CN105111288A - Acinetobacter baumannii subunit vaccine antigen protein, and applications thereof - Google Patents
Acinetobacter baumannii subunit vaccine antigen protein, and applications thereof Download PDFInfo
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Abstract
The invention belongs to the field of molecular biology and immunology, and more specifically provides an acinetobacter baumannii subunit vaccine antigen protein and applications thereof. The gene nucleic acid sequence of acinetobacter baumannii outer membrane protein OmpW is represented by SEQ IDNO:1, an obtained encoded protein is the acinetobacter baumannii subunit vaccine antigen protein, and amino acid sequence of the acinetobacter baumannii subunit vaccine antigen protein is represented by SEQ IDNO:2. A preparation method comprises following steps: prokaryotic expression plasmid OmpW-pThioHisA of OmpW vaccine atigen is constructed, and is transformed into BL21(DE3); after inducible expression, recycling and purification of OmpW recombinant protein are carried out, and the OmpW recombinant protein is mixed with aluminum hydroxide adjuvant so as to obtain a mixed solution which is capable of stimulating bodies to generate specific antibodies, wherein the specific antibodies possesses high efficiency immunoprotection effects on acinetobacter baumannii infection, and can be used for preventing acinetobacter baumannii infection.
Description
Technical field
The present invention relates to molecular biology and field of immunology, specifically a kind of immune protective subunit vaccine and application thereof.
Background technology
Along with the develop rapidly of medical science, particularly antibioticly to widely use, the Level of first-aid treatment of infectious diseases is constantly improved, but the consequent is increasing of abuse of antibiotics phenomenon, under antibiotic crunch, create a large amount of Resistant strain, these resistant organisms repeatedly with medicament contact after, reduce even to disappear to the susceptibility of medicine, cause medicine to reduce the curative effect of resistant organism even invalid.Acinetobacter calcoaceticus is that separation rate increases bacterial classification faster in Hospital Infection in recent years, and wherein Acinetobacter bauamnnii (Acinetobacterbaumannii, Ab) has become clinical pathogenic bacteria of nosocomial infection the most common.
Bao Man infects can cause septicemia, soft tissue or wound infection, catheter related infection, urinary tract infections, microbemia, Secondary cases meningitis etc.Bao Man threatens especially serious to critical patient, easily especially cause eruption and prevalence in intensive care unit(ICU) (ICU), has high lethality rate.
The major cause that Acinetobacter bauamnnii can cause bad clinical to endanger is: (1) Bao Man distributes very wide and can long-term surviving in hospital environment, mainly exist in the skin of people, respiratory tract, digestive tube and urogenital tract, have stronger resistibility to damp and hot, ultraviolet, chemostefilant, routine disinfection agent can only suppress its growth and can not be killed.(2) significantly, Bao Man resistance mechanism is complicated, and resistance is serious.In recent years, many provinces have occurred that Bao Man sends out with popular all.There are some researches show: Bao Man mainly presents multi-drug resistant by the synergy of the mechanism such as expression, adventitia permeability barrier, medicine Active efflux-pump of Multiple Classes of Antibiotics lytic enzyme.
Bao Man resistance strengthens year by year, and even occur " full resistance " bacterial strain in recent years, many existing antibiotic therapeutic actions are not obvious, bring a very large difficult problem to clinical treatment.New microbiotic slower development, and Bao Man resistance adapts to rapidly, therefore, seek new solution and seem very important.Domestic studying very major part to Acinetobacter bauamnnii all concentrates on the Monitoring on Dynamic Change of institute Nei Baoman resistance at present, or the research of resistance mechanism.External research is mainly from resistance mechanism; start with in the aspects such as the change of pathogenesis and resistance; research in vaccine mainly concentrates on the full bacterium of acinetobacter calcoaceticus deactivation, in the immunogenicity of full outer membrane protein (OMPs) and outer membrane protein vesica (OMVs) and the research of protectiveness.The result of study of the people such as MichaelJ.McConnell shows, the mouse of OMPs and OMVs immunity can resist infection and the invasion and attack of Bao Man, also proves that mouse accepts infection and the invasion and attack that antiserum(antisera) passive immunization can resist Bao Man equally simultaneously.
