Avian Tembusu virus infection effectively triggers host innate immune response through MDA5 and TLR3-dependent signaling pathways
© The Author(s) 2016
Received: 19 October 2015
Accepted: 17 May 2016
Published: 22 July 2016
Avian Tembusu virus (ATMUV) is a newly emerged flavivirus that belongs to the Ntaya virus group. ATMUV is a highly pathogenic virus causing significant economic loss to the Chinese poultry industry. However, little is known about the role of host innate immune mechanism in defending against ATMUV infection. In this study, we found that ATMUV infection significantly up-regulated the expression of type I and type III interferons (IFN) and some critical IFN-stimulated genes (ISG) in vivo and in vitro. This innate immune response was induced by genomic RNA of ATMUV. Furthermore, we observed that ATMUV infection triggered IFN response mainly through MDA5 and TLR3-dependent signaling pathways. Strikingly, shRNA-based disruption of IPS-1, IRF3 or IRF7 expression significantly reduced the production of IFN in the 293T cell model. Moreover, NF-κB was shown to be activated in both chicken and human cells during the ATMUV infection. Inhibition of NF-κB signaling also resulted in a clear decrease in expression of IFN. Importantly, experiments revealed that treatment with IFN significantly impaired ATMUV replication in the chicken cell. Consistently, type I IFN also exhibited promising antiviral activity against ATMUV replication in the human cell. Together, these data indicate that ATMUV infection triggers host innate immune response through MDA5 and TLR3-dependent signaling that controls IFN production, and thereby induces an effective antiviral immunity.
Avian Tembusu virus (ATMUV), a newly emerged flavivirus, is the causative agent of acute egg-drop syndrome in domestic poultry of China since 2009 [1–4]. Clinical symptoms of the infected birds are characterized by anorexia, ataxia and abrupt drop in egg production [1–4]. Similar symptoms have been reported in young Pekin ducks from Malaysia, where infected birds showed neurological disorders, including ataxia, lameness and paralysis in year 2012 . To date, ATMUV infection has been confirmed in ducks, chickens and geese, and it causes significant economic losses to the poultry industry in China. In addition, a number of humans have been found to be positive for high levels of serum-neutralizing antibodies against Tembusu virus, suggesting that this virus has zoonotic potential . Moreover, RNA of ATMUV and neutralizing antibodies had also been detected in duck farm workers in Shandong, China . This evidence suggests that ATMUV could be a threat to farm workers. Despite its zoonotic risk, no commercial vaccine or specific therapy has been developed to prevent and control the ATMUV infection. Importantly, pathogenesis of ATMUV is still not fully understood.
The host innate immune system provides the first line of defense against pathogens, which is the more rapid immune response but lacks memory and specificity as compared to adaptive immunity [8, 9]. Host cells recognize the pathogens by sensing the different molecules or structure of the pathogen, which are known as pathogen associated molecular patterns (PAMP) via pattern recognition receptors (PRR). Such receptors include Toll-like receptors (TLR), the RIG-I like receptors (RLR) and NOD like receptors (NLR) . To date, 13 TLR in mammals and 10 TLR in chickens have been identified [11, 12]. RLR comprise three helicases: RIG-I, melanoma differentiation associated protein 5 (MDA5), and laboratory of genetics and physiology 2 (LGP2) [8, 13, 14]. Upon sensing viral infection, particular PRR that contain caspase-recruiting domains (CARD), interacts with interferon-β promoter stimulator-1 (IPS-1, also known as VISA, MAVS or Cardif) through CARD–CARD interaction. This interaction activates members of the IKK protein kinase family [15, 16]. The canonical IKK family members IKKa and IKKb mediate the phosphorylation and degradation of I-κB, an inhibitor of NF-κB, leading to activation of NF-κB. The non-canonical IKK family members TBK1 and IKBKE activate the interferon regulatory factor 3 (IRF3) and IRF7 to form a functional homodimer or heterodimer. Thus, the transcription factors IRF and NF-κB translocate to the nucleus to stimulate expression of interferon (IFN) and pro-inflammatory cytokines [16–18]. IFN induce the downstream synthesis of hundreds of antiviral proteins encoded by IFN-stimulated genes (ISG). Various ISG proteins such as IFIT, IFITM, Mx1 and OASL, play key roles in host immune defense against viral infections [19–21]. Therefore, the IFN-activated signaling pathway is an important component of the innate immune system and has been implicated in clinical antiviral treatment .
