CN109420162A - Purposes of the nuclear receptor binding domain protein 3 in viral infection resisting - Google Patents

Abstract

The present application relates to the use of nuclear receptor binding domain protein 3 in antiviral infection. Specifically, it relates to the use of nuclear receptor binding domain protein 3 in the preparation of a drug for treating viral infection, wherein the virus is selected from RNA viruses and DNA viruses. The method of the present application can reduce the replication of the virus, reduce the titer of the virus, improve the survival of the subject, and improve the expression level of type I interferon. The present application also relates to the use of an agent targeting nuclear receptor binding domain protein 3 in preparing an animal model of virus infection. Compared to control animals, the animal model exhibits decreased antiviral capacity, increased viral replication, increased viral titers, decreased expression levels of type I interferon, and decreased survival. The present application can realize the regulation of the effect of type I interferon in the treatment of viral infection, and provide a new target for the prevention and treatment of viral infection and related diseases.

Description

Use of nuclear receptor binding domain protein 3 in antiviral infection

technical field

This application belongs to the fields of biotechnology and medicine. Specifically, the present application relates to the use of a protein molecule NSD3 (nuclear receptor-binding SET domain 3) containing a SET domain in the prevention or treatment of viral infection-related diseases.

Background technique

The natural immune response is the first line of defense against the invasion of pathogenic microorganisms from outside the body, and viral infection seriously threatens human health. The body's immune cells and other tissue cells can recognize the DNA and RNA of the invading virus through pattern recognition receptors (PRRs), activate the corresponding signal transduction pathways, and then induce type I interferons (IFNs) and other Proinflammatory cytokine production (Honda, K et al. Immunity. 25, 349-360, 2006).

TLR3 (Toll-like Receptor 3) located in the endosome can recognize the double-stranded RNA (dsRNA) of the engulfed virus; TLR7, TLR8, TLR9 located in the endosome recognize the DNA of the engulfed virus (Heil F et al. Human Science. 303:1526–1529, 2004). After TLRs recognize viral DNA or RNA, they recruit the linker molecule MyD88 or TRIF, and then activate the IκB kinase complex and IKK-related kinases, such as TBK1 and IKKε. The transcription factor NFκB is activated by the activated IκB kinase complex and enters the nucleus to promote IκB kinase complex. Type interferons and pro-inflammatory cytokine production (Yamamoto M, Sato S et al. Science. 301(5633):640-3, 2003). RLRs (RIG-I-likereceptors) located in the cytoplasm, such as RIG-I (Retinoic acid-inducible gene 1) (Schlee M. Immunobiology. 218: 1322–1335, 2013), MDA5 (Melanoma differentiation-Associated protein 5) ( Melanoma differentiation-Associated protein 5) (Peisley A et al. ProcNatl Acad Sci U S A. 109(49):E3340-9, 2012), recognizes viral RNA in the cytoplasm, and RIG-I recognizes short 5'-triphosphate dsRNA , MDA5 recognizes long dsRNA. The binding of the two to viral RNA triggers the signaling pathway mediated by the adaptor protein MAVS located on the mitochondrial surface. The MAVS protein molecule is activated by polymerization, and then binds to TBK1 or IKKε to activate it through phosphorylation. At the same time, IRF3 binds to MAVS, TBK1 phosphorylates IRF3, and then the phosphorylated IRF3 dimerizes, enters the nucleus, binds to the promoter region of type I interferon gene, and promotes its transcription and expression. Simultaneous activation of TBK1 and IKKε can phosphorylate IRF7, which also dimerizes into the nucleus, binds to the promoter of the target gene, and initiates transcription (Honda, K et al. Immunity. 25, 349–360, 2006).

