KR102596057B1 - Lipid metabolite markers for diagnosing Mycobacterium avium complex infectious diseases - Google Patents
Lipid metabolite markers for diagnosing Mycobacterium avium complex infectious diseases Download PDFInfo
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- KR102596057B1 KR102596057B1 KR1020210151438A KR20210151438A KR102596057B1 KR 102596057 B1 KR102596057 B1 KR 102596057B1 KR 1020210151438 A KR1020210151438 A KR 1020210151438A KR 20210151438 A KR20210151438 A KR 20210151438A KR 102596057 B1 KR102596057 B1 KR 102596057B1
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- mycobacterium
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- phosphatidylcholine
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- triacylglycerol
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Classifications
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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
- G01N33/569—Immunoassay; Biospecific binding assay; Materials therefor for microorganisms, e.g. protozoa, bacteria, viruses
- G01N33/56911—Bacteria
- G01N33/5695—Mycobacteria
-
- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N30/00—Investigating or analysing materials by separation into components using adsorption, absorption or similar phenomena or using ion-exchange, e.g. chromatography or field flow fractionation
- G01N30/02—Column chromatography
- G01N30/62—Detectors specially adapted therefor
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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
- G01N33/68—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids
- G01N33/6893—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving proteins, peptides or amino acids related to diseases not provided for elsewhere
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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
- G01N33/92—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing involving lipids, e.g. cholesterol, lipoproteins, or their receptors
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2405/00—Assays, e.g. immunoassays or enzyme assays, involving lipids
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- G—PHYSICS
- G01—MEASURING; TESTING
- G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
- G01N2800/00—Detection or diagnosis of diseases
- G01N2800/52—Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
Abstract
본 발명은 혈액 내 특정 지질대사체를 측정함으로써, 비결핵 항산균의 감염 여부를 정확히 판정하는 진단용 조성물에 관한 것이다. 본 발명은 비결핵 항산균(NTM), 특히 객관적이고 신뢰성 높은 진단 표지자가 부족한 마이코박테리움 아비움 복합체(MAC)에 있어서, 상기 대사체들을 신속 정확하며 신뢰도 높은 측정을 위한 바이오마커로 적용함으로써, 비결핵 항산균 감염 질환의 보다 효율적인 진단에 유용하게 이용될 수 있다. The present invention relates to a diagnostic composition that accurately determines infection by non-tuberculous acid-fast bacteria by measuring specific lipid metabolites in the blood. The present invention applies the metabolites as biomarkers for rapid, accurate, and reliable measurement in non-tuberculous mycobacteria (NTM), especially Mycobacterium avium complex (MAC), which lacks objective and reliable diagnostic markers. , can be useful for more efficient diagnosis of non-tuberculous acid-fast bacterial infection diseases.
Description
본 발명은 마이코박테리움 아비움 복합체 감염질환 진단용 지질대사체 마커에 관한 것이다.The present invention relates to lipid metabolite markers for diagnosing Mycobacterium avium complex infectious diseases.
마이코박테리움 (Mycobacterium) 종류에는 결핵, 우형결핵(Mycobacterium bovis), 나병(Mycobacterium leprae)과 같이 사람과 동물에 심각한 질병을 일으키는 균 종(species)뿐 아니라, 기회 감염균으로 일컬어지는 균 종, 그리고 자연환경에서 볼 수 있는 수포성 종(saprophytic species) 등 현재까지 약 72 종이 알려져 있으며, 그 중 인체 질환과 관련된 것이 25종에 이르는 것으로 알려져 있다. 이러한 마이코박테리움 속은 일반적으로 사용되는 염색액으로는 용이하게 염색되지 않지만 일단 염색되면 알코올이나 염산 등으로 처리시에도 용이하게 탈색되지 않기 때문에 항산균이라고도 불린다.Mycobacterium includes not only species that cause serious diseases in humans and animals such as tuberculosis, Mycobacterium bovis, and leprosy, but also species called opportunistic bacteria, and Approximately 72 species are known to date, including saprophytic species that can be found in the natural environment, and among them, 25 species are known to be related to human diseases. These Mycobacterium genus are not easily dyed with commonly used dyes, but once dyed, they are also called acid-fast bacteria because they are not easily decolorized even when treated with alcohol or hydrochloric acid.
