CN105572352B - One group of tuberculosis latent infection diagnosis marker and application thereof - Google Patents
One group of tuberculosis latent infection diagnosis marker and application thereof Download PDFInfo
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- CN105572352B CN105572352B CN201610089096.2A CN201610089096A CN105572352B CN 105572352 B CN105572352 B CN 105572352B CN 201610089096 A CN201610089096 A CN 201610089096A CN 105572352 B CN105572352 B CN 105572352B
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- G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
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Abstract
The invention discloses one group of tuberculosis latent infection diagnosis marker and application thereof, the sequence pair of this group of tuberculosis latent infection diagnosis marker answers SEQ：ID：NO：1‑SEQ：ID：NO：8.The new biomarker thing of the technology for detection mycobacterium tuberculosis latent infection, so as to find latent infection person as early as possible, strengthens the management of tuberculosis latent infection person, is finally reached control TB endemic and the purpose propagated.
Description
Technical field
The invention belongs to technical field of bioengineering, it is related to one group of tuberculosis latent infection diagnosis marker and application thereof.
Background technology
Tuberculosis is the chronic infectious disease as caused by mycobacterium tuberculosis, is listed in one of China's serious infectious diseases.At present
Mycobacterium tuberculosis infection population radix is big, and the incidence of disease is high, effective rapid serological diagnostic method is there is no so far, to tuberculosis
Preventing and controlling bring severe challenge.Therefore, the today faced a severe challenge is controlled in tuberculosis epidemic situation, screening tuberculosis is new
A kind of candidate biomarker thing, the exploitation for seeking new diagnostic techniques, new drug and novel vaccine is extremely urgent.
Tuberculosis is a kind of communicable disease that human health is seriously endangered as caused by mycobacterium tuberculosis.The mankind are to knot
Core mycobacteria is generally susceptible, and the people that counting the whole world according to WHO has 1/3rd infected mycobacterium tuberculosis, and 200 are there are about every year
Ten thousand patients die from tuberculosis.But the people for infecting the crowd only 10% or so of mycobacterium tuberculosis develops into active tuberculosis
Bacterium in disease, most of human body exists with a kind of state of latent infection, and the immunologic mechanism of human body makes bacterium be in life
Long to suppress or halted state, protection body is from morbidity.There is no the infected of clinical manifestation for those, there is a considerable amount of one
There is the metainfective a kind of sub-clinical state of the mycobacterium tuberculosis of latent infection, i.e. mycobacterium tuberculosis, nothing in groups of people's body
Clinical symptoms, without bacteriology according to, it is positive without actinoscopy sign, PPD skin tests and/or T-Spot.The immune system energy of body
Enough control mycobacterium tuberculosis duplication is without showing clinical symptoms but can not thoroughly remove the mycobacterium tuberculosis of infection.
Mycobacterium tuberculosis stops replicating but maintaining vigour in the case where being unfavorable for its growth, when immunity of organisms is low
It can again replicate and cause clinical symptoms.Therefore, the new biomarker thing of mycobacterium tuberculosis latent infection is found for morning
Phase finds latent infection person, and taking corresponding measure to make latent infection, person does not fall ill or develop into active tuberculosis early stage at it
Row, which is intervened, has positive effect.