Through the above signal transduction process, the production of type I interferon and other pro-inflammatory factors is promoted, and a large number of interferon-responsive genes (ISGs) are subsequently expressed, which ultimately kills, inhibits and clears the infected virus (Stark GR, Darnell JE Jr et al. Immunity). .36(4):503-14, 2012). The PRRs that recognize DNA viruses in the cytoplasm include AIM2, cGAS, RNA polymerase III and so on. After binding to viral dsDNA in the cytoplasm, AIM2 activates the inflammasome and induces the production of IL-β and IL-18 (Paludan SR et al. Immunity. 38(5):870-80, 2013); cGAS and viral dsDNA After binding, cGAMP production is promoted. STING (IFN gene stimulator, also known as MITA, ERIS or MPYS) senses cGAMP, which activates IRF3 and induces the production of type I interferons (Wallach D et al. Mol Cell; 50(1):1-2, 2013). RNA polymerase III can recognize AT-rich DNA in the cytoplasm and transcribe it into 5'-triphosphate RNA, which is then folded into 5'-triphosphate dsRNA, which is recognized by RIG-I and finally activates IRF3-induced The production of type I interferon. Therefore, the immune response is a very complex response system. The body achieves a moderate immune response through fine positive and negative regulation, which can not only effectively remove pathogenic microorganisms, but also avoid immune damage to the body. Low immune response can lead to chronic infection of pathogenic microorganisms, such as HBV, HCV, HIV, etc., leading to the occurrence of malignant tumors; excessive immune response can cause acute immune damage, such as acute respiratory failure caused by SARS virus.

Interferon regulatory factor 3 (IRF3) is a key transcription factor that regulates the production of type I interferon and plays an important role in antiviral immune responses. How to precisely regulate the antiviral effect mediated by IRF3 is crucial for the body's antiviral and immune homeostasis. Downregulation of IRF3 function can lead to immune disorders such as infections and inflammatory diseases. Therefore, discovery and identification of regulators of IRF3 are of great significance for understanding host antiviral responses and clinical applications.

Under physiological conditions, IRF3 is localized in the cytoplasm of cells. When stimulated by pathogens, IRF3 is phosphorylated by TBK1 and IKK, undergoes dimerization and nuclear translocation, and drives transcription of target genes in the nucleus (Takeuchi, O and Akira, S. Immunol. Rev. 227, 75-86.2009 ). Current studies have found that IRF3 transcriptional signals are regulated in various ways, mainly post-translational modifications (PTMs), such as phosphorylation, dephosphorylation and ubiquitination. IRF3 can be dephosphorylated by protein phosphatases (such as PTEN, PP2A, MAPK) and lose its transcriptional activity (Li, S et al. 2016. Nat. Immunol. 17, 241-249; Png, C.W and Zhang, Y.. Oncotarget 6, 19348-19349.2015). IRF3 can be ubiquitinated and degraded by the proteasome, downregulating IRF3 expression and reducing its transcriptional activity. For example, E3 ligase RBCC protein binds to PKC1 and RTA-associated ubiquitin ligase (RAUL) (Zhang, M et al. Cell Res. 18, 1096-1104.2008; Yu, Y and Hayward, G.S. Immunity 33, 863-877.2010 ).

In addition to the above-mentioned traditional PTMs, PTMs such as hematoxylation, glycosylation and acetylation have been found in IRF3 (Maarifi, G et al. Virus. J. Virol. 90, 6598-6610, 2016). However, the research on whether there is methylation modification state of IRF3, the effect of methylation on its own transcriptional activity and the role of which methylase is still in the blank.

Protein methylation is an important PTM, especially protein lysine methylation plays an important role in regulating intracellular signaling and molecular functions. Protein methylation exists not only in histone lysine methylated forms, but also in non-histone lysine methylated forms (Biggar, K.K. et al. 2015. Nat. Rev. Mol. Cell Biol. 16, 5-17 ; Gunawan, M et al. 2015. Nat. Immunol. 16, 505-516).

In recent years, non-histone lysine methylation has attracted much attention. In particular, some important transcription factors can be methylated by protein lysine methyltransferases (PKMTs) to determine their transcriptional activity. Different protein lysine methylation modifications have different biological effects. For example, the methyltransferase SETD7 monomethylates p53 in the nucleus, enhancing p53 stability and transcriptional activity (Chuikov, S et al. (2004). Regulation of p53 activity through lysine methylation. Nature 432, 353-360); while Smyd2 mediates p53 activity through lysine methylation. The induced methylation of p53 inhibits its transcriptional activity (Huang, J et al. 2006. Nature 444, 629-632). Furthermore, STAT3-driven transcription is dependent on the methylation of EZH2 (Dasgupta, M et al. 2015. Proc. Natl. Acad. Sci. USA 112, 3985-3990).