It should be noted that Acinetobacter bauamnnii OMPs or OMVs is made up of much albumen, and the abstraction and purification of these albumen is numerous and diverse processes, and output is difficult to be improved, effective constituent mixes with a large amount of unrelated protein and impurity.Although increase relative in full bacterial immunity security with OMPs or OMVs immunity, wherein contain a lot of adventitia and the cell wall constituent of thalline, comprise LPS, still can produce significant toxic side effect.
Utilize Immunoinformatics and reverse genetics, analyze antigenicity and the immunogenicity of multidrug resistant acinetobacter calcoaceticus outer membrane protein component, and carry out gene clone, protein expression, purifying, and immunological investigation, filter out effective outer membrane protein component, inquire into the potential of Acinetobacter bauamnnii immune control strategy, to validity and the security of vaccine be promoted, thus than OMPs, OMVs or whole-bacterial-vaccine, there is more real and tempting application prospect.
Summary of the invention
Acinetobacter bauamnnii strains A TCC17978 is cultivated in LB substratum, thalline is collected when being cultured to logarithmic phase, be that template carries out pcr amplification with thalline, obtain the nucleotide sequence (shown in SEQIDNO:1) of Acinetobacter bauamnnii ATCC17978OmpW, prokaryotic expression carrier is connected into genetic engineering means after double digestion, recombinant plasmid transformed is entered picking positive recombinant after bacillus coli DH 5 alpha, extract plasmid and carry out order-checking and identifies.
OmpW recombinant plasmid transformed is entered BL21 (DE3) competent cell, with IPTG abduction delivering restructuring OmpW albumen (shown in SEQIDNO:2), expression product after ultrasonic disruption, collect inclusion body and dissolved, refolding.
Restructuring OmpW albumen is obtained after albumen after refolding is carried out purifying with cation seperation column and affinity column.
Immune mouse after this recombinant protein is mixed with sodium hydroxide aluminium adjuvant 1:1, collect immunized mice serum, carry out the Specific antibody titre that ELISA detects anti-Acinetobacter bauamnnii OMVs, find to create higher specific antibody level in OmpW immunized mice body; And carry out with this anti-OmpW serum the Acinetobacter bauamnnii tropina that Westernblot detects the clinical separation of many strains, find the OmpW albumen in the clinical Acinetobacter bauamnnii thalline of the many strains of this antibody capable specific recognition.
The resistance Acinetobacter bauamnnii of clinical separation is injected to mouse peritoneal, Continuous Observation one week, find that the mouse survival rate after OmpW immunity is 100%, control group survival rate is only 16.7%, the bacterial loads simultaneously in mouse peripheral blood, liver, lung, kidney, spleen in vaccine group comparatively control group reduce 10
4-10
6times, and the inflammatory cytokine levels in serum significantly reduces, and shows this subunit vaccine antigenic and has higher immune protective.
The antiserum(antisera) of OmpW immunized mice is entered in Mice Body by tail vein injection, infect with the resistance Acinetobacter bauamnnii of clinical separation again, find that the mouse after passive immunization maintains the survival rate of 83.3%, and control group is only 16.7%, the bacterial loads in mouse peripheral blood, liver, lung, kidney, spleen in vaccine group comparatively control group reduce 10
2-10
3doubly, and inflammatory cytokine levels significantly reduces in serum, and the antiserum(antisera) shown for OmpW has passive immune protection effect, has effective fungicidal activity in vivo.
Prove that OmpW antibody has external conditioning killing activity through external conditioning experiment, the Acinetobacter bauamnnii of the clinical separation of the many strains of opsonification specific killing can be played, embody the extensive intersecting protective of OmpW as Acinetobacter bauamnnii subunit vaccine.
Accompanying drawing explanation
Fig. 1 shows active immunity and the passive immunization program of Acinetobacter bauamnnii subunit vaccine antigenic OmpW, and the infection program of the Acinetobacter bauamnnii bacterial strain of clinical separation.
Fig. 2 shows the OmpW of amalgamation and expression at BL21(DE3) situation in bacterial strain before and after abduction delivering, and the albumen situation after purifying, picture is that the SDS-PAGE of full bacterium and purifying protein after coomassie brilliant blue staining analyzes.
