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WO2016133324A1 - Procédé pour le diagnostic de maladies respiratoires inflammatoires à l'aide de vésicules de membrane externe dérivés de bactéries - Google Patents

Procédé pour le diagnostic de maladies respiratoires inflammatoires à l'aide de vésicules de membrane externe dérivés de bactéries Download PDF

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Publication number
WO2016133324A1
WO2016133324A1 PCT/KR2016/001502 KR2016001502W WO2016133324A1 WO 2016133324 A1 WO2016133324 A1 WO 2016133324A1 KR 2016001502 W KR2016001502 W KR 2016001502W WO 2016133324 A1 WO2016133324 A1 WO 2016133324A1
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bacteria
extracellular vesicles
derived
lung cancer
asthma
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English (en)
Korean (ko)
Inventor
김윤근
김유선
지영구
오연목
조유숙
최준표
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Asan Foundation
Ewha Womans University
Industry Academic Cooperation Foundation of Dankook University
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Asan Foundation
Ewha Womans University
Industry Academic Cooperation Foundation of Dankook University
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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids

Definitions

  • the present invention relates to a method for diagnosing respiratory inflammatory disease using bacterial-derived extracellular vesicles, and more specifically to measuring asthma and chronic obstruction by measuring specific antibodies against bacterial-derived extracellular vesicles or proteins derived from these vesicles in indoor dust. Lung diseases, and methods for diagnosing lung cancer.
  • Indoor dust includes Bacillus sp . , Staphylococcus aureus , Staphylococcus epidermidis , and Pseudomonas.
  • Substances derived from these bacteria, such as lipopolysaccharide (LPS) or peptidoglycan are known to induce the production of inflammatory cytokines in immune cells and lung epidermal cells.
  • LPS lipopolysaccharide
  • peptidoglycan are known to induce the production of inflammatory cytokines in immune cells and lung epidermal cells.
  • Gram-negative bacteria constantly secrete extracellular vesicles (also called outer membrane vesicles). Nanometer-sized extracellular vesicles secreted by bacteria are substances that are secreted to exchange information between cells, which are ultrafine dust. Extracellular vesicles secreted by Gram-negative bacteria are spherical phospholipid bilayers, 20-200 nm in size. The extracellular vesicles have outer membrane proteins that can control the inflammatory response of the host as well as LPS. In addition, gram-positive bacteria have been reported to secrete extracellular vesicles to the outside, and proteome analysis has reported that endoplasmic reticulum contains proteins that induce inflammation. Therefore, inhalation of extracellular vesicles in indoor dust can cause inflammatory reactions in alveolar macrophages as well as airway epithelial cells.
  • respiratory inflammatory diseases can be largely classified into rhinitis and sinusitis occurring in the upper airway, asthma and bronchitis in the lower respiratory tract, bronchiolitis and emphysema in the small airways.
  • asthma is characterized by reversible airway obstruction, there are 350 million people worldwide, about 2.3 million patients in Korea.
  • Chronic obstructive pulmonary disease COPD
  • Chronic obstructive bronchitis, chronic obstructive bronchiolitis, emphysema and the like are the causes of chronic obstructive pulmonary disease.
  • protein antigens allergens
  • stimulating factors such as smoking are known to be important in the cause of chronic obstructive pulmonary disease.
  • the present invention by identifying the bacteria that can act as a causative agent of asthma, chronic obstructive pulmonary disease, lung cancer in bacteria-derived extracellular vesicles isolated from the indoor dust through a metagenome analysis was completed.
  • an object of the present invention is to provide a method for diagnosing asthma, chronic obstructive pulmonary disease, and lung cancer using bacterial extracellular vesicles or proteins derived from the endoplasmic reticulum contained in indoor dust.
  • the present invention provides a method for diagnosing a respiratory inflammatory disease, comprising the following steps.