In recent years, studies have found that protein lysine methylation also plays an important role in innate immunity, such as SETD6-mediated p65 methylation plays an important role in the regulation of inflammatory cytokines (Kim, E et al. 2013 .Cancer cell 23, 839-852). These studies suggest that non-histone lysine methylation plays an important role in regulating the transcriptional activity of transcription factors.

Nuclear receptor-binding SET domain proteins are a family of NSD proteins that belong to the histone lysine methyltransferase (HMTase) family. The NSD family includes three members: NSD1, NSD2/MMSET/WHSC1 and NSD3/WHSC1L1 (Wagner EJ et al. Nat. Rev. Mol. Cell Biol. 13, 115-126). The main domains of NSD family members include: 1 catalytic domain SET (determining methyltransferase activity), 4 PHD domains (PHD1-4) and 2 PWWP domains (mediating protein-protein interactions) binding and interacting with each other) (Pei H et al. 2011. Nature, 470, 124-128). NSD protein was originally thought to be a proto-oncogene, which is highly expressed in a variety of tumors, such as NSD1 is highly expressed in melanoma, lung cancer, neuroma and other tumor tissues; NSD3 is highly expressed in breast cancer, bladder cancer, lung cancer and liver cancer, etc. ( Hudlebusch HR et al. 2011. Clin Cancer Res, 17, 2919-2933; Kuo AJ et al. 2011. Mol Cell, 44, 609-620). The main mechanism of action of NSD family members is to methylate histones and regulate the expression of target genes. The current study found that the main target protein of the NSD family is H3K36. NSD1, NSD2 and NSD3 can mono- and di-methylate H3K36 to form H3K36me1 and H3K36me2 states and regulate the transcription of tumor-related genes (Yang, P et al. 2012.Mol.Cell.Biol.32,3121-3131) . For example, NSD1 promotes the expression of HOXA gene by methylating histone H3K36, which promotes leukemia. In recent years, studies have found that NSDs can target non-histone proteins and play important physiological functions. NSD1 can methylate NF-κB, promote its transcriptional activity and mediate inflammatory cytokine production (Lu, T et al. 2010. Proc. Natl. Acad. Sci. US A 107, 46-51); NSD2 can Directly targeting some signaling pathways, such as TWIST1, Wnt, NF-κB, etc., promote tumor formation (Yang, P et al. 2012. Mol. Cell. Biol. 32, 3121-3131); NSD3 can target NEK7 and CCNG1, plays an important role in tumor formation. The above studies suggest that there are non-histone methylation patterns in the NSD family. At present, there is no report on the role of NSDs in antiviral innate immunity.

In summary, in the field of antiviral innate immunity, there is an urgent need to develop new immunomodulatory molecules that regulate the body's antiviral immune response.

SUMMARY OF THE INVENTION

The purpose of this application is to develop new immunomodulatory molecules against viral innate immune responses, and to provide new methods and targets for the diagnosis and treatment of viral infection and viral infection-related diseases or inflammatory damage.

The present application can realize the regulation of the effect of type I interferon in the treatment of viral infection, and provide a new target for the prevention and treatment of viral infection and related diseases.

According to some embodiments of the present disclosure, there is provided the use of nuclear receptor binding domain protein 3 in the manufacture of a medicament for the treatment of viral infection.

According to some embodiments of the present disclosure, the use of nuclear receptor binding domain protein 3 as a target in the preparation of a medicament for treating viral infection is provided.

In some embodiments, the virus is selected from RNA viruses and DNA viruses.

In some specific embodiments, the RNA virus is vesicular stomatitis virus, influenza A virus, or Sendai virus.

In some specific embodiments, the DNA virus is herpes simplex virus.

In some embodiments, treating a viral infection is manifested by any one selected from the group consisting of decreasing viral replication, decreasing viral titer, increasing survival of the subject, increasing expression levels of type I interferons, and combinations thereof.

In some specific embodiments, the type I interferon is IFN-beta.