Fig. 3 to show after the last immunity of subunit vaccine antigenic OmpW the titre levels (n=6) of specific antibody in mice serum after 1 week and 3 weeks.
Fig. 4 shows the situation of the Acinetobacter bauamnnii bacterial strain detecting the clinical separation of OmpW antiserum(antisera) specific recognition with Westernblot, with anti-Acinetobacter bauamnnii OMV(AbOMVs) antibody is for positive control, and control serum is negative control.
Fig. 5 shows after OmpW active immunity, infects the mouse survival rate situation (n=6) of Acinetobacter bauamnnii.
Fig. 6 shows after OmpW passive immunization, infects the mouse survival rate situation (n=6) of Acinetobacter bauamnnii.
Fig. 7 shows after OmpW active immunity, infects mouse each organ carrying capacity situation (n=6) of Acinetobacter bauamnnii.
Fig. 8 shows after OmpW passive immunization, infects mouse each organ carrying capacity situation (n=6) of Acinetobacter bauamnnii.
Fig. 9 shows after OmpW active immunity, infects inflammatory cytokine secretion situation (n=6) in the mice serum of Acinetobacter bauamnnii.
Figure 10 shows after OmpW passive immunization, infects inflammatory cytokine secretion situation (n=6) in the mice serum of Acinetobacter bauamnnii.
The external bacterial killer that Figure 11 shows the anti-OmpW serum after gradient dilution and hot deactivation complement is active, and showing this antiserum(antisera) can effectively kill and wound Acinetobacter bauamnnii and depend on scavenger cell.
Figure 12 shows the external conditioning of anti-OmpW serum to the Clinical isolation of different sources and kills and wounds situation.
SEQIDNO:1 is Acinetobacter bauamnnii outer membrane protein W(OmpW in the present invention) gene order.
SEQIDNO:2 is Acinetobacter bauamnnii outer membrane protein W(OmpW in the present invention) aminoacid sequence.
Embodiment
The present invention is described in detail, so that those of ordinary skill in the art can understand the present invention better by following examples.Following embodiment only for exemplary purposes, is not intended to limit scope of the present invention.Endeavour to ensure the accuracy of Values, but should consider there is some errors and deviation.
embodiment
embodiment 1: the structure of Acinetobacter bauamnnii outer membrane protein OmpW prokaryotic expression plasmid
By Acinetobacter bauamnnii strains A TCC17978 incubated overnight in LB substratum, treat that thalli growth is to logarithmic phase (OD
600=0.4-0.6), get bacterium liquid and carry out pcr amplification, pcr amplification primer is OmpW-F (5'
gGATCCand OmpW-R (5' ATGGGGGTGTCTTCATTTACTT3')
gAATTCtTAGAATTTATAGCTATAGCCT3'); PCR system is specially: bacterium liquid: 2 μ L; OmpW-F:2 μ L; OmpW-R:2 μ L; DNTP:2 μ L; Taq enzyme: 0.25 μ L; 10 × Taq enzyme buffer:2.5 μ L; Water: 14.25 μ L.PCR program is: 1. 94 DEG C of denaturations 5 minutes; 2. sex change 94 DEG C, 30 seconds; Anneal 56 DEG C, 30 seconds; Extend 72 DEG C, 1 minute, circulate 35 times; 3. finally 72 DEG C are extended, 10 minutes.PCR primer is carried out glue recovery (sky, Beijing root is biological), reclaim product and be connected to pMD19T-simple carrier (Takara company) with T-A, linked system is specially: pMD19T-simple carrier: 0.5 μ L; Fragment: 4.4 μ L; T4 ligase enzyme: 0.5 μ L; T4 ligase enzyme buffer:0.6 μ L.16 DEG C of connections are spent the night.Recon after connecting is converted into bacillus coli DH 5 alpha competent cell, and picking positive colony is identified with carrier T sequencing primer.PThioHisA prokaryotic expression carrier (Invitrogen company) and positive carrier T recombinant plasmid are carried out double digestion with restriction enzyme (Takara company) BamHI and EcoRI, and the enzyme system of cutting is: carrier/plasmid: 13 μ L; EcoRI enzyme: 2 μ L; BamHI:2 μ L; 10 × buffer:3 μ L, 37 DEG C of enzymes cut 3 hours.Glue adds DNA ligase (Takara company) after reclaiming digestion products and connects, and linked system is: OmpW fragment: 4.7 μ L; PThioHisA carrier: 0.2 μ L; DNA ligase: 0.5 μ L; DNA ligase buffer:0.6 μ L, 16 DEG C of connections are spent the night.DNA is connected product conversion and enter escherichia coli DH5a competent cell, picking positive colony qualification of checking order.