  • the extracellular vesicles, and proteins Staphylococci (Staphylococcus), Acinetobacter (Acinetobacter), Pseudomonas (Pseudomonas) and Enterobacter (Enterobacter) derived from one or more bacteria selected from the group consisting of It may be.
  • the Staphylococcus aureus is Staphylococcus aureus
  • the Acinetobacter is Acinetobacter baumannii
  • the Pseudomonas aeruginosa is Pseudomonas aeruginosa , May be Enterobacter aerogenes .
  • the patient sample may be selected from the group consisting of blood and sputum.
  • the IgG antibody may be IgG1 or IgG4.
  • the extracellular vesicles are characterized in that the average diameter of 10-300 nm.
  • the respiratory inflammatory disease may be selected from the group consisting of asthma, chronic obstructive pulmonary disease, and lung cancer.
  • the present invention provides a diagnostic use of respiratory inflammatory diseases of indoor dust bacteria-derived extracellular vesicles.
  • Staphylococcus aureus present in a large quantity in dust in the room air (Staphylococcus), Acinetobacter (Acinetobacter), Pseudomonas (Pseudomonas), and Enterobacter (Enterobacter) in germ cells derived from outside the ER because it can lead to respiratory inflammatory diseases
  • the present invention It can be usefully used as a method for diagnosing asthma, chronic obstructive pulmonary disease and lung cancer by measuring the antibody-specific extracellular vesicles or specific antibodies to the vesicle-derived proteins in a patient sample.
  • 5 is a result of analyzing the distribution of bacteria and extracellular vesicles separated from the indoor dust seasonally at the genus level through a metagenomic analysis.
  • FIG. 6 shows the distribution and the positive rate of extracellular vesicle-specific IgG antibodies in indoor dust measured from blood and sputum samples of control, asthma, chronic obstructive pulmonary disease (COPD), lung cancer patients (Lung cancer). Is the result.
  • COPD chronic obstructive pulmonary disease
  • Figure 7 shows the number of sensitized to each bacteria-derived extracellular vesicles in the control group (Asthma), chronic obstructive pulmonary disease (COPD), lung cancer patients (positive) showed positive extracellular vesicle-specific IgG antibody This figure shows the distribution of.
  • FIG. 8 shows the number of sensitized bacteria-derived extracellular vesicles in normal, control, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer patients with positive extracellular vesicle-specific IgG1 antibodies.
  • Figure shows the distribution.
  • FIG. 9 shows the number of sensitized bacteria-derived extracellular vesicles in normal, control, asthma, chronic obstructive pulmonary disease (COPD), and lung cancer patients with positive extracellular vesicle-specific IgG4 antibodies.
  • Figure shows the distribution.
  • the present invention relates to a method for diagnosing asthma, chronic obstructive pulmonary disease, and lung cancer using a bacterial-derived extracellular vesicle or a protein derived from the endoplasmic reticulum present in indoor dust causing respiratory inflammatory disease.
  • the characteristics of bacteria-derived extracellular vesicles present in indoor dust causing inflammatory respiratory diseases were evaluated and the causative factors (bacteria) of extracellular vesicles were identified.
  • the DNA of the extracellular vesicles separated from the indoor dust was separated and then subjected to metagenomic analysis to analyze the distribution of bacteria and bacteria-derived extracellular vesicles.
  • samples from three patients and normal groups suffering from the disease to evaluate the sensitization of bacteria-derived extracellular vesicles present in indoor dust and its association with asthma, chronic obstructive pulmonary disease, and lung cancer
  • the amount of extracellular vesicle-specific IgG antibody was obtained.
  • Correlation analysis revealed that 4.4% of normal subjects, 13.6% of asthmatic patients, 29.3% of patients with chronic obstructive pulmonary disease, and 54.9% of lung cancer patients were sensitized to extracellular vesicles (see Example 4). .