In some embodiments, the subject refers to a mammalian subject infected with a virus.

According to some embodiments of the present disclosure, there is provided the use of an agent targeting nuclear receptor binding domain protein 3 in the manufacture of a medicament for the treatment of viral infection.

In some embodiments, the agent targeting nuclear receptor binding domain protein 3 refers to an agent capable of modulating the expression level or activity of nuclear receptor binding domain protein 3 at the nucleic acid level or at the protein level.

In some specific embodiments, the agent targeting nuclear receptor binding domain protein 3 can recognize and bind to the nuclear receptor binding domain protein 3 gene or its expression product.

In some embodiments, the agent targeting nuclear receptor binding domain protein 3 is capable of modulating the level or activity of the nuclear receptor binding domain protein 3 gene or its expression product.

In some specific embodiments, the agent targeting nuclear receptor binding domain protein 3 can reduce the level or activity of the nuclear receptor binding domain protein 3 gene or its expression product.

In some specific embodiments, the agent targeting nuclear receptor binding domain protein 3 is capable of knocking out the nuclear receptor binding domain protein 3 gene.

In some specific embodiments, the agent targeting nuclear receptor binding domain protein 3 can increase the level or activity of the nuclear receptor binding domain protein 3 gene or its expression product.

In some embodiments, the expression product of the nuclear receptor binding domain protein 3 gene refers to various forms of molecules of the nuclear receptor binding domain protein 3 gene at various stages, such as, but not limited to, the nuclear receptor binding domain protein 3 gene Molecules produced during amplification, replication, transcription, splicing, processing, translation, modification, such as cDNA, mRNA, precursor proteins, mature proteins, and fragments thereof.

In some embodiments, the agent targeting nuclear receptor binding domain protein 3 is selected from the group consisting of: nucleic acids or polypeptides. In some embodiments, the nucleic acid is selected from DNA, RNA, DNA/RNA; the polypeptide is selected from: an antibody or an antigen-binding fragment thereof.

In a specific embodiment, the reagent targeting nuclear receptor binding domain protein 3 is selected from the group consisting of: knockout reagent, antisense oligonucleotide, siRNA, dsRNA, ribozyme, small interfering RNA prepared by endoribonuclease III (esiRNA) or short hairpin RNA (shRNA), eukaryotic expression vector expressing nuclear receptor binding domain protein 3.

In some specific embodiments, the knockout reagents refer to those known in the art, including but not limited to those methods mentioned in "Guide to Gene Knockout Experiments" by Marieke Aarts (in Science Press) or reagents. In some specific embodiments, the knockout reagent is a cre_loxp gene knockout system.

In some specific embodiments, targeting nuclear receptor binding domain protein 3 refers to targeting the nuclear receptor binding domain protein 3 gene or its expression product (eg, by knockout, RNA interference, overexpression) so that Modulate (increase or decrease) the level or activity of the virally infected cell nuclear receptor binding domain protein 3 gene or its expression product.

According to some embodiments of the present disclosure, the use of an agent targeting nuclear receptor binding domain protein 3 in preparing an animal model of virus infection is provided.

In some specific embodiments, the animal models of the present disclosure have any one selected from the group consisting of reduced antiviral capacity, increased viral replication, increased viral titers, decreased type I interference compared to control animals hormone (preferably IFN-beta) expression levels, decreased survival, or a combination thereof. In some specific embodiments, the expression level or activity of nuclear receptor binding domain protein 3 is not modulated in the control animal.

In some specific embodiments, in the animal model according to the present application, the expression level or activity of the nuclear receptor binding domain protein 3 is modulated at the nucleic acid level or at the protein level. The modulation is selected from the group consisting of decreasing, increasing, maintaining, activating, inactivating, knocking out, modifying, or a combination thereof.

In some specific embodiments, the expression level or activity of the nuclear receptor binding domain protein 3 is reduced or inhibited in an animal model according to the present application. In some specific embodiments, in the animal model according to the present application, the nuclear receptor binding domain protein 3 is knocked out.