embodiment 2: the abduction delivering of Acinetobacter bauamnnii OmpW recombinant protein
Recombinant plasmid transformed is entered BL21 (DE3) competent cell, picking mono-clonal carries out abduction delivering, concrete grammar is, positive colony is seeded in the LB substratum having added Ampicillin Trihydrate (100mg/mL), cultivating after 16 hours enters in the LB substratum of new band Ampicillin Trihydrate with the ratio of 1:5 switching bacterium liquid, when strain growth is to logarithmic phase, add IPTG(1mmol/L) carry out abduction delivering, controlling abduction delivering temperature is 30-37 DEG C, abduction delivering 6 hours (Fig. 2).
the preparation of embodiment 3:OmpW subunit vaccine antigenic and purifying
Sample after being spent the night by abduction delivering centrifugal 10 minutes with room temperature 12000g, collect thalline, carry out ultrasonic disruption after washing twice thalline with PBS, broken condition is 10% peak power, works 5 seconds, stops 5 seconds, continues 10 minutes.Sample after fragmentation centrifugal 10 minutes with 12000g, collection inclusion body precipitates, by inclusion body with Washbuffer (20mMtris-Hcl, pH8.8, 1M urea) wash 3 times after add Solutionbuffer (20mMtris-Hcl, pH8.8, 8M urea) dissolve, by the inclusion body after dissolving with Bindingbuffer (20mMtris-Hcl, pH8.8) dialysis 4 DEG C is spent the night and is carried out refolding, dialyzate carries out purifying with anion-exchange chromatography post HiTrapQFF (GEHealthcare), through Elutionbuffer (20mMtris-Hcl, pH8.8, 2MNacl) collect the purified product of different components after gradient elution and detect with SDS-PAGE, collect OmpW place component (Fig. 2).
embodiment 4: the animal immune of recombinant subunit vaccine antigen OmpW
The OmpW of restructuring is mixed with 1mg aluminum hydroxide adjuvant 1:1 with 0.2-2 μ gOmpW/g body weight, carried out three subcutaneous or intramuscular immunisation (Fig. 1) at 0 day, 14 days, 28 days respectively with mixed solution.Mouse feeder is in the environment of SPF rank.After last immunity, the ELISA detection of antibody horizontal is carried out in blood sampling in 3 weeks, and antigen coated when ELISA detects is 10ug Acinetobacter bauamnnii OMVs, and detected result confirms that Specific antibody titre is more than 1 × 10
5(Fig. 3); Carry out Westernblot detection with Post-immunisation serum, result proves the OmpW albumen (Fig. 4) in the serum energy specific recognition many strains clinical separation strain after OmpW immunity.Prove that mouse creates high-caliber specific antibody level after Acinetobacter bauamnnii OmpW immunity with this.
embodiment 5: active immunity Protection in the body of recombinant subunit vaccine antigen OmpW
Mouse after OmpW subunit vaccine antigenic immunity three times, carries out the abdominal cavity infection (Fig. 1) of the resistance Acinetobacter bauamnnii of clinical separation for three weeks, the last time with 1 × 10 after immunity
6the pig mucoitin (Sigma company) of the Acinetobacter bauamnnii mixing 10% of CFU concentration is by abdominal cavity infection mouse, Continuous Observation was carried out to mouse in metainfective 7 days, find that the mouse survival rate after OmpW immunity is 100%, control group survival rate is only 16.7%(Fig. 5), the bacterial loads simultaneously in mouse peripheral blood, liver, lung, kidney, spleen in vaccine group comparatively control group reduce 10
4-10
6doubly (Fig. 7), and in serum, inflammatory cytokine levels significantly reduces (Fig. 9), shows this subunit vaccine antigenic and has higher immune protective.