  • the above-described one staphylococci Staphylococcus
  • Acinetobacter Acinetobacter
  • Pseudomonas Pseudomonas
  • Acinetobacter extracellular vesicles were isolated from baumannii
  • Pseudomonas aeruginosa and Enterobacter aerogenes
  • the extracellular vesicle specific IgG, IgG1, IgG4 antibodies of each group were measured.
  • the risk of asthma, chronic obstructive pulmonary disease, and lung cancer increased by 4.5 and 17.5 times, and Enterobacter When sensitized to aerogenes- derived extracellular vesicles, the risk of asthma, chronic obstructive pulmonary disease, and lung cancer was increased by 2.4, 2.8, and 8.3 times (see Example 6).
  • the association between the number of sensitization and asthma, chronic obstructive pulmonary disease, lung cancer in the four bacteria-derived extracellular vesicles was measured for at least three bacterial-derived vesicles in asthma, chronic obstructive pulmonary disease, and lung cancer patients.
  • IgG1 all four bacterial-derived vesicles were found in chronic obstructive pulmonary disease and lung cancer patients only. Increased. In the case of IgG4, it was confirmed that two or three bacteria-derived vesicles increased in lung cancer patients (see Example 7).
  • 'metagenome' used in the present invention also referred to as 'gunoelectric', refers to the sum total of the genome including all viruses, bacteria, fungi, etc. in an isolated area such as soil and animal intestine. It is used as a concept of genome explaining the identification of many microorganisms at once using sequencer to analyze microorganisms that are not.
  • the metagenome does not refer to one genome or genome, but to a kind of mixed dielectric as the genome of all species of one environmental unit. This is a term from the point of view of defining a species in the course of the evolution of biology in terms of functional species as well as various species that interact with each other to create a complete species.
  • rapid sequencing is used to analyze all DNA and RNA, regardless of species, to identify all species in one environment, and to identify interactions and metabolism.
  • the present invention comprises the steps of reacting a patient sample with extracellular vesicles or proteins derived from the indoor dust bacteria; Reacting the reaction with an anti-human IgG antibody to determine the amount of IgG antibody in the sample; And it provides a method for diagnosing respiratory inflammatory disease comprising the step of determining the respiratory inflammatory disease when the amount of IgG antibody in the sample is increased more than two times compared to the normal person.
  • extracellular vesicles refers to nanoscale nanovesicles secreted by various bacteria.
  • the extracellular vesicles present in the indoor dust are caused by bacteria living in the room, house dust mites, wheels, pets, humans, etc., or by various kinds of bacteria living in and around structures including structures.
  • the extracellular vesicles may be produced, but the average diameter may be 10-300 nm, but is not limited thereto.
  • a protein contained in the extracellular vesicles may be used as an antigen instead of the extracellular vesicles, but is not limited thereto.
  • Staphylococcus aureus Staphylococcus
  • Acinetobacter Acinetobacter
  • Pseudomonas Pseudomonas
  • Enterobacter Enterobacter
  • staphylococcus aureus is Staphylococcus aureus
  • the acinetobacter is Acinetobacter Baumani ( Acinetobacter) baumannii
  • the pseudomonas is Pseudomonas aeruginosa
  • the enterobacter may be Enterobacter aerogenes , but is not limited thereto.
  • the patient sample of the present invention may be selected from the group consisting of blood and sputum, but is not limited thereto.
  • the antibody of the present invention may be IgG, IgA, or IgE, IgG antibody may be IgG1 or IgG4, but is not limited thereto.
  • the respiratory inflammatory disease of the present invention may be selected from the group consisting of asthma, chronic obstructive pulmonary disease, and lung cancer, but is not limited thereto.
  • the dust present in the filter of the vacuum cleaner was transferred to a clean glass bottle to measure the mass. 5 g of indoor dust was placed in a beaker containing 200 ml of PBS (phosphate-buffered saline) and dissolved at 4 ° C. for 12 hours. Afterwards, the large amount of foreign matter is first filtered out, the filtered solution is divided into high speed centrifuge tubes, and high speed centrifugation is performed at 10,000 xg for 15 minutes at 4 ° C. Performed twice in succession.
