CN101942011A - Neutralizing epitope of human adenovirus type 3 (HAdV-3) and type 7 (HAdV-7) and application thereof - Google Patents
Neutralizing epitope of human adenovirus type 3 (HAdV-3) and type 7 (HAdV-7) and application thereof Download PDFInfo
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Abstract
The invention discloses three neutralizing epitope of human adenovirus type 3 (HAdV-3) and type 7 (HAdV-7) and an application thereof. The amino acid sequence of the neutralizing epitope of the HAdV-3 and HAdV-7 is selected from the amino acid sequence shown in SEQ ID NO: 1, 2, 3, and the nucleotide sequence of the neutralizing epitope of HAdV-3 and HAdV-7 is selected from the nucleotide sequence shown in the SEQ ID NO: 4, 5, 6. The neutralizing epitopes of HAdV-3 and HAdV-7 can be used for preparing vaccines or antibody and antigen binding fragments for preventing infection of human adenovirus type 3 and human adenovirus type 7, and the antibody and the antigen binding fragments can be used for preparing drugs for preventing or curing adenovirus infection. The drugs contain the antibody or antigen binding fragments. The invention also provides a method for preventing and curing adenovirus infection, i.e. the vaccines or drugs with immune effective quantity are applied. The three neutralized epitopes of HAdV-3 and HAdV-7 can be served as target protein for developing a diagnostic kit.
Description
Technical field
The invention belongs to bio-pharmaceutical engineer technology domain, be specifically related to human 3-type, 7 type adenovirus in and epitope and application thereof.
Background technology
Adenovirus particles is an icosahedral symmetrical structure, and housing is made up of 252 housing subunits, and what wherein be positioned at icosahedral 12 pre-angles is penton albumen and the fiber initiation that length is 10-30nm; Other 240 non-drift angle particles are to be made of six adjacent body tripolymers, can stimulate body to produce neutralizing antibody and group and type specificity antibody.The aminoacid sequence of the hexon of different type adenovirus has the homology up to 78-95%, its change mainly concentrate on the hypervariable region that is exposed to the capsid surface (Hypervariable Regions, HVRs); And the recognition site of type specificity neutralizing antibody just concentrates on these hypervariable regions.
Adenovirus hominis (Adenovirus) is nineteen fifty-three to separate on one's body, identify from the acute respiratory disease patient, is main infected person respiratory tract of a class and gastral pathogenic agent.Cut so far, the mankind have had been found that the adenovirus of 52 kinds of different serotypes of 6 kinds; Wherein have 1/3 can cause approximately as diseases such as acute respiratory infection, epidemic keratitis, acute hemorrhagic conjunctivitis, pharyngoconjunctivitis, acute pharyngitis, urocystitis, infant's lethality pneumonia; The patient mainly is infant and weak crowd.In China, have 5% to cause in the respiratory tract disease of children acute below 5 years old approximately by adenovirus; Wherein, the pneumonia that adenovirus causes is particularly serious, is a kind of virus pneumonia that is only second to respiratory syncytial virus pneumonia in the infantile pneumonia sickness rate; Serious adenovirus pneumonia not only can cause heart failure, respiratory insufficiency, can also cause that lung gets involved outward, as encephalitis, hepatic injury, myocarditis or cardiac damage etc., even causes death.The popular scope of adenovirus is wide, and velocity of propagation is fast, in recent years in a plurality of countries and regions outburst and popular, has brought great threat for people's public health security.In China, the adenovirus hypotype that causes serious respiratory tract infection mainly is 3 types, 4 types, 7 types.