The conventional method of current diagnosis tuberculosis latent infection has：1. tuberculin skin test：Tuberculosis branch for a long time
The diagnosis of bacillus latent infection relies on tuberculin skin test (tuberculin skin test, TST), and it is to use PPD
The diagnostic method of intracutaneous injection is carried out as envelope antigen with the tuberculin based on OT, this method is simple and easy to apply, applied to tuberculosis
Diagnosis, examination and the epidemiological study of disease are more than 100 years, at present still as finding that latent infection person predominantly detecting
Means, but its maximum shortcoming is that the most protein in PPD and OT is identical with other mycobacterias and unrelated bacterium.Cause
This, in BCG vaccination rate and the higher area of non-tuberculous mycobacteria infection rate, the specificity of TST methods is relatively low.This method
Judge that someone whether there is mycobacterium tuberculosis latent infection by boundary of certain numerical value.Different dividing values may be drawn to individual
Divide and produce mistake, influence sensitivity and the specificity of method., may and patient must observe result by 48~72h after injection
Cause outpatient's lost to follow-up.In addition, acute infectious diseases, vaccine injection, the use of immunodepressant or inhibitive ability of immunity
The factors such as disease, malnutrition, sarcoidosis, tumour, other refractory diseases and the elderly, can non-specifically influence experiment to tie
Really there is false negative, influence the accuracy of diagnosis.2. interferon-γ release experiment (GIRAs)：In view of TST detection methods
Limitation, the interferon-γ release experiment based on T cell developed in recent years is the latent sense of diagnosis of tuberculosis mycobacteria
Dye brings new hope.This method principle is：It can be produced when running into cognate antigen again by the T cell of antigen of mycobacterium tuberculosis sensitization
Raw interferon-γ, producing high-caliber interferon-γ means the infection of mycobacterium tuberculosis.Current detection is selected from antigen
The specific proteins of mycobacterium tuberculosis gene group difference section 1 (RD1) gene code, the antigen target protein of such as Early insulin secretion
(ESAT6) and culturing filtrate protein 10 (CFP10), it is to avoid with intersecting for BCG vaccine and most of non-tuberculous mycobacteria antigens
Reaction.GIRAs substantially increases the specificity of reaction.The QuantiFERON-TB of current U.S. FDA approved and Europe are used
T-SPOT-TB experiments, be all the GIRAs using ESAT-6 and CFP-10 as antigen, can be applied to mycobacterium tuberculosis infection, including knot
Core branch latent infection and diagnosis lungy.But, IGRAs methods have the shortcomings that it is costly, lymphocyte need to be counted, can only
Carried out in the laboratory for possessing corresponding conditionses.It is many in order to solve diagnosis and the proactive problem of mycobacterium tuberculosis latent infection
Scholar makes great efforts to separate and identify that specific antigen is used as the screening indexes of mycobacterium tuberculosis latent infection from tubercle bacillus.
By the numerous studies of domestic and international researcher, the specific antigen of mycobacterium tuberculosis infection mainly has immunity albumen
MPT64；Secreted protein antigen：The complex antigens of antigen 85, i.e. Ag 85A (also referred to as P32, MPB44), Ag 85B (also referred to as a-
Ag, MPB59) and Ag 85C, and ESAT-6 and CFP-10 albumen etc.；Lipoprotein antigen：38k Da, 27k Da, 16k Da
Antigen etc.；Sugared lipid antigen：LAM antigen, tuberculosaccharide lipoid antigen etc..It was found that in these antigens,
In addition to secreted protein ESAT-6 and CFP-10 albumen are used for diagnosis of tuberculosis latent infection in T-SPOT-TB experiments,
The relevant report of the biological marker on mycobacterium tuberculosis latent infection is not found at present.
The content of the invention
It is an object of the invention to the defect for overcoming above-mentioned technology presence, there is provided one group of tuberculosis latent infection diagnosis marker
And application thereof, the new biomarker thing of the technology for detection mycobacterium tuberculosis latent infection, so as to find latent infection as early as possible
Person, strengthens the management of tuberculosis latent infection person, is finally reached control TB endemic and the purpose propagated.
Its concrete technical scheme is：
One group of tuberculosis latent infection diagnosis marker, including it is anti-Rv0494-IgG antibody, anti-Rv3301c-IgM antibody, anti-
Rv1860-IgG antibody, anti-Rv1821-IgG antibody, anti-Rv0280-IgM antibody, anti-Rv0351-IgM antibody, anti-Rv2031c-
IgG antibody and anti-Rv1441c-IgM antibody, its sequence pair answer SEQ：ID：NO：1-SEQ：ID：NO：8.
Purposes of the tuberculosis latent infection diagnosis marker of the present invention in screening tuberculosis latent infection diagnostic products.