  • PBS phosphate-buffered saline
  • the filtered supernatant was divided into a 70 mL ultracentrifuge tube, and then stored at 4 ° C., 100,000 xg. The ultracentrifugation (ultracetrifugation) was performed for 4 hours at. The supernatant was discarded and the extracellular vesicles were extracted by dissolving the precipitate under the tube with PBS.
  • the dust separated from the two mattress bed mattress in spring, summer, autumn and winter contains 115.6, 83.8, 71.3, 96.1 ⁇ g (protein / g dust) extracellular vesicles, respectively It was confirmed.
  • the extracellular vesicles were observed by transmission electron microscopy (TEM) to evaluate the properties of the extracellular vesicles separated by the method of Example 1.
  • TEM transmission electron microscopy
  • 10 ⁇ l was placed on 400-mesh copper grids.
  • staining with 2% uranyl acetate (uranyl acetate) and blowing water was observed under 100 kV using a JEM1011 microscope (JEOL, Peabody, MA, USA).
  • the size of the extracellular vesicles separated from the bed mattress dust was measured by dynamic light scattering. After diluting the extracellular endoplasmic reticulum to 10 ⁇ g / ml concentration, 1 mL into the cuvette (cuvette) and measured the degree of light scattering at 633 nm wavelength using Zetasizer Nano S (Malvern Instrument Ltd. Worcestershire, UK) (30 X 10 times / sample).
  • the size of the extracellular vesicles separated from the bed mattress dust in spring, summer, autumn and winter was 30-220, 20-100, 30-220 and 50-250 nm, respectively.
  • DNA was extracted from bacteria and extracellular vesicles present in the indoor dust and subjected to metagenomic analysis to analyze the distribution of bacteria and bacteria-derived extracellular vesicles at the phylum level and genus level.
  • DNA was extracted from the bacterial and extracellular vesicles present in the indoor dust using a DNA extraction kit (Bioneer Inc., Daejeon, Korea), and the DNA library was prepared according to the GS FLX titanium library prep guide. Subsequently, the production library was quantified using Picogreen assay (Invitrogen, Carlsbad, CA, USA), and emulsion PCR (emulsion PCR; emPCR) using GSFLX titanium emPCR Kit (454 Life Sciences, Basel, Switzerland) for amplification of the production library. It was performed by.
  • Picogreen assay Invitrogen, Carlsbad, CA, USA
  • emulsion PCR emulsion PCR; emPCR
  • the production library was fixed on the beads, mixed with an amplification mix and oil, mixed vigorously in Tissue Lyser II (Qiagen, Limburg, Netherlands) to form “micro-reactors”, and the fluid was dispensed on 96-well plates. PCR amplification reactions were performed.
  • DNA sequencing of the isolated DNA the DNA isolated by the above method was amplified by a polymerase chain reaction, and then the bead containing the amplified library was separated through the filter by breaking the emulsion state. Then, only beads having amplified libraries were purified using biotinylated primer A (complementary to adapter A), which can be attached to streptavidin-coated magnetic beads (streptavidin-coated magnetic beads).
  • the distribution of bacteria and bacteria-derived extracellular vesicles present in the dust was analyzed at the genus level.
  • a Le Clerc cyano (Leclercia) in bacteria is achieved when the main yirueotgo, Gram-positive bacteria in the main all four seasons, Staphylococcus (Staphylococcus) in bacteria belonging to the Firmicutes door in all seasons.
  • samples were prepared from blood and sputum in four groups.
  • the first group consisted of 294 Asthma patients who had undergone a medical diagnosis based on reversible airway obstruction.
  • the second group had a 1-second expiratory volume / total lung capacity (FEV1 / FVC) after bronchodilator use regardless of smoking history.
