Type I interferon receptor-independent and -dependent host transcriptional responses to mouse hepatitis coronavirus infection in vivo
© Raaben et al; licensee BioMed Central Ltd. 2009
Received: 23 April 2009
Accepted: 3 August 2009
Published: 3 August 2009
The role of type I IFNs in protecting against coronavirus (CoV) infections is not fully understood. While CoVs are poor inducers of type I IFNs in tissue culture, several studies have demonstrated the importance of the type I IFN response in controlling MHV infection in animals. The protective effectors against MHV infection are, however, still unknown.
In order to get more insight into the antiviral gene expression induced in the brains of MHV-infected mice, we performed whole-genome expression profiling. Three different mouse strains, differing in their susceptibility to infection with MHV, were used. In BALB/c mice, which display high viral loads but are able to control the infection, 57 and 121 genes were significantly differentially expressed (≥ 1.5 fold change) upon infection at 2 and 5 days post infection, respectively. Functional association network analyses demonstrated a strong type I IFN response, with Irf1 and Irf7 as the central players. At 5 days post infection, a type II IFN response also becomes apparent. Both the type I and II IFN response, which were more pronounced in mice with a higher viral load, were not observed in 129SvEv mice, which are much less susceptible to infection with MHV. 129SvEv mice lacking the type I interferon receptor (IFNAR-/-), however, were not able to control the infection. Gene expression profiling of these mice identified type I IFN-independent responses to infection, with IFN-γ as the central player. As the BALB/c and the IFNAR-/- 129SvEv mice demonstrated very similar viral loads in their brains, we also compared their gene expression profiles upon infection with MHV in order to identify type I IFN-dependent transcriptional responses. Many known IFN-inducible genes were detected, several of which have previously been shown to play an important protective role against virus infections. We speculate that the additional type I IFN-dependent genes that we discovered may also be important for protection against MHV infection.
Transcriptional profiling of mice infected with MHV demonstrated the induction of a robust IFN response, which correlated with the viral load. Profiling of IFNAR-/- mice allowed us to identify type I IFN-independent and -dependent responses. Overall, this study broadens our present knowledge of the type I and II IFN-mediated effector responses during CoV infection in vivo.
Cytokines are key regulators that dictate many aspects of innate and adaptive immunity. Induction of type I interferons (IFNs), a well-known subset of cytokines with antiviral activity, is triggered by a selection of cellular pattern recognition receptors, including TLRs (Toll-like receptors), RIG-I (retinoic acid-inducible gene I), and MDA5 (melanoma differentiation-associated protein 5). These receptors are activated in response to a range of pathogen-specific factors, which includes double-stranded RNA produced during virus infection [1, 2]. Secreted type I IFNs (i.e. IFN-α and IFN-β), subsequently induce an antiviral transcription program in the infected cell as well as in adjacent cells, thereby magnifying the "danger" signal and protecting against the infection.
The role of type I IFNs in controlling coronavirus (CoV) infections is not well understood. A number of studies has shown that CoVs, like the mouse hepatitis virus (MHV) and the severe acute respiratory syndrome (SARS)-CoV, are poor inducers of type I IFNs in cell culture, and even escape from detection by cytoplasmic pattern recognition receptors [3–8]. Consistently, virus-encoded IFN antagonistic functions have been described for both MHV and SARS-CoV [9, 10]. In vivo, however, MHV infection appeared to induce the production of IFN-α in plasmacytoid dendritic cells (pDCs) by a TLR7-dependent mechanism . Moreover, MHV infections of primary neuronal cultures and of the central nervous system (CNS) induced IFN-β gene expression, indicating that the production of type I IFNs in vivo is not limited to pDCs [12, 13]. Furthermore, neuronal cultures infected with MHV exhibited increased expression of several type I IFN-induced transcription factors . More recently, Roth-Cross and co-workers reported that macrophages and macrophage-like microglia cells produce IFN-β in the CNS of MHV-infected mice in a MDA5-dependent manner .
Several studies have demonstrated the importance of the type I IFN response in controlling MHV infection in vivo. The exogenous delivery of type I IFNs was shown to inhibit MHV infection of and spread to the mouse brain [16, 17]. Consistently, infection of mice lacking the functional type I IFN receptor (IFNAR-/-) with MHV resulted in increased viral replication and extended tissue tropism [11, 17, 18]. Although many type I IFN-responsive genes have been identified , the protective effectors against MHV infection are yet unknown .