Compared with prior art, beneficial effects of the present invention are：
The present invention is hidden by commercialization MtbProtTM mycobacterium tuberculosis protein matter group cDNA microarrays tuberculosis point skill bacillus
Infect And Diagnose molecular marker, the chip covers ＞ 95% encoding gene, includes 4262 recombinant proteins of Mycobacterium tuberculosis.
Clinical serum sample includes Normal group, latent infection group and active tuberculosis group, is separately reacted with chip,
With in test experience group for a certain or several antigen proteins, specific TB antibody with generality (IgG or
IgM).Based on primary dcreening operation result, the more obvious 94 mycobacterium tuberculosis protein matter of selection differences and this research team both passed through
6 mycobacterium tuberculosis differential expression proteins that two dimensional gel electrophoresis separation is obtained, self-control is containing 100 differential expression eggs
The small chip of white matter, send company's spot film, and each albumen repeats two point point systems, carries out the clinical verification of more than 200 part serum samples, finally
Obtain candidate markers (Rv0494-IgG, Rv3301c-IgM, Rv1860-IgG, the Rv1821- of 8 diagnosis of tuberculosis latent infections
IgG, Rv0280-IgM, Rv0351-IgM, Rv2031c-IgG and Rv1441c-IgM).This 8 protein of Conjoint Analysis accordingly resist
The testing result of body, whether be tuberculosis point skill bacillus latent infection, as a result show if judging tested person, it is auxiliary that the present invention provides small chip
The specificity for helping the best operating point of diagnosis of tuberculosis latent infection is 90.9%, and sensitivity is 83.1%, is above prior art
The index of middle tuberculosis latent infection diagnosis.
Brief description of the drawings
Discoveries and screening process of the Fig. 1 for the tuberculosis latent infection diagnosis marker based on MtbProtTM protein-chips
Schematic diagram.
Embodiment
Technical scheme is described in more detail with specific embodiment below in conjunction with the accompanying drawings.
First, the discovery and checking of serodiagnosis mark
(1) discovery and screening of the diagnosis of tuberculosis mark based on MtbProtTM protein-chips：
1. Cleaning Principle：Buy BoChong biotech firm MtbProtTM mycobacterium tuberculosis protein matter group chips, the chip bag
Containing 4262 recombinant proteins of Mycobacterium tuberculosis, cover ＞ 95% encoding gene.Clinical serum sample include Normal group,
Tuberculosis latent infection group and active tuberculosis group, separately react with chip, a certain to be directed in test experience group
Plant or several antigen proteins, the specific TB antibody (IgG or IgM) with generality, these antigen proteins can be made
Morbid state is characterized for diagnosis marker.
2. experimental implementation people：By chip, service group producers perform operation.
3. flow chart is as shown in Figure 1.
4. laboratory operating procedures：
1) pre- closing：Box (self-control of Guangzhou ChongBo companies) is incubated using chip, 5ml confining liquids is added, Quality Control chip will be treated
From -80 DEG C of taking-ups, face-up it is placed in incubation box；Laterally it is placed on again on side-sway shaking table (domestic), 50-60rpm, room temperature,
10min。
2) close：Confining liquid is abandoned, the new confining liquids of 5ml, side-sway shaking table 20-30rpm, room temperature 1h is rapidly added.
3) serum sample is incubated：Confining liquid is abandoned, preprepared albumen sample incubation liquid 3ml, side-sway is rapidly added
Shaking table 20-30rpm, room temperature 3h.Albumen sample incubation liquid：3ml Incubating Solutions add 30 μ l serum, and (fresh preparation is frozen in -80
Degree, is provided by patent applicant).
4) clean：Chip is taken out, the chip cleaning box for adding and there are 40ml cleaning fluids is placed in, acutely rocks 10-15 times, and
Liquid is replaced and cleaned, is acutely rocked 10-15 times again, free primary antibody is fully removed；Liquid is replaced and cleaned again, as horizontal shaker
On, 60-70rpm, 5min every time, is cleaned 3 times.