In some embodiments, the animal is a mammal other than a human. In some specific embodiments, the animal is selected from the group consisting of: mice, rats, guinea pigs, rabbits, horses, monkeys, dogs. In some specific embodiments, the animal is a mouse, rat or guinea pig.

In some specific embodiments, the animal model according to the present application is infected with a virus selected from the group consisting of RNA viruses and DNA viruses.

In some specific embodiments, the RNA virus is vesicular stomatitis virus, Sendai virus, or influenza A virus.

In some specific embodiments, the DNA virus is herpes simplex virus.

In some specific embodiments, animal models according to the present application are used to screen drugs for the treatment of viral infections. For drug screening, it refers to: taking the nuclear receptor binding domain protein 3 gene or its expression product as the target, screening candidates to find the ability to regulate (inhibit, promote, reduce, increase) nuclear receptor binding domain protein 3 A candidate for the level or activity of a gene or its expression product as a drug for the treatment of viral infection or viral infection-related diseases.

According to some embodiments of the present disclosure, there is also provided a method for preparing an animal model of virus infection, which includes the step of knocking out the nuclear receptor binding domain protein 3 gene.

Description of drawings

Figure 1. NSD3 expression (mRNA) in NSD3 conditional knockout.

Figure 2. NSD3 expression (protein level) in NSD3 conditional knockout.

Figure 3. Effects of loss of NSD3 expression on macrophage phenotype.

Figure 4. Effects of loss of NSD3 expression on apoptosis in macrophages.

Figures 5A and 5B. Effects of loss of NSD3 expression on type I interferon production in virus-triggered macrophages (Figure 5A: mRNA; Figure 5B: protein levels).

Figure 6A. The content of IFN-β in peripheral blood of NSD3 knockout mice.

Figure 6B. mRNA levels of IFN-β in organs of NSD3 knockout mice.

Figure 7A. Effects of NSD3 knockout on viral replication, VSV replication assay.

Figure 7B. Effects of NSD3 knockdown on viral replication, VSV titer assay.

Figures 8A to 8D are HE staining detection of lung tissue, and detection of antiviral resistance of NSD3 knockout mice.

Figure 9 shows the analysis of mouse survival time, and the detection of antiviral resistance of NSD3 knockout mice.

Figure 10 shows the effect of NSD3 on the transcriptional activity of IFN-β mediated by IRF3 in the detection of reporter gene.

Figure 11 is a reporter gene assay, the effect of NSD3 deletion on IRF3-mediated IFN-β transcriptional activity.

Detailed ways

Example 1. Model establishment

Experiment 1. Identification of Lyz2cre conditional knockout mice

The inventors crossed NSD3loxp/loxp mice and Lyz2cre tool mice to cultivate myeloid knockout NSD3 expression conditional knockout mice NSD3lyz2-Cre ⁺ . NSD3lyz2-Cre ^- served as littermate control mice. The peritoneal myeloid cells (including: including neutrophils, macrophages and monocytes) derived from NSD3lyz2 ^- Cre- and NSD3lyz2-Cre ⁺ mice were isolated, and the knockout efficiency was verified by RT-PCR and Western. The results showed that the knockout efficiency of NSD3 in myeloid cells derived from conditional knockout mice (Fig. 1: mRNA; Fig. 2: protein level) was over 80%.

Experiment 2. Isolation of NSD3lyz2 ^- Cre- and NSD3lyz2-Cre ⁺ mouse-derived peritoneal macrophages. The effect of NSD3 on the phenotype and survival of macrophages was examined by flow cytometry (FCAS). It was found that loss of NSD3 expression did not affect macrophage phenotype (Fig. 3) and cell survival (Fig. 4).

Example 2. NSD3 knockout reduces virus-triggered type I interferon production in macrophages

Experiment 1. The inventors obtained the peritoneal macrophages derived from ^{NSD3lyz2 -} Cre- and conditional knockout mouse NSD3lyz2-Cre respectively, respectively, through virus (RNA virus: Sendai virus, VSV and influenza virus (influenza A virus); DNA virus: HSV) infection for 8 hours. Total RNA was collected, and the mRNA level of IFN-β was detected by RT-QPCR method. At the same time, the cell culture supernatant was collected, and the secretion of IFN-β was detected by ELISA. The results showed that the mRNA (Fig. 5A) and protein levels (Fig. 5B) of virus-induced IFN-β were significantly reduced in macrophages derived from NSD3lyz2-Cre ⁺ mice.