There are three distinct interferon families that have been identified in both mammalian and avian species: type I IFN, type II IFN and type III IFN . Type I IFN is comprised of IFN-α and IFN-β; while the type II is comprised of IFN-γ only. The recently classified type III IFN is comprised of IFN-λ (lambda) which consists of three members named as IFN-λ1, IFN-λ2 and IFN-λ3 (also called IL-29, IL-28A and IL-28B, respectively) [24, 25]. However, only one IFN-λ gene appears to exist in chickens . Type I and type III IFN are the principal cytokines that mediate early antiviral responses, whereas type II IFN produced by T cells and NK cells is an important regulator of cellular immunity and is a classical regulator of Th1 immunity . It is well known that expression of type I IFN is regulated through two phases during viral infection. At the early phase of viral infection, phosphorylated IRF3 and IRF7 translocate to the nucleus and trigger the expression of small amounts of early IFN-β and IFN-α. In the second phase of infection, robust transcription of IFN genes is induced and newly synthesized IFN bind to the type I IFN receptor (IFNAR) and activate the JAK/STAT pathway, leading to the up-regulation of hundreds of ISG [27–29]. These antiviral components inhibit viral replication and cause apoptosis of infected cells, subsequently resulting in the clearance of the infectious pathogens . However, precise mechanisms underlying interaction between host innate immune system and numerous viruses including some flaviviruses are still not fully understood [31–34].
The flaviviruses express two key PAMP: one is the genomic ssRNA of the virus and the second is dsRNA replication intermediates. It has been previously shown that RLR and TLR3, 7 and 8 are involved in sensing the RNA viruses [10, 13, 35]. Recently, innate immune response to some Flavivirus infections have been studied, such as innate immunity against Dengue virus, Japanese encephalitis virus, and West Nile virus [15–17, 19, 34–37]. However, little information is available on the role of the innate immune system in the control of ATMUV infection. In this study, we investigated the innate immune signaling relevant to the host response against ATMUV infection. We found that ATMUV infection resulted in significant up-regulation of mRNA levels of type I and type III IFN in vivo and in vitro mainly through MDA5 and TLR3 dependent signaling pathways. Disrupting the expression of PRR, IPS-1, IRF3, IRF7 and suppressing NF-κB significantly inhibited the production of IFN-β, IL-28A/B and IL-29 in the host following ATMUV infection. These results reveal that ATMUV infection can activate host innate immune signaling pathways that govern IFN-mediated antiviral immune response.
Materials and methods
The animal protocol used in this study was approved by the Research Ethics Committee of the College of Animal Science, Fujian Agriculture and Forestry University (Permit Number PZCASFAFU2014002). All chicken experimental procedures were performed in accordance with the Regulations of the Administration of Affairs Concerning Experimental Animals approved by the State Council of China.
The antibodies used in this study are described as follows: Mouse Anti-β-actin (ab8226, Abcam, Cambridge, UK), Rabbit anti-IKBα (ZS3710, ZSQB-BIO, Beijing, China), HRP Goat anti-Rabbit IgG antibody (LP1001a, ABGENT, USA) and HRP Goat anti-Mouse IgG antibody (LP1002a, ABGENT). The pharmacological NF-κB inhibitor BAY11-7082 was purchased from Merck (Darmstadt, Germany). Recombinant human IFN-β was purchased from Pepro-Tech (Rocky Hill, NJ, USA). Avian IFN were purchased from Dalian Sanyi Animal Medicine Co. Ltd (Dalian, China). Lipofectamine 2000 was obtained from Invitrogen (Carlsbad, CA, USA).