The seriousness of morbific popularity of adenovirus and harm makes the control of adenovirus seem very important, and the inoculation adenovirus vaccine is one of effective means of prevention adenovirus infection.But because the neutralizing antibody that adenovirus produces can only be resisted the infection of homotype adenovirus, can not prevent other type adenovirus infections, so the antibody that 4,7 type adenovirus vaccines produce can not be resisted 3 type adenovirus infections effectively.In addition, external 4, the 7 type adenovirus vaccines that use are oral live-virus vaccines, and vaccine can produce symptomless infection and reach the effect of immunization at enteron aisle, but the adenovirus vaccine strain of discharging through ight soil still has infectious possibility.And since between the different subtype adenovirus gene have homology, take simultaneously between the adenovirus vaccine of two or more different subtypes and may carry out homologous recombination, and produce new, infective adenovirus particles is arranged, bring new infection risk.In China, the clinical use or the blank out of adenovirus vaccine.Repeatedly break out the adenovirus epidemic situation from China recent years, the independent research adenovirus vaccine is very necessary.Then can effectively address the above problem if develop a kind of replication defect type vaccine of many types of adenovirus infection that can prevent simultaneously.
Summary of the invention
For overcoming above-mentioned technological deficiency, the purpose of this invention is to provide among three of adenovirus hominis and epitope and related application thereof.
Specifically, one of purpose of the present invention provide human 3-type, 7 type adenovirus in and epitope.
In human 3-type of the present invention, the 7 type adenovirus and the aminoacid sequence of epitope be selected from following sequence: the aminoacid sequence shown in the SEQ ID NO:1,2,3; Simultaneously, allow one or more amino acid whose insertions, disappearance, substitute or add, but need to keep its structure and activity.
In above-mentioned human 3-type, the 7 type adenovirus and the nucleotide sequence of epitope be selected from following sequence: the nucleotide sequence shown in the SEQID NO:4,5,6; Simultaneously, allow one or more Nucleotide insertion, disappearance, substitute or add, but need to guarantee in the structure of this nucleotide sequence polypeptide expressed and active and above-mentioned human 3-type, the 7 type adenovirus and the structure and the activity of the aminoacid sequence polypeptide expressed of epitope consistent.
Above-mentioned aminoacid sequence be SEQ ID NO:1 or nucleotides sequence classify as shown in the SEQ ID NO:4 in and the epitope human 3-type adenovirus in and epitope, abbreviate the ADV3 epitope as.Above-mentioned aminoacid sequence be SEQ ID NO:2 and 3 or nucleotides sequence classify as shown in SEQ ID NO:5 and 6 in and epitope people 7 type adenovirus in and epitope, abbreviate ADV7-1 epitope and ADV7-2 epitope respectively as.
Two of purpose of the present invention provide these three-type-person's 3 types, 7 type adenovirus in and the related application of epitope.One of application can utilize in these three-type-person's 3 types, the 7 type adenovirus and the epitope preparation prevents 3 types or/and the vaccine of 7 type adenovirus infections.
Above-mentioned vaccine comprise these three-type-person's 3 types, 7 type adenovirus in and the polypeptide of epitope.If this vaccine only contains the ADV3 antigenic peptide, then this vaccine can only be used to prevent the infection of 3 type adenovirus hominiss.If or/and the ADV7-2 antigenic peptide is formed, then this vaccine can only be used to prevent the infection of 7 type adenovirus hominiss to this vaccine by the ADV7-1 antigenic peptide.If vaccine comprises ADV3 antigenic peptide and ADV7-1 antigenic peptide, perhaps ADV3 antigenic peptide and ADV7-2 antigenic peptide, perhaps ADV3 antigenic peptide, ADV7-1 antigenic peptide and ADV7-2 antigenic peptide, then this vaccine can be used for preventing simultaneously the infection of 3 types and 7 type adenovirus hominiss.
Two of application can utilize in these three-type-person's 3 types, the 7 type adenovirus and epitope prepares antibody or Fab, this antibody or Fab can be specifically with corresponding human 3-type, 7 type adenovirus in and epitope combine.
Further, utilize this antibody or Fab can prepare the medicine that is used to prevent or treat adenovirus infection, this medicine contains above-mentioned antibody or Fab.
Further, the present invention also provides the method for prophylactic treatment adenovirus infection, promptly uses the above-mentioned vaccine or the medicine of immune significant quantity.
Application three with in these three-type-person's 3 types, the 7 type adenovirus and epitope as target protein, be used to develop diagnostic kit.
Further, the invention provides a kind of method that detects adenovirus infection, even use above-mentioned diagnostic kit.