Experiment 2. VSV was injected intraperitoneally into NSD3 knockout mice and littermate control mice (n=5), and the virus was infected for 18 hours. Orbital venous blood was collected, and serum was collected. The mice were sacrificed by cervical dislocation, and the liver, spleen and lung of the mice were isolated. The content of IFN-β in peripheral blood and IFN-β in each organ was detected. The results showed that the loss of NSD3 expression significantly inhibited the production of virus-induced IFN-β in peripheral blood (Fig. 6A) and various organs of mice (Fig. 6B).

The above results indicated that knockdown of NSD3 could significantly inhibit the production of virus-induced type I interferon.

Example 3. The antiviral infection ability of NSD3 knockout mice is weakened

Experiment 1. The inventors first established a VSV infection mouse model, and injected VSV (5×10 ⁷ pfu/g, n=5) into NSD3lyz2-Cre ^- mice and NSD3lyz2-Cre ⁺ mice by intraperitoneal injection respectively, and the virus infected 18 Hour. Mice were sacrificed by cervical dislocation, and the livers, spleens and lungs of mice were isolated. Virus replication and virus titers were detected by QPCR. The results showed that virus replication (Fig. 7A) and virus titer (Fig. 7B) were significantly increased in NSD3-deficient mouse tissues.

Experiment 2. Part of each tissue sample taken in Experiment 1 was taken, fixed with 4% paraformaldehyde, and stained with HE to observe the pathological changes of lung tissue. It was found that massive inflammatory cell infiltration and destruction of alveolar structure appeared in the lung tissue of NSD3lyz2-Cre ⁺ mice after VSV infection (Figures 8A to 8D).

Experiment 3. According to the VSV infection mouse model established in Experiment 1, the effect of NSD3 on the survival period of virus-infected mice was observed. After VSV infection of NSD3lyz2-Cre ^- mice and NSD3lyz2-Cre ⁺ (n=6), the survival of mice in each group was observed every 12 hours. Conditional knockout mice NSD3lyz2-Cre ⁺ mice were found to be dead at 48 hours; 80% died at 96 hours. The littermate control mice survived well, only 20% died (Figure 9).

The above results indicated that knockout of NSD3 could significantly inhibit the production of virus-induced type I interferon and its antiviral effect.

Example 4. NSD3 enhances IRF3-mediated transcriptional activity of IFN-β

Experiment 1. The inventors further studied the mechanism by which NSD3 promotes the production of IFN-β. The effect of NSD3 on IRF3 transcriptional activity was analyzed using a reporter gene analysis system. The target gene (NSD3), luciferase reporter gene vector, PRL-TK-Renilla internal reference fluorescent reporter gene vector and corresponding amount of IRF3 expression vector were co-transfected into HEK293T cells. The activity of the target gene on IRF3-mediated IFN-β was detected. The total amount of plasmid was adjusted to consistency with empty vector. After about 24 hours, the cells were washed twice with PBS, the remaining PBS was aspirated, 50 μl/well of PLB lysis solution was added (96-well plate), the cells were lysed by shaking at room temperature for 20 min, and then 25 μl/well (Greiner 96 Flat bottom plate) was added to the machine. Read the board. Luciferase activity in cell lysates was detected using Promega's dual-luciferase reporter gene system. During data analysis, Renilla fluorescence values were used to normalize to eliminate the effect of transfection efficiency. The results showed that NSD3 could significantly promote the transcription of IFN-β mediated by IRF3 ( FIG. 10 ).

Experiment 2. The inventors constructed deletions of different domains of NSD3, including: PWWP1 (deletion of PWWP1 domain), PWWP1+PHD1-3 (deletion of PWWP1 domain), PWWP2+SET+PHD4 (deletion of PWWP2+SET+PHD4 domain), SET+PHD4 (SET+PHD4 domain missing), PHD4 (PHD4 domain missing). The effect of different deletion variants on the transcriptional activity of IRF3 was detected by reporter gene. As a result, it was found that SET+PHD4 depleted of the SET domain and NSD3 of PWWP2+SET+PHD4 could not promote the transcriptional activity of IRF3 ( FIG. 11 ).

