CN103130873B - Antituberculous CTL (Cytotoxic T Lymphocyte) epitope peptide with drug-resistant related efflux protein source for tuberculosis and application of epitope peptide - Google Patents
Antituberculous CTL (Cytotoxic T Lymphocyte) epitope peptide with drug-resistant related efflux protein source for tuberculosis and application of epitope peptide Download PDFInfo
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Abstract
The invention discloses an antituberculous CTL (Cytotoxic T Lymphocyte) epitope peptide with a drug-resistant related efflux protein source for tuberculosis. The antituberculous CTL epitope peptide is nonapeptide, wherein the amino acid sequence of the nonapeptide is P9: ALGML IAGL. Predicative analysis is carried out on HLA-A*0210 restrictive CTL epitope of drug-resistant related protein antigen for tuberculosis by adopting immune-informatics means and SYFPEITH1, BIMAS and NetCTL1.2 databases according to the primary structure of the antigen, so that the epitope peptide is obtained by screening; and the identified nonapeptide has not been reported in any document. An in-virto ELISPOT (Enzyme-Linked Immunospot Assay) is adopted to identify the epitope peptide; and the identification result provides a theoretical basis for developing tuberculosis vaccine based on drug-resistant related protein antigen and provides more information for designing multi-epitope peptide vaccine for tuberculosi based on the mixed T cell epitope.
Description
Patent application of the present invention is number of patent application: 201110138646.2, the applying date: on 05 26th, 2011, denomination of invention was the divisional application of the relevant efflux protein source anti-tuberculosis CTL epitope peptide of < < Drug Resistance for Tuberculosis and application > > thereof.
Technical field
The present invention relates to tuberculotherapy polypeptide vaccine, especially relate to the anti-tuberculosis CTL epitope peptide with therapeutic activity that utilizes tubercule bacillus self resistance related antigen to filter out, the invention still further relates to this peptide in the application of preparing in tuberculotherapy polypeptide vaccine.
Background technology
Day by day increasing of Drug-Resistant Mycobacterium tuberculosis quantity is the major reason that causes tuberculosis in recent years to revive, stage a comeback.Main point of natural drug resistance mechanism of drug resistance of Mycobacterium tuberculosis mechanism and acquired resistance mechanism.Acquired resistance is mainly the point mutation due to drug resistance related gene, and natural drug resistance mechanism is mainly due to the permeability obstacle of cell walls with enliven extra-pumping system.Therefore, drug efflux system can become important resistance tuberculosis treatment target spot.
In animal model and clinical study, find in recent years CD8
+cTL plays a part important and unique in resisting tuberculosis infection protective response, CD8
+cTL brings into play lethal effect to target cell, must be able to identify the specific antigens epi-position of being combined with corresponding MHC-I quasi-molecule in target cell surface, i.e. cytotoxic T lymphocyte (Cytotoxic T lymphocyte, CTL) epi-position.The CD8 of research at present
+cTL Protein Epitopes, mainly concentrates on the special secretory protein of tubercule bacillus, as ESAT-6, CFP-10, CFP-21, MPT64, Ag85 mixture etc., and for membranin especially drug efflux PROTEIN C D8+CTL epi-position report seldom.
Summary of the invention
The anti-tuberculosis CTL epitope peptide that the object of the present invention is to provide the relevant efflux protein of paratuberculosis resistance source, the present invention also provides such peptide in the application of preparing in tuberculotherapy polypeptide vaccine.
For achieving the above object, the present invention can take following technical proposals:
The relevant efflux protein of Drug Resistance for Tuberculosis of the present invention source anti-tuberculosis CTL epitope peptide is nonapeptide, and the aminoacid sequence of described nonapeptide is:
P9：Ala-Leu-Gly-Met-Leu-Ile-Ala-Gly-Leu?。
The relevant efflux protein of Drug Resistance for Tuberculosis of the present invention source anti-tuberculosis CTL epitope peptide is in the application of preparing in tuberculotherapy polypeptide vaccine.
The present invention is the primary structure according to antigen, adopt Immunoinformatics means, use SYFPEITHI, BIMAS and NetCTL 1.2 databases to carry out forecast analysis to the HLA-A*0201 restricted CTL epitope of Drug Resistance for Tuberculosis associated protein antigen, screening obtains epitope peptide.Then by external ELISPOT experiment, prediction epitope peptide is identified.The present invention adopt method preliminary evaluation theoretical and that experiment combines go out can external evoked CTL epitope peptide, the nonapeptide of identifying has no bibliographical information, for the Vaccinum Calmette-Guerini of development based on drug resistance-associated proteins antigen provides theoretical basis, and provide more information for the tuberculosis multi-epitope peptide vaccine of design based on mixing t cell epitope.