embodiment 6: the passive immune protection experiment of recombinant subunit vaccine antigen OmpW
Through OmpW subunit vaccine antigenic immunity three times after mouse, get its antiserum(antisera), carry out Acinetobacter bauamnnii infect within first 1 hour, enter (Fig. 1) in Mice Body, subsequently with 1 × 10 by tail vein injection
6the pig mucoitin of the Acinetobacter bauamnnii mixing 10% of CFU concentration is by abdominal cavity infection mouse, Continuous Observation was carried out to mouse in metainfective 7 days, find that the mouse after passive immunization maintains the survival rate of 83.3%, and control group is only 16.7%(Fig. 6), the bacterial loads in mouse peripheral blood, liver, lung, kidney, spleen in vaccine group comparatively control group reduce 10
2-10
3doubly (Fig. 8), and inflammatory cytokine levels significantly reduces (Figure 10) in serum, and the antiserum(antisera) shown for OmpW has passive immunization effect, has effective fungicidal activity in vivo.
embodiment 7: the external complement of anti-OmpW serum and conditioning experiment
Cultivate mouse macrophage RAW264.7 cell with 1640 perfect mediums (containing 10% foetal calf serum), with the PMA irritation cell of 100nM collecting cell after 3 days, add 96 porocyte culture plates, adjustment cell quantity is 2 × 10
5cells/well; In Tissue Culture Plate, add resistance Acinetobacter bauamnnii strains A b3 that Acinetobacter bauamnnii ATCC17978 is separated with clinical, Ab4, Ab7 and Ab14 subsequently, every hole adds bacterial count and is adjusted to 7 × 10
4cFU/ hole; Add anti-OmpW serum and control serum again, serum is respectively with final concentration 1:10, and 1:100,1:1000 dilute, and another part serum hatches 30 minutes with hot inactivating endogenous complement with 56 DEG C.Antiserum(antisera), bacterium and scavenger cell are mixed in 96 orifice plates, put into incubator 37 DEG C hatch 1 hour after gradient dilution coat LB flat board, calculate bacterial count (Figure 11) of living.Prove that OmpW antiserum(antisera) has external conditioning killing activity through external conditioning experiment; the Acinetobacter bauamnnii of the clinical separation of the many strains of opsonification specific killing can be played, embody the extensive intersecting protective (Figure 12) of OmpW as Acinetobacter bauamnnii subunit vaccine.
gene order SEQIDNO1: Acinetobacter bauamnnii outer membrane protein W(OmpW)
ATGGGGGTGTCTTCATTTACTTTTGCTGGTAATTGGCAAGTAAAATTTGGGGGCAGCGTTATTGCTCCATCGGAAGATACAACAACTGCTTTAGGTGTGGTAAAGGCGGACCATGAATATGCATTTACTCCATCAGTAGAATACTTTTTTGGTCAATCTCCATTTTCGGCAGAATTATTATTAGCAACGCCGGTTAATCATGATGTTTTATTAGATGGTCAGAAAGTAGCGCGTATTAAACAATTGCCACCAACAATTACCGCGAAATATCATTTTAAAAACTCGACTCGTTTTACACCGTATATTGGTATCGGGGCAACAGCATTTATTCCTTGGGATGAACAAGGCGTAGCTGACAAAGTAAAAGAAGATTTTGGTGTGGCTGGCCAAATTGGTTTTAATTTCCAACCTGCTGATGCTAAAAATTGGGGAGTATTTGTAGATGTTCGTTATGCAGATATTAGTCCAGAAGTTACTTTAACAAATGGTGCTAAATTTGACTTAGATATTAACCCGTTTGTTTACACTTTAGGCTATAGCTATAAATTCTAA
aminoacid sequence SEQIDNO2: Acinetobacter bauamnnii outer membrane protein W(OmpW)
MGVSSFTFAGNWQVKFGGSVIAPSEDTTTALGVVKADHEYAFTPSVEYFFGQSPFSAELLLATPVNHDVLLDGQKVARIKQLPPTITAKYHFKNSTRFTPYIGIGATAFIPWDEQGVADKVKEDFGVAGQIGFNFQPADAKNWGVFVDVRYADISPEVTLTNGAKFDLDINPFVYTLGYSYKF
Claims (3)
1. an Acinetobacter bauamnnii subunit vaccine antigenic protein, it is characterized in that: Acinetobacter bauamnnii outer membrane protein OmpW gene nucleic acid sequence is as shown in sequence table SEQ IDNO:1, and the albumen of its coding is shown in Acinetobacter bauamnnii subunit vaccine antigenic protein aminoacid sequence SEQIDNO:2.