The above findings suggest that NSD3 promotes IRF3-mediated IFN-β production and is kinase activity-dependent.

Claims (8)

1. Use of nuclear receptor binding domain protein 3 in the preparation of a medicament for the treatment of viral infection, wherein: The virus is selected from RNA viruses and DNA viruses; Preferably, the RNA virus is vesicular stomatitis virus, Sendai virus, or influenza A virus; Preferably, the DNA virus is herpes simplex virus. 2. purposes according to claim 1, wherein said treatment performance is selected from following any one: reduce the replication of described virus, reduce the titer of described virus, improve the survival of experimenter, increase I The expression level of IFN-type, and its combination; Preferably, the type I interferon is IFN-beta. 3. Use of a reagent targeting nuclear receptor binding domain protein 3 in the preparation of a medicament for the treatment of viral infection, wherein: The virus is selected from RNA viruses and DNA viruses; Preferably, the RNA virus is vesicular stomatitis virus, Sendai virus, or influenza A virus; Preferably, the DNA virus is herpes simplex virus. 4. The use according to claim 3, wherein: The described reagent targeting nuclear receptor binding domain protein 3 refers to a reagent capable of regulating the expression level or activity of nuclear receptor binding domain protein 3 at the nucleic acid level or at the protein level; Preferably, the reagent targeting nuclear receptor binding domain protein 3 is selected from: nucleic acid or polypeptide; the polypeptide is selected from antibodies or antigen-binding fragments thereof; the nucleic acid is selected from DNA, RNA, DNA/RNA; More preferably, the reagent targeting nuclear receptor binding domain protein 3 is selected from: knockout reagents, antisense oligonucleotides, siRNA, shRNA, eukaryotic expression vectors expressing nuclear receptor binding domain protein 3; The modulation is selected from: reducing, increasing, maintaining, activating, inactivating, knocking out, modifying, or a combination thereof; Preferably, the knockout reagent is the cre_loxp gene knockout system. 5. purposes according to claim 3, wherein said treatment performance is selected from following any one: reduce the replication of described virus, reduce the titer of described virus, improve the survival of experimenter, increase I The expression level of IFN-type, and its combination; Preferably, the type I interferon is IFN-beta. 6. Use of a reagent targeting nuclear receptor binding domain protein 3 in the preparation of an animal model of virus infection, wherein: Compared with a control animal, the animal model has any one selected from the group consisting of attenuated antiviral ability, increased viral replication, increased viral titer, decreased expression level of type I interferon, decreased survival; Preferably, the type I interferon is IFN-beta; The expression level or activity of nuclear receptor binding domain protein 3 in the control animal is not modulated; The described reagent targeting nuclear receptor binding domain protein 3 refers to a reagent capable of regulating the expression level or activity of nuclear receptor binding domain protein 3 at the nucleic acid level or at the protein level; Preferably, the reagent targeting nuclear receptor binding domain protein 3 is selected from: nucleic acid or polypeptide; the polypeptide is selected from antibodies or antigen-binding fragments thereof; the nucleic acid is selected from DNA, RNA, DNA/RNA; More preferably, the reagent targeting nuclear receptor binding domain protein 3 is selected from: knockout reagents, antisense oligonucleotides, siRNA, shRNA, eukaryotic expression vectors expressing nuclear receptor binding domain protein 3; The modulation is selected from: reducing, increasing, maintaining, activating, inactivating, knocking out, modifying, or a combination thereof; Preferably, the knockout reagent is a cre_loxp gene knockout system; Preferably, the animal is a mammal other than human, selected from the group consisting of: mouse, rat, guinea pig, rabbit, horse, monkey, and dog. 7. The use according to claim 6, wherein: the virus is a DNA virus or an RNA virus; The RNA virus is vesicular stomatitis virus, Sendai virus, or influenza A virus; The DNA virus is herpes simplex virus. 8. The use according to claim 6, wherein: The animal model is used for screening antiviral drugs.