In order to get more insight into the antiviral gene expression induced in the brains of MHV-infected mice, we performed whole-genome expression profiling. Three different mouse strains (BALB/c, 129SvEv and IFNAR-/- 129SvEv mice), differing in their susceptibility to infection with MHV, were used. Previously, we have observed that 129SvEv mice are significantly more resistant to infection via the intranasal route than BALB/c mice . The reason for the significant difference in susceptibility is not known, but may be related to different antiviral immune responses in these two mouse strains. Furthermore, gene expression profiling of 129SvEv mice lacking the type I IFN receptor, which are not able to control the MHV infection , allowed us to identify type I IFN-independent transcriptional responses.
Results & discussion
Next, the RNA extracts were processed for microarray analysis using the PBS-inoculated groups as the reference. In total, 57 and 121 genes were significantly differentially expressed (≥ 1.5 fold change) in BALB/c mice at 2 and 5 days post infection, respectively. In contrast, in the 129SvEv mice, no significant induction of gene expression was observed. The results are depicted in Figure 1B as a gene tree that was built based on the genes with a significantly altered expression level in BALB/c mice at 5 days post infection (i.e. expression-based cluster analysis). From these data we were able to identify host genes, the increased expression (≥ 1.5 fold) of which could already be detected at day 2 (i.e. early genes; Figure 1C) or only at day 5 (i.e. late genes; Figure 1D). The group of early-induced transcripts contained many IFN-inducible genes, including the well-known interferon regulatory factor 7 (Irf7), signal transducer and activator of transcription 1 (Stat1), and 2'-5' oligoadenylate synthetase (Oas) genes (Additional file 1A). Within the cluster of "late" genes (Additional file 1B) several chemokines (i.e. Ccl2, Ccl5, Ccl7, Cxcl9, and Cxcl10) could be identified.
To confirm and extend these observations, we next analyzed the induction of type I and II IFN gene expression (i.e. IFN-α4 and IFN-β1, and IFN-γ, respectively) by using quantitative RT-PCR. In agreement with the microarray expression profiles, significant induction of these type I and II IFNs could only be detected in the MHV-infected BALB/c animals (Figure 1E). The observation that the BALB/c mice, unlike the 129SvEv mice, exhibited abundant expression of IFN-responsive genes upon MHV infection appears counter intuitive as the 129SvEv mice are much more resistant to the infection than the BALB/c mice. Apparently, the resistance of 129SvEv mice to MHV infection is not controlled by a more robust IFN response. The reason for the observed difference in susceptibility between the different mouse strains after intranasal inoculation is not known. MHV-A59 was recently shown to replicate efficiently in the liver of 129SvEv mice after intraperitoneal inoculation . Interestingly, the resistance of 129SvEv mice after intranasal inoculation is not restricted to infection with MHV, as it was also observed for vesicular stomatitis virus .
Whole-genome expression profiling of brains of the IFNAR-/- mice revealed the significantly induced expression of 73 genes (≥ 1.5 fold) at 5 days post infection. In contrast, at day 2, hardly any alterations in gene expression could be detected in these knock-out mice (Additional file 3). Figure 4C shows an expression-based cluster analysis of these 73 genes for the wild-type and IFNAR-/- mice. Comparison of the complete expression profiles of these mice revealed that the transcriptional profile at day 5 in the IFNAR-/- mice has a larger similarity with the profile at day 2 of the parental 129SvEv mice than with that of the knock-out mice at day 2 post infection (Figure 4C). This observation may suggest the presence of an early host response to infection with MHV in the parental mice, even though no significant induction (≥ 1.5 fold) of gene expression could be detected (Figure 1B). Such a response, may not be evident in transcriptional profiles of whole organs, but might only be apparent at the cellular level. We speculate that early decisive events are happening in initial target cell populations such as DCs and macrophages . These responses could prevent extensive viral replication very early after infection, thereby reducing subsequent type I IFN responses.
As the knock-out mice lack a functional type I IFN receptor, the upregulation of gene expression observed in these mice apparently occurs independently of type I IFN signalling. Not much is known yet about type I IFN-independent responses to infection. The observation that the transcriptional upregulation of Irf1 was independent of type I IFN signalling is consistent with the notion that IFN-γ can also induce expression of this gene [32, 33]. Likewise, we also observed increased transcription of Ifitm1 and Ifitm3 independent of type I IFN signalling, again corresponding with the literature [34, 35]. Interestingly, the expression of various genes encoding proteins involved in antigen presentation (i.e. H2, B2m, Psmb8, Psmb9, and Ctss) was also increased in the absence of type I IFN signalling. Psmb8 and Psmb9 encode immunoproteasome subunits which facilitate antigen presentation to CD8+ T cells after virus infection, a process that is primarily regulated by IFN-γ . Furthermore, also the expression of the major histocompatibility complex class II (MHC II) invariant chain, also called CD74 , was increased upon infection of the knock-out mice. These data are in agreement with the observation that the induction of genes involved in antigen processing is independent of STAT1 activation by IFN-α . We also observed the transcriptional upregulation of the 3 isoforms of metallothionein (Mt1, Mt2, and Mt3), which encode proteins known to scavenge toxic metals . The induction of these genes, which was not apparent in either wild-type mice, could reflect an acute-phase reaction in the brain of MHV-infected IFNAR-/- mice, which likely contributes to pathogenesis as has been shown for other viruses [40–42].