Cell lines, birds, virus and infection
Chicken embryo fibroblasts (CEF) were prepared from 11 day-old SPF chicken embryo as previously described . 293T cells were purchased from American Type Culture Collection (Manassas, VA). Both CEF and 293T cells were cultured at 37 °C with 5% CO2 in DMEM (Sigma, USA) supplemented with 10% fetal bovine serum (FBS, HyClone, Logan, Utah, USA). ATMUV strain CJD05 used in this study was previously isolated from naturally infected egg-laying fowl in China which shares 98.3–99.3% complete genome homology with waterfowl ATMUV . Cells were infected with CJD05 and incubated for 1 h at 37 °C. Then the cells were washed once with phosphate-buffered saline (PBS) and cultured in DMEM supplemented with 2% FBS at 37 °C with 5% CO2 for 3–4 days. Three further passages of ATMUV in 293T and CEF were done using cell suspensions from the previous passage. 293T and CEF cells were infected with the 4th passage virus at the multiplicity of infection (MOI) of 1.0 and harvested at different time points (0–42 h in CEF and 0–48 h in 293T cell) post infection. Five day old specific pathogen-free (SPF) chicks (Harbin Veterinary Research Institute, Chinese Academy of Agricultural Sciences) were challenged with 0.4 mL of CJD05 (the 5th passage allantoic fluid virus, ELD50 = 10−6.0/mL) per chick by intramuscular injection. Before and post infection, three chicks were sacrificed per day and the spleens were harvested for further examination.
Viral genomic RNA and viral RNA preparation and their transfection
The ATMUV genomic RNA (VG RNA) was extracted from the purified virus particles using EasyPure Viral RNA Kit (TransGen Biotech, Beijing Co., Ltd) according to the manufacturer’s instructions and viral RNA was isolated from ATMUV infected CEF cells and control cellular RNA were prepared from uninfected CEF cells as previously described . Approximately 2.0 × 106 CEF cells per well in 6-well plates were transfected with 3 μg of VG-RNA, viral RNA and cellular RNA using Lipofectamine 2000 Transfection Reagent, respectively. The samples were examined by RT-PCR analysis 6 h after transfection.
RT-PCR, quantitative real-time PCR
Primers used in this study for RT-PCR and real time qRT-PCR
TLR3-siRNA and generation of shRNA-based knockdown cell lines
The siRNA specifically targeting human TLR3 (TLR3-siRNA) and negative control siRNA (NC-siRNA) were purchased from Sangon Biotech Co., Ltd (Shanghai, China). The TLR3-siRNA sense sequence was: 5′-CCAACUCCUUUACAAGUUUTT-3′; Antisense: 5′-AAACUUGUAAAGGAGUUGGTT-3′. NC-siRNA sense sequence: 5′-UUCUCCGAACGUGUCACGUTT-3′; NC-siRNA antisense sequence: 5′-ACGUGACACGUUCGGAGAATT-3′. Cell lines stably expressing short hairpin RNA (shRNA) specifically targeting either MDA5, TLR3, IPS-1, IRF3, IRF7, or luciferase control were generated by infection of 293T cells with lentiviruses encoding these shRNA in pSIH-H1-GFP vector as previously described [33, 39, 42].
Cell lysates were prepared, and Western blotting was performed as previously described . Briefly, protein samples were fractionated by electrophoresis on 12% SDS polyacrylamide gels, transferred to nitrocellulose membranes, and then probed with appropriate dilutions of the indicated antibodies.
The results are shown as mean values ± standard error (mean ± SE). Statistical significance was determined by the Student’s t test analysis. A level of P < 0.05 was considered to be significant.
ATMUV infection induces robust expression of particular type I and type III IFN and some critical ISG in chicken embryo fibroblasts
To define the molecular basis of how ATMUV triggers host innate immune response, we investigated the PAMP of ATMUV that induced IFN expression. For this, ATMUV VG-RNA (RNA from the purified virus particles), viral RNA (RNA from ATMUV infected CEF cells) or control cellular RNA (RNA from uninfected CEF cells) were prepared and transfected into CEF cells using Lipofectamine 2000. Indeed, expression of IFN-β, IFN-λ, Mx1 and OASL was greatly up-regulated by transfection of CEF cells with either VG-RNA or viral RNA, whereas total RNA derived from normal control cells failed to stimulate IFN and ISG expression (Figure 1G; Additional file 1B). These results indicate that ATMUV genomic RNA serves as PAMP that is sufficient to induce host innate immune response.