  • the study consisted of 242 patients with chronic obstructive pulmonary disease (COPD).
  • COPD chronic obstructive pulmonary disease
  • the third group consisted of patients diagnosed with lung cancer at Dankook University Hospital from November 2003 to March 2011.
  • the fourth group was the control group. It consists of 90 members of the public.
  • the four groups are shown in detail in Table 1 below.
  • vesicle-specific IgG antibodies were measured in samples obtained from the patients and controls.
  • 50 ng of extracellular vesicles were placed in each well of a 96-well plate for one day.
  • anti-human IgG antibodies were placed in place of extracellular vesicles.
  • 5% skim milk powder filled the antibody and extracellular vesicle seating gap, and the obtained sample was reacted by diluting 1000-fold in 5% skim milk powder.
  • horseradish peroxidase conjugated secondary antibody (Horseradish peroxidase-conjugated anti-IgG) (abcam, Cambridge, UK) was diluted in 5% skim milk solution, and then reacted with an IgG antibody through a microplate reader. The amount was measured. Sensitization to extracellular vesicles in dust was defined as positive when more than 95% of vesicle-specific IgG antibody values present in normal samples.
  • Example 6 Chronic Obstructive Pulmonary Disease In lung cancer patient samples Staphylococcus , Acinetobacter , Pseudomonas , Enterobacter Bacterial origin Extracellular Endoplasmic reticulum IgG , IgG1, IgG4 Antibody measurement
  • Each bacterium originated Extracellular Endoplasmic reticulum separation and Extracellular Endoplasmic reticulum IgG , IgG1 , IgG4 antibody measurement
  • Example 3 within the Staphylococcus aureus of the meta-house dust in genome analysis (Staphylococcus), and based on the findings that the Acinetobacter (Acinetobacter), Pseudomonas (Pseudomonas), Enterobacter (Enterobacter) in germ cells derived from outside the endoplasmic reticulum are large amounts present Specific IgG, IgG1, IgG4 antibodies against extracellular vesicles derived from the bacteria were measured in the four groups described in Example 4, namely, asthma, chronic obstructive pulmonary disease, lung cancer, and blood and sputum of normal persons. .
  • Bacteria corresponding to each genus, Staphylococcus aureus , Acinetobacter baumannii ), Pseudomonas aeruginosa ), and enterobacter aerogenes were inoculated in a liquid nutrient medium and incubated at 37 ° C. under agitation / constant incubator until the absorbance was 1.5. Thereafter, centrifugation was performed at 4 ° C. at 10,000 ⁇ g for 20 minutes using a high-speed centrifuge to separate bacteria and supernatant, and only the supernatant was removed and passed once through a 0.45 ⁇ m membrane filter.
  • the supernatant was concentrated to 300 ml with a quickstand (GE healthcare) for concentration for high-speed centrifugation, and then passed once through a membrane filter (0.22 ⁇ m). This was divided into ultra high-speed centrifuge tubes (45 Ti, 70 ml, Beckman coulter), and ultra-high centrifugation was performed at 4 ° C. and 100,000 x g for 3 hours. Outer endoplasmic reticulum was isolated.
  • each secondary antibody (Horseradish peroxidase-conjugated anti-IgG, anti-IgG1, anti-IgG4) (abcam, Cambridge, UK) conjugated with horseradish peroxidase was diluted and reacted with 5% skim milk powder. Then, the amount of each IgG antibody was measured through a microplate reader. Sensitization to each bacterial-derived extracellular vesicles was defined as positive when showing at least 95% of the vesicle-specific IgG, IgG1, IgG4 antibody values present in normal human blood and sputum.