5) secondary antibody is incubated：Cleaning fluid is abandoned, preprepared secondary antibody Incubating Solution 3ml, side-sway shaking table 20- is rapidly added
30rpm, lucifuge, room temperature 45min.Secondary antibody Incubating Solution：Using anti-human IgG fluorescence secondary antibody, (549anti- human IgGs, are excited
Light 532nm, or 635anti- people IgM, exciting light 635nm, Jackson ImmunoResearch), Incubating Solution dilution antibody is extremely
Its working solution concentration, cumulative volume is 3ml.Lucifuge when secondary antibody is incubated.
6) clean：Same step " 4 ".Notice that the process answers lucifuge to operate.
7) 5min x are cleaned with ddH20 after the completion of 2 times, and rinses 10s.Notice that the process answers lucifuge to operate.
8) dry.Chip is placed in chip drier (rich difficult to understand biological, Slidewasher), centrifugal drying.
9) scan.According to scanner (rich difficult to understand biological, Luxscan 10K) working specification and operation instruction operation, ginseng is set
Number is：532nm (or correspondence wavelength of fluorescence), Power 100%, PMT value 500
10) data are extracted：By correspondence GAL File Opens, chip image and each array of GAL files are integrally alignd, pressed
Lower automatic aligning button, extracts data and preserves LPR files.
(2) checking of the tuberculosis latent infection diagnosis marker based on the small chip of designed, designed (self-control) protein
Primary dcreening operation result based on the first step, the more obvious 94 mycobacterium tuberculosis protein matter of selection differences and this research
Team both separated 6 differential expression proteins obtained by two dimensional gel electrophoresis, and second step designed, designed (self-control) contains
100 small chips of differential expression protein, send company's spot film, and each albumen repeats two point point systems, carries out more than 200 part serum samples
Clinical verification.
1. Cleaning Principle：Specific antibody (including IgG, IgM or other type antibodies) and the egg being fixed on chip
Be combined in vain, cleaning removes uncombined antibody and other oroteins, then with anti-human IgM fluorescence labelings secondary antibody (cy5 is marked,
It is presented red) and anti-human igg fluorescence secondary antibody (cy3 is marked, and green is presented) detection, signal, signal are read by Fluorescence Scanner
Power and the affinity and quantity of antibody be proportionate.
2. sample requirement：Patients serum, freezes and spends (being provided by patent applicant) in -80.
3. prepare following solution：
1) confining liquid：1ml 10%BSAm, add 9ml 1x PBSml solution, mix.
2) Incubating Solution：1x PBST 1x PBST1 solution.
3) cleaning fluid：1x PBST.
4. operating procedure：
1) pre- closing：Box is incubated using chip, 5ml confining liquids are added, by chip from -80 DEG C of taking-ups, is face-up placed in
It is incubated in box；Laterally it is placed on again on side-sway shaking table, 50-60rpm, room temperature, 10min.
2) close：Confining liquid is abandoned, the new confining liquids of 5ml, side-sway shaking table 20-30rpm, room temperature 2h is rapidly added.
3) sample incubation：Confining liquid is abandoned, respectively using 1XPBS, 0.2XPBS ddH 20q are cleaned 1 time, 5min/ times；So
Centrifugal drying afterwards.Fence special is installed and adds sample：Incubating Solution dilution is then centrifuged for drying.Fence special is installed and adds sample
This：Incubating Solution dilution is then centrifuged for drying.Fence special is installed and adds sample：Incubating Solution dilution 1：200, and add chip
200ul volumes, side-sway shaking table 20-30rpm, 4 spend night.
4) clean：Chip is taken out and (notes the upper surface that can not be touched or scratch) and extracts fence, being placed in addition has 40ml
The chip cartridges of cleaning fluid, are acutely rocked 10-15 times, and are replaced and cleaned liquid, then are acutely rocked 10-15 times, fully remove free one
It is anti-；Liquid is replaced and cleaned again, every time, is cleaned 3 times as 60-70,5min is fully removed on horizontal shaker.