Several studies have shown that MHV [11, 15, 17] as well as several other viruses [48–50] replicate to much higher levels (up to 105 fold difference) in IFNAR-/- mice than in their wild-type counterparts. In this study we show that a strong correlation exists between the amplitude of type I and II IFN host responses with the viral load. The huge differences in virus replication between wild-type and IFNAR-/- mice therefore do not permit a fair comparison between gene expression profiles of these mice, with the aim of identifying type I IFN-dependent responses. Indeed, as no significant gene expression is observed in the wild-type 129SvEv mice, a comparison with the expression profile of the IFNAR-/- mice only provides information about type I IFN-independent and not IFN-dependent responses. We now observe, in agreement with our previous study, that the brain of BALB/c and IFNAR-/- 129SvEv mice contain very similar MHV loads at day 2 and 5 post infection . Since the type I IFN-responsive pathway is very well conserved among many different species , we considered it acceptable to compare the gene expression profiles of these mice with the aim of identifying type-I IFN-dependent responses, although comparing transcriptional profiles of wild-type and IFNAR-/- mice from a different genetic background should obviously be done very cautiously. Ideally, a comparison between wild-type BALB/c and IFNAR-/- BALB/c mice would have been more accurate. While the induced expression of a number of genes was similar for the two mouse strains (i.e. type I IFN signalling-independent gene-expression), that of other genes was only observed in the BALB/c mice (i.e. tentative type I IFN signalling-dependent gene expression). The expression of yet other genes appeared to be partially dependent of type I IFN signalling: increased expression of these genes was observed in the IFNAR-/- mice, but much more so in the BALB/c mice.
Genes, the expression of which was upregulated (≥ 1.5 fold) in the BALB/c mice but not significantly changed in the IFNAR-/- mice upon infection with MHV, were tentatively designated as type I IFN-dependent. Genes, the transcriptional upregulation of which was at least 2 times higher in the BALB/c mice than in the IFNAR-/- mice, were also added to the list of tentative type I IFN-dependent genes. As expected, this set of genes (n = 82) contained many known IFN-responsive genes like Isg20, Ifit1, Ifit3, Isgf3g, Mx2 and Ube1l (Additional file 4). Functional association network analyses showed Irf1 and Irf7 to be the key players in the network (Additional file 5). Several of the tentative type I IFN-dependent genes (including Mx2 and Ube1l) have previously been shown to play an important protective role against virus infections [52–56]. We speculate that other genes present in this list may also be important for full protection against MHV infection.
Transcriptional profiling of mice infected with MHV demonstrated the induction of a robust IFN response, which correlated with the viral load. Profiling of IFNAR-/- mice allowed us to identify type I IFN-independent and -dependent responses. Overall, this study broadens our present knowledge of the type I IFN-mediated effector responses during CoV infection in vivo.
Mouse infection experiments
6–8 week old BALB/c were obtained from Charles River Laboratories, while type I IFN receptor knock-out mice (IFNAR-/-)  and the parental 129SvEv mice were obtained from B&K Universal Ltd. Mice were inoculated intranasally with 106 TCID50 of MHV strain A59 and sacrificed at the indicated time-points for organ dissection. Control animals were treated with PBS. The study protocol was approved by the animal ethics committee of the Utrecht University, and all experiments were performed in accordance with accepted institutional and governmental policies.
Tissue homogenization and isolation of total RNA
Whole brains and livers were dissected from the MHV-infected and control mice. The tissues were added to Lysing Matrix D tubes (MP Biomedical), containing 1 ml of RNApro™ solution (Q-BIOgene), and processed using a FastPrep instrument (MP Biomedical). The tissues were homogenized at 6,000 rpm for 40 sec and immediately placed on ice. Subsequently, the homogenates were centrifuged at 14,000 rpm for 10 minutes at 4°C and supernatants were harvested and stored at -80°C. Total RNA was isolated from the homogenates using the TRIzol reagent (Invitrogen) according to the manufacturer's protocol. RNA was further purified using the RNeasy mini-kit with subsequent DNaseI treatment on the column (Qiagen). RNA integrity was determined by spectrometry and by a microfluidics-based platform using a UV-mini1240 device (Shimadzu) and a 2100 Bioanalyzer (Agilent Technologies), respectively.