Accompanying drawing explanation
Fig. 1-8th, the mass spectroscopy collection of illustrative plates of epitope peptide of the present invention.
Fig. 9-16th, the ability of the specific CTL secretion of gamma-IFN of epitope peptide induction of the present invention.
Embodiment
The relevant efflux protein of Drug Resistance for Tuberculosis of the present invention source anti-tuberculosis CTL epitope peptide is nonapeptide, and the aminoacid sequence of described nonapeptide is:
P5:Tyr-Leu-Gly-Gly-Thr-Thr-Gly-Pro-Val (YLGGTTGPV) molecular weight: 864.6(theoretical value: 863.44)
Or P6:Tyr-Ile-Val-Gly-Phe-Cys-Leu-Leu-Val (YIVGFCLLV) molecular weight: 1026.7(theoretical value: 1025.86)
Or P7:Thr-Leu-Thr-Trp-Leu-Phe-Ala-Phe-Val (TLTWLFAFV) molecular weight: 1097.7(theoretical value: 1097.32)
Or P8:Gly-Leu-Val-Ala-Gly-Leu-Ser-Ala-Val (GLVAGLSAV) molecular weight: 786.7(theoretical value: 786.7)
Or P9:Ala-Leu-Gly-Met-Leu-Ile-Ala-Gly-Leu (ALGMLIAGL) molecular weight: 858.7(theoretical value: 857.81)
Or P10:Met-Leu-Ile-Ala-Gly-Leu-Pro-Cys-Leu (MLIAGLPCL) molecular weight: 930.6(theoretical value: 930.24)
Or P11:Leu-Leu-Cys-Ala-Ile-Phe-Ala-Glu-Val (LLCAIFAEV) molecular weight: 978.6(theoretical value: 977.52)
Or P12:Arg-Leu-Trp-Pro-Thr-Val-Gly-Cys-Leu (RLWPTVGCL) molecular weight: 1044.6(theoretical value: 1043.56).
The present invention mainly adopts the method for integrating theory with practice, according to the primary structure of antigen, adopt Immunoinformatics means, use SYFPEITHI, BIMAS, with NetCTL 1.2 databases, the HLA-A*0201 restricted CTL epitope of the relevant efflux protein of resistance has been carried out to forecast analysis, screening obtains epitope peptide and adopts the Fmoc scheme of standard to synthesize, after HPLC purifying, its purity is greater than 90%, and mass spectroscopy also confirms that its molecular weight meets theoretical value.Each peptide Mass Spectrometric Identification figure is shown in Fig. 1-8.
Synthetic and the preparation of epitope peptide of the present invention: adopt the synthetic CTL epitope peptide of solid-phase synthesis.Basic procedure is as follows: first an amino is connected on insoluble solid phase carrier Wang resin by the amino acid of Fmoc radical protection, and the then protecting group of desamidizate, first amino acid be connected on solid phase carrier; Secondly amino is activated with condensing agent by second amino acid whose carboxyl of Fmoc radical protection; amino acid after activation reacts with first the amino acid whose amino that is connected on solid phase carrier and forms peptide bond, now on solid phase carrier, has just generated a dipeptides with protecting group.Repeat above-mentioned peptide bond and form reaction, make peptide chain from C end to the growth of N end, until reach needed peptide chain length, finally cutting obtains object peptide.After HPLC purifying, its purity is greater than 90%, and mass spectroscopy also confirms that its molecular weight meets theoretical value.(referring to: 1. only moral, Chen Changqing work of Huang, polypeptide is synthetic, Science Press, 1985.2. .N. Xiu Ede, H.D. Jia Kubuke work, Liu Keliang etc. translate, peptide: chemistry and biology, Science Press, 2005.）
The separation of human peripheral blood single nucleus cell (PBMCs) and ELISPOT experiment detect:
The peripheral blood that extracts health donors separates through density gradient centrifugation, obtains PBMCs, adds interleukin II (IL-2, Peprotech company) and people β
2microglobulin induction differentiation CTL cell, further ELISPOT verifies in vitro.Method is as follows:
1. the separation of PBMCs and induction: (1) is with 40ml PBS(PH 7.2) dilution anti-freezing peripheral blood 40ml after treatment; (2) in centrifuge tube, add 4ml Lymphoprep parting liquid (Axis-Shield company); (3) add in 8ml step (1) peripheral blood after dilution on 4ml Lymphoprep parting liquid liquid level; (4) 20 ℃ centrifugal (2000rmp × 20min); (5) after centrifugal, be divided into four layers, discard the superiors, with glass pipette, drawing the second layer is tunica albuginea layer (being rich in PBMCs); (6) PBS(pH 7.2 for tunica albuginea layer of sucking-off) twice of centrifuge washing; (7) with 24 orifice plate bed boards, the concentration of cell is 1 × 10
6/ ml, every hole 1ml; Within (8) second days, every hole adds 3 μ g people β
2microglobulin and 10 μ g epitope peptides set up PBS group (substituting epitope peptide using PBS) as negative control group simultaneously; Within (9) the 3rd days, every hole adds 50u IL-2; Within every 2～3 days, change liquid, after Yu Qitian, carrying out the second wheel load peptide (is that 50u IL-2,10 μ g people β are added in every hole
2microglobulin and 10 μ g epitope peptide/PBS), after fortnight, carry out third round lotus peptide.After third round lotus peptide 3 days, obtain effector cell CTL, then carry out ELISPOT experiment and detect IFN-γ and discharge.