5) fluorescence labeling IgG/IgM secondary antibodies are incubated：Cleaning fluid is abandoned, preprepared secondary antibody Incubating Solution is rapidly added
3ml (1: 1000 dilution), side-sway shaking table 20-30rpm, lucifuge, room temperature 45min.Note needing lucifuge.
6) clean：Same step " 4 ".Notice that the process answers lucifuge to operate.7) 5min x are cleaned 2 times with ddH 20 after the completion of,
And rinse 10s.Notice that the process answers lucifuge to operate.
8) dry.Chip is placed in chip machine, centrifugal drying.
9) scan.According to the working specification and operation instruction of scanner, arrange parameter is：635nm, Power 100%
Power, PMTvalue 400；532nm, Power 100%, PMT value 400.
10) data are extracted：By correspondence GALGAL File Opens, each array of chip image GAL files is integrally alignd, pressed
Lower automatic aligning button, extracts data and preserves gpr file.
2nd, data analysis and documents and materials are consulted
1. in order to eliminate error that the systematic divergence between different samples, different chip brings, it is necessary to chip data
It is normalized.During normalization, corresponding two points of each albumen are averaged the signal responded as the albumen
Value.
2. data analysis：It it is 3 groups by sample components by diagnosis of tuberculosis meaning：Normal group, tuberculosis latent infection
Group and active tuberculosis group, carry out statistical analysis to find the diagnostic serum molecules mark of tuberculosis latent infection.
3. candidate markers are relatively independently filtered out first：According to response signal value of each albumen to each sample, it is assumed that
The albumen there is significant difference in the two groups of samples contrasted and in TB group samples be in stronger response (immune response compared with
By force), and its credibility is calculated, is characterized with T test P values, as P value ＜ 0.05, represent that there is significant difference；
The signal average diversity ratio of two groups of samples is calculated simultaneously, and table is come with fold change (fc, fc=log2 (TB groups/control group))
Show, fc is bigger, represent that responsiveness is higher；In addition, for the combination of candidate markers, according to the response of known packet samples
Value, based on SPSS statistical analysis softwares, builds discriminant function, and finally draws ROC curve, provides clinical diagnosis evaluation index：
Specificity and sensitivity.
4. further by SPSS statistical softwares, optimization optimum combination, and generate discriminant function (Discrimination
Function), parameter is specially：Using step-forward methods, using average as characterising parameter, the statistics based on fisher function coefficients
Analysis, serum molecules mark is preferably gone out from mark.
5. the practical problem diagnosed for mycobacterium tuberculosis latent infection, from great amount of samples, preferential progress is normal right
Diagnosed according to group, latent infection group and active tuberculosis group, it is final to obtain 8 mark combinations, respectively Rv0494-
IgG, Rv3301c-IgM, Rv1860-IgG, Rv1821-IgG, Rv0280-IgM, Rv0351-IgM, Rv2031c-IgG and
Rv1441c-IgM.These marks are combined, and can relatively accurately distinguish control group and active tuberculosis group, can be used as diagnosis
The candidate markers of mycobacterium tuberculosis latent infection, specificity is 90.9%, and sensitivity is 83.1%.
The foregoing is only a preferred embodiment of the present invention, protection scope of the present invention not limited to this, any ripe
Those skilled in the art are known in the technical scope of present disclosure, the letter for the technical scheme that can be become apparent to
Altered or equivalence replacement are each fallen within protection scope of the present invention.
Claims (1)
1. one group of tuberculosis latent infection diagnosis marker, it is characterised in that including Rv0494-IgG, Rv3301c-IgM,
Rv1860-IgG, Rv1821-IgG, Rv0280-IgM, Rv0351-IgM, Rv2031c-IgG and Rv1441c-IgM, Rv0494,
Rv3301c, Rv1860, Rv1821, Rv0280, Rv0351, Rv2031c SEQ corresponding with Rv1441c nucleotide sequence：ID：
NO：1- SEQ：ID：NO：8.
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| CN102187224A (en) * | 2008-09-22 | 2011-09-14 | 俄勒冈健康科学大学 | Methods for detecting a mycobacterium tuberculosis infection |
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