2. the Acinetobacter bauamnnii subunit vaccine described in claim 1; it is characterized in that: described Acinetobacter bauamnnii subunit vaccine antigenic protein OmpW has excitating organism and produces specific antibody, has efficient immanoprotection action to the infection of Acinetobacter bauamnnii.
3. the application of the subunit vaccine antigenic protein of Acinetobacter bauamnnii described in claim 2, it is characterized in that: by the inoculum size of described Acinetobacter bauamnnii subunit vaccine antigenic protein OmpW according to 0.2-2 μ gOmpW/g body weight, mix according to volume ratio 1:1 with 1mg aluminum hydroxide adjuvant, mixed solution carries out subcutaneous or intramuscular inoculation.
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Cited By (5)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105582531A (en) * | 2016-01-27 | 2016-05-18 | 中南大学湘雅医院 | Acinetobacter baumannii combined subunit protein vaccine and preparation method thereof |
| CN105907776A (en) * | 2016-05-20 | 2016-08-31 | 金福赛（北京）生物科技有限公司 | Subunit vaccine capable of inducing immune response to porcine reproductie and respiratou syndrome virus |
| CN110950939A (en) * | 2019-12-04 | 2020-04-03 | 南京医科大学第二附属医院 | Acinetobacter baumannii Omp22 recombinant multi-antigen epitope polypeptide and application thereof |
| CN116445448A (en) * | 2023-06-14 | 2023-07-18 | 四川大学华西医院 | Acinetobacter baumannii PLPFP recombinant protein, preparation method and application |
| CN116478953A (en) * | 2023-06-14 | 2023-07-25 | 四川大学华西医院 | Acinetobacter baumannii DlaT recombinant protein, preparation method and application |
-
2015
- 2015-07-24 CN CN201510440339.8A patent/CN105111288A/en active Pending
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| SMITH, M. G.等: "Acinetobacter baumannii ATCC 17978 chromosome, complete genome", 《GENBANK DATABASE》 * |
| WEIWEI HUANG等: "OmpW is a potential target for eliciting protective immunity against Acinetobacter baumannii infections", 《VACCINE》 * |
Cited By (9)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN105582531A (en) * | 2016-01-27 | 2016-05-18 | 中南大学湘雅医院 | Acinetobacter baumannii combined subunit protein vaccine and preparation method thereof |
| CN105582531B (en) * | 2016-01-27 | 2020-06-12 | 中南大学湘雅医院 | Acinetobacter baumannii combined subunit protein vaccine and preparation method thereof |
| CN105907776A (en) * | 2016-05-20 | 2016-08-31 | 金福赛（北京）生物科技有限公司 | Subunit vaccine capable of inducing immune response to porcine reproductie and respiratou syndrome virus |
| CN105907776B (en) * | 2016-05-20 | 2019-10-29 | 金福赛（北京）生物科技有限公司 | The subunit vaccine of the immune response for pig blue-ear disease poison can be induced |
| CN110950939A (en) * | 2019-12-04 | 2020-04-03 | 南京医科大学第二附属医院 | Acinetobacter baumannii Omp22 recombinant multi-antigen epitope polypeptide and application thereof |
| CN116445448A (en) * | 2023-06-14 | 2023-07-18 | 四川大学华西医院 | Acinetobacter baumannii PLPFP recombinant protein, preparation method and application |
| CN116478953A (en) * | 2023-06-14 | 2023-07-25 | 四川大学华西医院 | Acinetobacter baumannii DlaT recombinant protein, preparation method and application |
| CN116478953B (en) * | 2023-06-14 | 2023-09-12 | 四川大学华西医院 | Acinetobacter baumannii DlaT recombinant protein, preparation method and application |
| CN116445448B (en) * | 2023-06-14 | 2023-09-12 | 四川大学华西医院 | Acinetobacter baumannii PLPFP recombinant protein, preparation method and application |
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Application publication date: 20151202 |
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| WD01 | Invention patent application deemed withdrawn after publication |