The invention provides three-type-person's 3 types, 7 type adenovirus in and epitope, utilize in this and can prepare the bivalent vaccine that prevents 3 types and 7 type adenovirus infections simultaneously with epitope, this recombiant vaccine has following advantage: because the adenovirus molecular weight is big, thereby can stimulate body to produce immune response effectively; Insert an exogenous antigen epi-position in hexon, then each adenovirus just can be expressed 720 epitopes, and epitope is given full expression to; The purpose antigen peptide is inserted in the hypervariable region of six adjacent bodies, is easy to be exposed to the surface of capsid, can stimulate body to produce immune response effectively; For research shows that based on the adenovirus-epitope of 3 type adenovirus carriers the recombinant vectors system lays the first stone.Simultaneously three-type-person's 3 types provided by the invention, 7 type adenovirus in and epitope can also prepare medicine antibody thing and detection kit.
Description of drawings
Fig. 1 is the 3 dimensional drawing that the present invention utilizes the hypervariable region of bioinformatic analysis prediction human 3-type, 7 type adenovirus.
Embodiment
For making the present invention easier to understand,, further set forth the present invention below in conjunction with specific embodiment.Should be understood that these embodiment only to be used to the present invention is described and be not used in to limit the scope of the invention that NM concrete experimental technique in the following example carries out according to the normal experiment method usually.
Embodiment 1: and the hypervariable region of bioinformatic analysis prediction adenovirus hominis (HypervariableRegions, HVRs)
The concrete steps of bioinformatic analysis are as follows: at first carry out adenovirus hominis hexon aminoacid sequence comparison, utilize then among the Emboss " Antigenic " instrument in possible and epitope predict.And then the 3D three-dimensional arrangement of people's 3,7 type adenovirus six adjacent bodies carried out modeling and the structural potential neutralizing epitope of 3D is drawn.Find the site that is exposed to six adjacent bodies " ring " surfaces at last and be positioned non-constant district (hypervariable region) on the sequence.
Fig. 1 is the 3 dimensional drawing of above-mentioned analytical results, and A row is vertical view, and B row is side-view.Analyze by result Fig. 1, can in potential on people's 3,7 type adenovirus six adjacent bodies and epitope position, and obtain its aminoacid sequence.Shown in aminoacid sequence is specific as follows, HVR1 wherein, 2,5,7 represent hypervariable region 1,2 respectively, 5,7:
3 type adenovirus (ADV3):
HVR1：ivttnrdnavttttnt
HVR2：keglqigkditttegeekpiyadk
HVR5：dgrdavagalapeivlyten
HVR7：ikvktddangwekdan
7 type adenovirus (ADV7):
HVR1：ivttgednattyt
HVR2：kegleigkditadnkpiyadk
HVR5：dgreaadafspeivlyten
HVR7：ikprdtawekdt
Embodiment 2: construction of recombinant virus
For by serum neutralization test and attack 3 types that malicious experimental analysis prediction obtains and 7 type adenovirus hominiss hypervariable region (HVR) in and epitope, the contriver is with overlapping PCR (overlapping PCR) method construction of recombinant virus.
With overlapping PCR (overlapping PCR) method HVR1,2,5 and 7 sequences of 7 type adenovirus are replaced to the PBR322-L-R plasmid, again with PBR-Adv3-EGFP plasmid homologous recombination.The recombinant plasmid that specifically obtains is PBR-Adv3 (Adv7-1)-EGFP, PBR-Adv3 (Adv7-2)-EGFP, PBR-Adv3 (Adv7-5)-EGFP, PBR-Adv3 (Adv7-7)-EGFP, wherein, PBR-Adv3 (Adv7-1)-EGFP represents that the hypervariable region 1 of Adv3 replaced by the hypervariable region 1 of Adv7, and other by that analogy.
Positive plasmid transfectional cell with above-mentioned reorganization obtains obtains recombinant virus MH1, MH2, MH5 and MH7; Wherein recombinant virus MH1 is obtained by recombinant plasmid PBR-Adv3 (Adv7-1)-EGFP transfectional cell, by that analogy.