ATMUV infection triggers effectively innate immune response in chickens
ATMUV infection causes robust expression of type I and type III IFN and ISG in human 293T cells
ATMUV infection triggers innate immune response via MDA5 and TLR3-dependent signaling pathways
Furthermore, we examined an effect of silencing simultaneously both MDA5 and TLR3 on the expression of IFN in 293T cells. For this, 100 nM TLR3-siRNA or NC-siRNA was transfected into MDA5-knockdown or luciferase-knockdown 293T cell lines (approximately 1.0 × 106 cells/well). Twenty-four hours post transfection, the cells were infected with ATMUV at the MOI of 1.0 and harvested at 36 h post infection. Strikingly, transfection of TLR3-siRNA and MDA5 shRNA significantly disrupted the expression of both TLR3 and MDA5, associated with lower mRNA levels of IFN-β, IL-28A/B, IL-29 after ATMUV infection than those observed in cells silencing MDA5 only (Figures 5D and E). These data indicate that both TLR3 and MDA5 are implicated in host IFN response to ATMUV infection.
IPS-1 plays an essential role in ATMUV-induced up-regulation of IFN
IRF3, IRF7 and NF-κB are required for efficient expression of IFN induced by ATMUV
NF-κB is a major transcription factor that regulates genes responsible for a variety of immune responses . In non-stimulated cells, the NF-κB dimmers are sequestered in the cytoplasm by IκB. Degradation of IκB causes activation of NF-κB that enters the nucleus where it turns on the transcription of targeting genes. To evaluate the role of NF-κB in response to ATMUV infection, the protein expression of IκB-α was examined by Western blotting. We observed that IκB-α protein levels were consistently reduced in CEF and 293T cells infected with ATMUV as compared to mock control, suggesting that NF-κB is activated during the ATMUV infection (Figures 7D and E). To further determine the functional relevance of NF-κB, 293T cells were treated with either BAY11-7082, an inhibitor of NF-κB, or DMSO for 3 h, followed by ATMUV infection. As expected, expression of IFN-β, IL-28A/B and IL-29 was clearly inhibited by inactivation of NF-κB in cells infected with ATMUV (Figure 6F and Additional file 7C). Together, these data reveal that transcription factors IRF3, IRF7 and NF-κB play important roles in regulating the type I and type III IFN production in response to ATMUV infection.
Pretreatment of host cells with IFN significantly impairs replication of ATMUV
Although ATMUV was identified a long time ago, its pathogenesis is poorly understood. Sitiawan virus, a broiler-origin ATMUV, was the first strain of ATMUV that was shown to cause encephalitis and retard growth of chicks in 2000 . Since 2009, the Chinese ATMUV strain has become highly pathogenic to domestic chickens, ducks and geese with symptoms characterized by a severe egg drop and neurological syndrome [1, 2, 4]. Over the past several years, studies have been focused on ATMUV isolation, identification, genomic sequencing, diagnosis and clinical investigations [52–55]. However, the molecular mechanism underlying interaction between ATMUV and its host remains to be determined. Host innate immunity is the first line of defense against pathogen infection. This includes production of various IFN and hundreds of ISG. In a previous study, ATMUV strain JD05 was characterized as a highly pathogenic virus to chickens and ducklings, but its pathogenesis is still not clear . In this study, we explored host innate immune response following ATMUV infection. Our data establish that ATMUV infection can effectively activate host innate immune signaling and cause robust expression of several critical IFN and ISG.