  • Staphylococcus aureus Staphylococcus aureus Origin Extracellular Endoplasmic reticulum Sensitization asthma, Chronic Obstructive Pulmonary Disease Association of lung cancer
  • Acinetobacter Baumani Acinetobacter baumannii Origin Extracellular Endoplasmic reticulum and asthma, Chronic Obstructive Pulmonary Disease Association of lung cancer
  • Pseudomonas aeruginosa Pseudomonas aeruginosa Origin Extracellular Endoplasmic reticulum Sensitization asthma, Chronic Obstructive Pulmonary Disease Association of lung cancer
  • Enterobacter Aerogenes Enterobacter aerogenes Origin Extracellular Endoplasmic reticulum and asthma, Chronic Obstructive Pulmonary Disease Association of lung cancer
  • Example 7 Origin of the above four bacteria Extracellular On the endoplasmic reticulum Sensitization Asthma, Chronic Association between obstructive pulmonary disease and lung cancer
  • Example 6 Four bacteria of Example 6, namely Staphylococcus aureus , Acinetobacter Baumani ( Acinetobacter) baumannii ), Pseudomonas aeruginosa ), Enterobacter The purpose of this study was to determine the relationship between the number of aerogenes ) -derived extracellular vesicles and their sensitivity to disease.

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Abstract

La présente invention concerne un procédé permettant de diagnostiquer des maladies respiratoires inflammatoires à l'aide de vésicules de membrane externe dérivés de bactéries et, plus spécifiquement, un procédé de diagnostic de l'asthme, la broncho-pneumopathie chronique obstructive et le cancer du poumon en mesurant des anticorps spécifiques dirigés contre des vésicules de membrane externe dérivés de bactéries existant dans la poussière intérieure ou contre des protéines dérivées des vésicules de membrane externe. Les vésicules de membrane externe dérivés de Staphylococcus spp., Acinetobacter spp., Pseudomonas spp. et de Enterobacter, qui existent en grande quantité dans la poussière dans l'air intérieur, peuvent provoquer des maladies respiratoires inflammatoires, et, par conséquent, la présente invention peut être utilisée favorablement comme procédé permettant de diagnostiquer l'asthme, la broncho-pneumopathie chronique obstructive et le cancer du poumon, par mesure des anticorps spécifiques dirigés contre les vésicules de membrane externe/protéines dérivé(e)s des bactéries dans des échantillons de patient.
PCT/KR2016/001502 2015-02-17 2016-02-15 Procédé pour le diagnostic de maladies respiratoires inflammatoires à l'aide de vésicules de membrane externe dérivés de bactéries Ceased WO2016133324A1 (fr)

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WO2019139279A1 (fr) * 2018-01-12 2019-07-18 주식회사 엠디헬스케어 Nanovésicules issues de bactéries morganella et utilisations associées
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EP3587596A4 (fr) * 2017-02-24 2020-12-16 MD Healthcare Inc. Procédé de diagnostic d'une maladie respiratoire obstructive chronique par analyse du métagénome bactérien
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KR102299252B1 (ko) * 2019-09-10 2021-09-08 주식회사 엠디헬스케어 미생물 유래 소포에 대한 항체 기반 폐질환 진단 방법
KR102482695B1 (ko) * 2020-12-04 2023-01-02 주식회사 엠디헬스케어 만성 두드러기의 진단 방법
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EP3587596A4 (fr) * 2017-02-24 2020-12-16 MD Healthcare Inc. Procédé de diagnostic d'une maladie respiratoire obstructive chronique par analyse du métagénome bactérien
WO2019139360A1 (fr) * 2018-01-12 2019-07-18 주식회사 엠디헬스케어 Nanovésicules issues de faecalibacterium prausnitzii et utilisations associées
WO2019139279A1 (fr) * 2018-01-12 2019-07-18 주식회사 엠디헬스케어 Nanovésicules issues de bactéries morganella et utilisations associées
US10858670B2 (en) 2018-01-12 2020-12-08 Md Healthcare Inc. Nano-vesicles derived from genus Morganella bacteria and use thereof
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