Embodiment 3: serum neutralization test
In order to prepare antiserum(antisera), carry out serum neutralization test.Recombinant virus MH1, MH2, MH5 and the MH7 of purifying and the wild 3 type ADV viruses (ADV3E) and the wild 7 type ADV viruses (ADV7) of band enhanced green fluorescence protein (EGFP) are injected the Balb/C mouse peritoneal respectively.Obtain the polyclonal antibody of MH1, MH2, MH5 and MH7 and ADV3E and ADV7 respectively, carry out neutralization test then.Divide two groups to carry out neutralization test: first group is the neutralization reaction that detects between anti-ADV3E and ADV7 serum and recombinant virus MH1, MH2, MH5 and the MH7, with whether comprise in the detection recombinant virus ADV3 and ADV7 in and epitope; Second group is to detect MH1, MH2, MH5, MH7, ADV3E, ADV7 and antiserum(antisera) of normal control mouse and the neutralization reaction between the ADV3, with detect antibody that recombinant virus produces whether have in and the ability of ADV3E virus.
Concrete experimental procedure is as follows:
1, cell is prepared: after the Hep-2 cell covers with, use trysinization, add and contain 10% new-born calf serum DMEM substratum and be diluted to 96 porocyte culture plates, cell density is every hole 2 * 10
4Individual, in 37 ℃ of 5%CO
2Incubator is cultivated.
2, virus is prepared: earlier various viruses are carried out TCID
50Titration, all viral MH1, MH2, MH5, MH7, ADV7, ADV3E all are diluted to concentration 100TCID
50
3, serum is prepared: will resist MH1, MH2, MH5, MH7, ADV7, ADV3E and normal mouse serum gradient dilution to become 2 with the no phenol red DMEM that contains 2% new-born calf serum
5, 2
7, 2
9, 2
11, 2
13, 2
15, 2
17Wherein normal mouse serum is as negative control.
4, different virus is done neutralization test mutually with different serum: will dilute good virus and each serum gradient and respectively add 50 μ l, mix, put to 37 ℃ of incubations 1 hour, treat that cell grew 24 hours in cell plate, approximately evenly be paved with at 60% o'clock, exhaust the substratum in the cell plate, wash twice, add the serum-virus of hatching with PBS.Each serum gradient is done 3 parallel holes, and while every cell plate reserve 5 hole normal cells and 5 hole virus infected cells are done contrast.After adding well, put 37 ℃ of 5%CO
2Incubator is cultivated.
5, the result reads: cultivate after 72 hours, (1) because viral MH1, MH2, and MH5, MH7, the ADV3E express fluorescent protein is earlier with the fluorescence microscope and the saving result of taking pictures.Careful with the substratum sucking-off in the cell plate, with the every porocyte of trysinization, use the PBS re-suspended cell again, change special-purpose the survey in fluorescent value 96 orifice plates over to, 485nm/518nm wavelength place reading will have been surveyed after the cell multigelation 3 times of fluorescent value, and every hole is got 50 μ l extracting nucleic acid and done quantitative PCR.(2) neutralization test of ADV7 virus is parallel does 2 parts, and portion is used for toluylene red dyeing, and portion is used for quantitative fluorescent PCR.ADV7 virus shows with the toluylene red coloration result owing to be not with fluorescent mark.Remove the substratum in the culture plate earlier, add 50 μ l, 0.5% toluylene reds (being dissolved among the PBS), hatched 1 hour in 37 ℃ of incubators, 150 μ lPBS wash 2 times, add staining fluid dyeing, in the 550nm wavelength readings.
The experimental result of first group neutralization reaction sees Table 1, and table 1 is anti-ADV3E serum, anti-ADV7 serum, normal control mice serum and anti-recombinant virus serum in MH1, MH2, MH5 and the MH7 virus and experimental result.