Chinese ATMUV was originally isolated from sick chickens or ducks, but viral RNA and antibodies were also detected in poultry workers . ATMUV has already evolved to cross the species barrier and shows a potential threat to humans. Previous investigations have observed ducklings’ immune response to ATMUV infection [43, 56]. However, little is known about human and chicken innate immunity against ATMUV infection. In the present study, we found ATMUV infection can effectively activate both MDA5 and TLR3 mRNA up-regulation in CEF cells, 293T cells and chickens. Interestingly, human 293T cells exhibited similar innate immune response to ATMUV infection as CEF did (such as PRR and interferon up-expression). Because we have previously generated 293T cell lines stably expressing specific shRNA targeting either MDA5, RIG-I, TLR3, IPS-1, IRF3, IRF7, or luciferase control [33, 39, 42], 293T cell was selected as a model cell system to perform experimentation in this study. Our results reveal that both TLR3 and MDA5 are involved in host innate immune response to ATMUV infection. Although RIG-I is absent in chickens, chicken MDA5 might compensate for RIG-I’s function.
Different PRR recognize different microbial components and play differential roles in host antiviral defense . It has been shown that viral double-stranded RNA (dsRNA) is a ligand for TLR3 and viral single-stranded RNA (ssRNA) is a ligand for TLR7/8 . Indeed, in this study, we observed that the mRNA level of TLR3 is greatly up-regulated in the ATMUV-infected host, whereas no significant effect of ATMUV was seen on expression of other TLR including TLR1, TLR2, TLR4, TLR5, TLR7, TLR15 and TLR21. Similarly, ATMUV infection also elevated the expression of MDA5 in the host. Furthermore, silencing MDA5 and TLR3 significantly reduced the production of IFN. These results provide strong evidence that sensing ATMUV infection by MDA5 and TLR3 is critical for innate immune response during this virus infection. Previous reports showed that TLR3, MDA5 and RIG-I are involved in intracellular detection of dengue virus infection . Because chicken lacks the RIG-I , it is still unclear whether RIG-I plays a role in sensing ATMUV infection in other hosts. This remains to be further defined.
IRF3, IRF7 and NF-κB are key transcription factors that regulate expression of type I IFN and downstream effectors of ISG. In this study, our experiments demonstrate for the first time that these transcription factors are also important in regulating the expression of type III IFN during the ATMUV infection. The non-redundant roles of IRF3 and IRF7 have been documented in pathogenesis of other viruses [32, 46]. For example, the roles of IRF3 and IRF7 in innate antiviral immunity against infection of West Nile Virus and dengue virus have been verified in previous studies [7, 59, 60]. Consistent with these observations, we found that disruption of IRF3 and IRF7 or inactivation of NF-κB significantly reduces type I and type III IFN production induced by ATMUV. These data suggest that ATMUV may trigger the same innate immune signaling pathways as other flavivirus do. However, further studies are needed to address whether other transcription factors (such as IRF1 and IRF5) play roles in innate immunity against ATMUV infection.
Interferons play a vital role in the early antiviral response . It has been shown that IFN pretreatment of the host could inhibit dengue viral replication . However, the effectiveness of IFN in countering ATMUV infection has not been determined. Here, our data suggest that both avian and human cells pretreated with specific IFN can successfully suppress the replication of ATMUV. These experiments suggest that ATMUV infection activates host innate immune signaling and induces an effective antiviral immune response through production of IFN, and provide a useful line of evidence for preventing and controlling ATMUV infection using IFN in the future.
In summary, our results establish for the first time that ATMUV infection triggers effectively IFN response through MDA5 and TLR3-dependent signaling pathways involving IPS-1, IRF3, IRF7 and NF-κB. In addition, our experiments provide evidence that IFN response functions effectively suppress the replication of ATMUV. However, further investigations are still required to address the molecular mechanisms underlying complex interaction between ATMUV and the host, including how the viral non structural protein(s) antagonizes IFN response and overcomes the host innate immunity.
The authors declare that they have no competing interests.
SC performed most of the experimental work, collected and analyzed data and drafted the manuscript. GL, SC and XZ helped with the animal experiment and participated in preliminary data acquisition and statistical analysis. XC and SW contributed to shRNA design and contributed to the interpretation of results. ZY and SL carried out RNA extraction and real time PCR assay. MUG helped to design primers and draft the manuscript. J-LC and SW conceived of the study, participated in study design and coordination. All authors read and approved the final manuscript.
This work was supported by the National Basic Research Program (973) of China (2015CB910502), Natural Science Foundation of China (U1305212, U1405216), and Intramural grant of Fujian Agriculture and Forestry University.
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