1 μg of total RNA was reverse transcribed into cDNA using 0.5 μM oligo(dT) primers and 20 U of M-MuLV-Reverse transcriptase (Fermentas) in a total reaction volume of 20 μl for 1 h at 37°C. Subsequently, gene expression levels of type I and II IFNs (i.e. IFN-α4 [NM_010504.2], IFN-β1 [NM_010510.1], and IFN-γ [NM_008337.3], respectively), were measured by quantitative PCR using Assay-On-Demand reagents and equipment (PE Applied Biosystems), according to the manufacturer's instructions. The quantitative PCR reactions were performed in a total reaction volume of 20 μl containing 10 μl Taqman® Universal PCR Master Mix (2×), 5 μl cDNA, 1 μl TaqMan® Gene Expression Assay Mix (20×), and 4 μl water using an ABI Prism 7000 sequence detection system under the following conditions: 95°C for 10 mins, followed by 40 cycles of 95°C for 15 secs and 60°C for 1 min. For all assays, we performed "no-RT" (reaction using total RNA as the substrate) and "no template" (reaction using water as the substrate) controls. In both cases, omitting cDNA from the reaction resulted in a lack of PCR product generation. All assays were analyzed with ABI Prism 7000 Software v1.2.3f2 (PE Applied Biosystems). The comparative Ct-method was used to determine the fold change for each gene (primer efficiencies were similar for both the endogenous control primer set and genes of interest primer sets [data not shown]). Note that the Ct values of all samples were within the limits of the standard curves (data not shown). The housekeeping gene GAPDH (NM_008084.2) was used as a reference in all experiments, since expression of this gene was found constant among samples. The amounts of viral RNA were determined by quantitative RT-PCR as described before .
The microarray experiments were performed as described previously . Briefly, mRNA was amplified from 1 μg of total RNA by cDNA synthesis with oligo(dT) double-anchored primers, followed by in vitro transcription using a T7 RNA polymerase kit (Ambion). During transcription, 5-(3-aminoallyl)-UTP was incorporated into the single stranded cRNA. Cy3 and Cy5 NHS-esters (Amersham Biosciences) were coupled to 2 μg cRNA. RNA quality was monitored after each successive step using the equipment described above. Corning UltraGAPS slides, printed with a Mouse Array-Ready Oligo set (Operon; 35,000 spots), were hybridized with 1 μg of each alternatively labeled cRNA target at 42°C for 16–20 h. Two independent dye-swap hybridizations (4 arrays) were performed for each experimental group. After hybridization the slides were washed extensively and scanned using the Agilent G2565AA DNA Microarray Scanner.
After data extraction using Imagene 5.6 Software (BioDiscovery), Lowess normalization  was performed on mean spot-intensities in order to correct for dye and print-tip biases . The microarray data was analysed using ANOVA (R version 2.2.1/MAANOVA version 0.98–7) http://www.r-project.org. Briefly, in a fixed effect analysis, sample, array and dye effects were modelled. P-values were determined by a permutation F2-test, in which residuals were shuffled 5,000 times globally. Genes with P < 0.05 after family wise error correction were considered significantly changed. Cluster analysis (standard correlation) was performed with GeneSpring GX 7.2 software (Silicon Genetics). When indicated, the confidence level was increased by applying a fold change cut-off. The resulting genelists were subjected to Genespring 7.2 software for further analysis.
ArrayExpress accession numbers
MIAME-compliant data in MAGE-ML format as well as complete descriptions of protocols have been submitted to the public microarray database ArrayExpress http://www.ebi.ac.uk/arrayexpress/ with the following accession numbers: microarray layout, P-UMCU-8; gene expression data of MHV-infected mice, E-MEXP-2081; protocols for total RNA isolation and mRNA amplification, P-MEXP-34397; cRNA labeling, P-MEXP-34400 and P-MEXP-35534; hybridization and washing of slides, P-MEXP-34401; scanning of slides, P-MEXP-34430; data normalization, P-MEXP-34431.
This work was supported by grants from the M.W. Beijerinck Virology Fund, Royal Netherlands Academy of Arts and Sciences, and the Netherlands Organization for Scientific Research (NWO-VIDI-700.54.421) to C.A.M. de Haan. We thank Connie Bergmann for advice and Monique Oostra, Marne Hagemeijer, and Mijke Vogels for stimulating discussions.
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