Table 1
After data presentation transform the HVR7 of ADV3 the HVR7 of ADV7 as in the table 1, anti-ADV3E serum occurred descending to the restraining effect of MH7, thereby HVR7 is the antigen neutralizing epitope of ADV3.Anti-ADV7 serum virus has the inhibition ability to MH2 and MH5 virus infection, thereby HVR2 and HVR5 are the antigen neutralizing epitopes of ADV7.Simultaneously, anti-ADV3E serum still has neutralising capacity to MH1, MH2, MH5 virus, show HVR1, HVR2 to ADV3E and HVR5 transform do not change ADV3E in and the site, improved virus is still possessed ADV3 virus neutralizing epitope.
The experimental result of second group neutralization reaction sees Table 2, and table 2 is anti-MH1 serum virus, anti-MH2 serum virus, anti-MH5 serum virus, anti-MH7 serum virus, anti-ADV3E serum virus, anti-ADV7 serum virus, the normal control mice serum is tested ADV3E virus neutralizing capacity:
Table 2
Result by table 2 can see, the anti-MH7 serum that obtains with the MH7 immune mouse is because the HVR7 of ADV3 has been transformed into the HVR7 of ADV7, and therefore the serum that produces weakens the neutralising capacity of ADV3 virus, and then among the explanation HVR7 ADV3 and epitope.
Embodiment 4: attack the poison experiment
In order further to prove conclusively the research of neutralizing epitope and this neutralizing epitope in the vaccine application facet, carried out attacking the poison experiment, the concrete steps of this experiment are as follows:
1, routinely immune programme for children with mouse peritoneal immunity MH1, MH2, MH5, MH7, ADV3E and ADV7.
2, give mouse infection ADV7 virus with the mode of collunarium, viral level is 109 copy numbers, and the collunarium amount is 50 μ l/ mouse.
3, the the 3rd, the 5th and the 7th day behind collunarium got the mouse lung page or leaf and ground homogenate, gets homogenate and does quantitative fluorescent PCR, to measure the content of ADV7 virus.
4, set up simultaneously and do not attack the contrast of malicious mouse, blank (not immune any virus) mouse is attacked poison contrast and normal mouse contrast (poison is not attacked in immunity)
Experimental result sees Table 3:
Table 3
Data in the table 3 are ADV7 viral levels of using in the mouse lung that quantitative fluorescent PCR measures.The result shows that the mouse of the immune ADV7 of mistake and immunity are crossed the mouse of MH5 owing to the neutralizing antibody that has in the body at ADV7, and therefore after infecting ADV7 virus, virus is neutralized rapidly, and therefore can not surveying has virus, proves that HVR5 is the neutralizing antibody epi-position of ADV7.The result of MH2 shows that HVR2 has weak protective capability.Blank is the viral level of lung after not having the immune mouse that crosses any virus to be infected by the ADV7 collunarium, and its content can be used as contrast for the highest.
Can draw by The above results, have adenovirus 3, the 7 type recombinant chous of ADV3 (HVR7) and ADV7 (HVR5) neutralizing epitope simultaneously, behind immune mouse, can produce humoral immunization, make mouse avoid the ADV7 virus infection.This experimental result shows can further be utilized in this and epitope prepares polyvalent vaccine and medicine.
Last institute should be noted that; above embodiment is only in order to illustrate technical scheme of the present invention but not limiting the scope of the invention; although the present invention has been done detailed description with reference to preferred embodiment; those of ordinary skill in the art is to be understood that; can make amendment or be equal to replacement technical scheme of the present invention, and not break away from the essence and the scope of technical solution of the present invention.