2. ELISPOT experiment: specific experiment step is as follows: (1) sealing: take out required lath, with the substratum sealing containing 5% FCS RPMI 1640 substratum, 200 μ L/holes, are deducted (FCS can seal the FCS acceptor of institute's coated antibody to reduce nonspecific reaction) after (25 ℃) standing 5 ~ 10 min under room temperature; (2) cell upper plate: the CTL action effect cell (1 × 10 of induction
5/ hole), the T2A2 cell of lotus peptide is as irritation cell (1 × 10
5/ hole) bed board.100 μ L/ holes.The distribution of cell in hole will try one's best evenly (after adding cell, do not shake again or bounce ELISPOT plate); ● positive control: cell concn is 1 × 10
5/ hole, add 10 μ L PHA, the secretion of this concentration energy effective stimulus IFN-γ; ● the negative contrast of background: RPMI 1640 substratum containing 5%FCS that add 100 μ L; (3) after adding all samples, cover plate lid, put into CO
2incubator, cultivates 18h for 37 ℃; (4) lysing cell: topple over cell and substratum in hole, 200 μ L/ holes add ice-cold deionized water, 4 ℃ of ice baths react 10 min (Low Osmotic Method lysing cell); (5) washing: topple over the liquid in hole, 1 × Washing Buffer, 200 μ L/ holes, washs 5 ~ 7 times, stop 30 ~ 60 s at every turn, last, buckle and do on thieving paper; (6) add detection antibody incubation: every hole adds the biotin labeling that 100 μ L have diluted to detect antibody, hatches 1h for 37 ℃; (7) washing: topple over the liquid in hole, 1 × Washing Buffer, 200 μ L/ holes, washs 5 times, each residence time is 30 ~ 60 s, last, buckles and do on thieving paper; (8) enzyme connection avidin is hatched: the enzyme connection avidin working fluid having diluted is joined to experimental port, and 100 μ L/ holes, hatch 1h for 37 ℃; (9) washing: topple over the liquid in hole, 1 × Washing Buffer, 200uL/ hole, wash 5 times, each residence time is 30 ~ 60 s, last, buckles and do on thieving paper; (10) colour developing: the AEC nitrite ion that thaws and prepared.Every hole adds the nitrite ion of 100 μ L, and the standing 15-45min of room temperature (at 20-25 ° of C, 25min is more suitable in colour developing), notes lucifuge; (11) color development stopping: topple over liquid in hole, open plate base, with deionized water wash 3 ~ 5 times, color development stopping process.Plate is tipped upside down on thieving paper, pat dry the tiny globule, take off afterwards protective layer, be placed on the place of ventilation, the standing 10-30min of room temperature, allows film naturally dry; With ELISPOT Quantimet, count the spot number of every hole formation in 96 orifice plates.
External ELISPOT experimental result shows: candidate's peptide all can induce and be obtained CTLs in the peripheral blood of health donors, and the CTLs obtaining compares with positive peptide and all has the IFN-of higher amount γ to secrete (as shown in Fig. 9-16) after stimulating.
The present invention utilizes the relevant efflux protein antigen selection of the resistance of tubercule bacillus self to go out to have antiphthisic therapeutic bioactive peptide, for the Vaccinum Calmette-Guerini of development based on epitope provides theoretical basis, and provide more information for the tuberculosis multi-epitope peptide vaccine of design based on mixing t cell epitope.
Claims (2)
1. the relevant efflux protein of a Drug Resistance for Tuberculosis source anti-tuberculosis CTL epitope peptide, is characterized in that: described epitope peptide is nonapeptide, and the aminoacid sequence of described nonapeptide is:
P10：Met-Leu-Ile-Ala-Gly-Leu-Pro-Cys-Leu。
2. the relevant efflux protein of Drug Resistance for Tuberculosis claimed in claim 1 source anti-tuberculosis CTL epitope peptide is in the application of preparing in tuberculotherapy polypeptide vaccine.
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