenance of Drosophila S2 cell line and treatment
Drosophila S2 cells were cultivated at 28°C in Schneider’s Drosophila medium (Ivitrogen, USA) supplemented with 10% fetal bovine serum (Gibco, USA). DCV was inoculated in S2 cells at a multiplicity of infection (MOI) of 1 for 4 days and collected for purification as described before . Then S2 cells were infected with purified DCV at a multiplicity of infection (MOI) of 1. DCV at a multiplicity of infection (MOI) of 1 was UV-inactivated by exposure to a total of 12, 000 mJ UV light (5×3 min) as inactivated DCV (inDCV), and then S2 cells were inoculated with UV-inactivated DCV. The WSSV were purified from WSSV-infected shrimp according to the previous methods . The WSSV virions were UV-inactivated by exposure to a total of 12, 000 mJ UV light (5×3 min). Subsequently the inactivated WSSV virions (1 × 107 copies/mL) were inoculated in S2 cells (1 × 106 cells/mL). After one hour, the S2 cells were collected and subjected to oligonucleotide microarray.
Analyses of mRNA expressions with oligonucleotide microarray
The total RNA was extracted from treated S2 cells by using Trizol reagent (Invitrogen, USA) according to the manufacturer’s instructions. The total RNA samples were then analyzed by CapitalBio Corp for Drosophila GeneChip (Affymetrix) assay. And each treatment has 3 biological replicates that were measured by this way. Gene expression analysis was performed by using the Affymetrix (Santa Clara, CA, USA) Drosophila GeneChip, using the laboratory methods in the Affymetrix GeneChip expression manual. Gene expression analysis was performed using triple arrays and triple independent mRNA samples for each treatment. Microarray data were analyzed by using Bio MAS (molecule annotation system) 3.0 software (CapitalBio Corporation, Beijing, China). Using the criterion of cutoff limitation as a fold change ≥ 2 or ≤0.5 and q-value ≤ 5%, differential expression genes were screened and clustered.
Biological pathway analysis
Through array analysis, the commonly altered genes were screened from DCV, and WSSV treatments. The selected genes were further analyzed in the context of Gene Ontology (GO) biological process and Kyoto Encyclopaedia of Genes and Genomes (KEGG) biological pathway. Then the results of signaling pathway and protein interaction about these genes were analyzed by MAS 3.0 software. To reveal the functions of predicted target genes, we used the ontology classification of genes based on gene annotation and summary information available through DAVID (Database for Annotation, Visualization and Integrated Discovery).
Transmission electron microscopy assay
The S2 cells were pelleted and fixed in the fixative containing 2% paraformaldehyde and 2% glutaraldehyde in 0.1 M sodium cacodylate buffer (pH 7.4) for 18 h at room temperature. Each sample was washed three times with 0.1 M sodium cacodylate buffer at room temperature. Then the sample was postfixed with 2% osmium tetroxide in 0.1 M sodium cacodylate buffer with constant rotation for 1h, followed by washes three times using 0.1 M sodium cacodylate buffer at room temperature. The sample was stained with 2% uranyl acetate in 0.2 M sodium acetate buffer (pH 5.2) for 1 h at room temperature and subsequently washed three times with 0.2 M sodium acetate buffer at room temperature. The sample was dehydrated in an ascending acetone series (50, 60, 70, 80, 90, 95, and 100%) and then in 100% propylene oxide for 10 min with constant rotation at room temperature. After infiltration of sample with EMBED 812/Araldite 502 resin at room temperature, sections were prepared in a Reichert Ultracut OMU3 microtome (Leica, Germany) at 100 nm thickness, followed by staining with 2% uranyl acetate/70% methanol. The images were collected on a Hitachi 7650 transmission electron microscope (Hitachi, Japan) operating at 70 kV.
Statistical significance was determined by Student's t-test (two-tailed distribution with a two sample equal variance). P-values of less than 0.05 were considered significant and less than 0.01 were considered very significant.
This work was financially supported by National Natural Science Foundation of China (31001127).
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