Sequence table
＜120〉human 3-type, 7 type adenovirus in and epitope and application thereof
<160>6
<210>1
<211>16
<212>ADV3?HVR7?PRT
<400>1
Ile?Lys?Val?Lys?Thr?Asp?Asp?Ala?Asn?Gly?Trp?Glu?Lys?Asp?Ala?Asn
1 5 10 15
<210>1
<211>21
<212>ADV7?HVR2?PRT
<400>2
Lys?Glu?Gly?Leu?Glu?Ile?Gly?Lys?Asp?Ile?Thr?Ala?Asp?Asn?Lys?Pro
1 5 10 15
Ile?Tyr?Ala?Asp?Lys
20
<210>1
<211>19
<212>ADV7?HVR5?PRT
<400>3
Asp?Gly?Arg?Glu?Ala?Ala?Asp?Ala?Phe?Ser?Pro?Glu?Ile?Val?Leu?Tyr?Thr?Glu?Asn
1 5 10 15
<210>1
<211>48
<212>ADV3?HVR7?DNA
<400>4
attaaagtta?aaaccgatga?cgctaatgga?tgggaaaaag?atgctaat 48
<210>1
<211>60
<212>ADV?7HVR2?DNA
<400>5
aaggaaggtt?tagaaattgg?gaaagacatt?actgcagaca?acaagcccat?ttatgccgat 60
<210>1
<211>57
<212>ADV7HVR5DNA
<400>6
gatggtagag?aagctgctga?cgctttttcg?cctgaaattg?tgctttacac?ggaaaat 57
Claims (9)
- Human 3-type, 7 type adenovirus in and epitope, it is characterized in that, in described and the aminoacid sequence of aminoacid sequence shown in SEQ ID NO:1,2,3 of epitope, and contain one or more aminoacid insertion, disappearance, substitute or add and keep its structure and active aminoacid sequence.
- 2. in human 3-type according to claim 1, the 7 type adenovirus and epitope, it is characterized in that, in described and the nucleotide sequence of nucleotide sequence shown in SEQ ID NO:4,5,6 of epitope, and contain that one or more Nucleotide insert, disappearance, the nucleotide sequence that substitutes or add.
- Claim 1 or 2 described human 3-types, 7 type adenovirus in and the application of epitope, it is characterized in that, be used to prepare prevention 3 types or/and the vaccine of 7 type adenovirus infections or medicine.
- 4. a vaccine is characterized in that, comprise claim 1 or 2 described human 3-types, 7 type adenovirus in and the polypeptide of epitope.
- 5. antibody or Fab is characterized in that, described antibody or Fab specifically with claim 1 or 2 described human 3-types, 7 type adenovirus in and epitope combine.
- 6. a medicine is characterized in that, described medicine contains described antibody of claim 5 or Fab.
- 7. the method for prophylactic treatment adenovirus infection is characterized in that, uses the described vaccine of claim 4 of immune significant quantity or the described medicine of claim 6 of significant quantity.
- Claim 1 or 2 described human 3-types, 7 type adenovirus in and the application of epitope, it is characterized in that, be used to develop diagnostic kit as target protein.
- 9. detect the method for adenovirus infection, it is characterized in that, used the described diagnostic kit of claim 8.
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| CN102060915A (en) * | 2010-10-29 | 2011-05-18 | 广州呼吸疾病研究所 | Modifiable loca of human type 3 adenovirus hexon and application thereof |
| CN103966174A (en) * | 2013-02-04 | 2014-08-06 | 广州医学院第一附属医院 | Recombinant human adenovirus 3, and preparation method and application thereof |
| CN103966174B (en) * | 2013-02-04 | 2018-07-20 | 广州医科大学附属第一医院 | A kind of recombination human 3-type adenovirus and its preparation method and application |
| CN107459562A (en) * | 2017-08-30 | 2017-12-12 | 广州医科大学附属第医院 | The adenovirus cilia protein peptide of recombination expression, adenovirus subunit vaccine and preparation method thereof |
| CN107459562B (en) * | 2017-08-30 | 2020-10-27 | 广州医科大学附属第一医院 | Recombinant expression adenovirus cilia protein peptide, adenovirus subunit vaccine and preparation method thereof |
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| CN109957009A (en) * | 2019-03-28 | 2019-07-02 | 中国人民解放军军事科学院军事医学研究院 | Anti-human 7 type adenovirus antibody 2-1H and its application |
| WO2020192080A1 (en) * | 2019-03-28 | 2020-10-01 | 中国人民解放军军事科学院军事医学研究院 | Human adenovirus type 7 antibody and application thereof |
| CN111044728A (en) * | 2019-09-27 | 2020-04-21 | 广州医科大学附属第一医院 | IgM antibody colloidal gold test strip for rapidly detecting adenovirus and preparation method thereof |
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Application publication date: 20110112 |