비결핵 항산균(Nontuberculous mycobacteria; NTM)은 결핵균(Mycobacterium tuberculosis complex) 및 나균(Mycobacterium leprae)을 제외한 항산균을 의미한다. 한편, 마이코박테리움 아비움 복합체(Mycobacterium avium complex; MAC)에 속하는 비결핵 항산균주 중 흔히 인간에게서 폐 질환을 일으키는 균주로는 공식적으로 대략 180 종 이상이 규명되었다. MAC는 주로 M. 아비움(M. avium)과 M. 인트라셀룰라(M. intracellulare)를 포함하고, 마이코박테리움 압세수스(Mycobacterium abscessus; MAB)는 주로 M. 압세수스 아종인 압세수스(M. abscessus subspecies abscessus)와 M. 압세수스 아종인 마실리엔스(M. abscessus subspecies massiliense)를 포함한다. 최근 전세계적으로 비결핵 항산균에 기인한 폐 감염 보고가 증가하고 있지만, 건강한 개체군으로부터 비결핵 항산균 폐 감염 질환자를 구별하기 위한 바이오마커나, 질환에 대한 병태 생리의 연구가 부족한 실정이다.Nontuberculous mycobacteria (NTM) refers to acid-fast bacteria excluding Mycobacterium tuberculosis complex and Mycobacterium leprae. Meanwhile, among the non-tuberculous acid-fast bacterial strains belonging to the Mycobacterium avium complex (MAC), more than 180 strains that commonly cause lung disease in humans have been officially identified. MAC mainly includes M. avium and M. intracellulare , while Mycobacterium abscessus ( MAB ) mainly includes M. abscessus subspecies Absessus. Includes M. abscessus subspecies abscessus and M. abscessus subspecies massiliense . Recently, reports of lung infections caused by non-tuberculous mycobacteria are increasing worldwide, but there is a lack of biomarkers to distinguish patients with non-tuberculous mycobacterial lung infections from a healthy population or studies on the pathophysiology of the disease.
본 명세서 전체에 걸쳐 다수의 논문 및 특허문헌이 참조되고 그 인용이 표시되어 있다. 인용된 논문 및 특허문헌의 개시 내용은 그 전체로서 본 명세서에 참조로 삽입되어 본 발명이 속하는 기술 분야의 수준 및 본 발명의 내용이 보다 명확하게 설명된다.Numerous papers and patent documents are referenced and citations are indicated throughout this specification. The disclosures of the cited papers and patent documents are incorporated herein by reference in their entirety to more clearly explain the content of the present invention and the level of technical field to which the present invention pertains.
본 발명자들은 객관적이고 신뢰성 높은 진단 마커의 개발이 어려운 비결핵 항산균(Nontuberculous mycobacteria; NTM), 특히 인간에게 매우 흔하게 폐 질환을 일으키는 마이코박테리움 아비움 복합체(Mycobacterium avium complex; MAC)에 감염된 환자를 건강한 대상체로부터 구별하기 위한 진단 표지자 발굴을 위하여 예의 연구 노력하였다. 그 결과, 비결핵 항산균 감염환자와 비감염 대상체를 명확히 구분할 수 있는 진단 표지자로서 24종의 지질 대사체를 발견함으로써, 본 발명을 완성하게 되었다.The present inventors studied patients infected with Nontuberculous mycobacteria (NTM), for which it is difficult to develop objective and reliable diagnostic markers, and especially Mycobacterium avium complex (MAC), which causes lung disease very commonly in humans. Extensive research efforts were made to discover diagnostic markers to differentiate from healthy subjects. As a result, the present invention was completed by discovering 24 types of lipid metabolites as diagnostic markers that can clearly distinguish between non-tuberculous mycobacterial infection patients and non-infected subjects.
따라서 본 발명의 목적은 비결핵 항산균 감염 질환의 진단용 조성물 및 이를 이용한 진단방법을 제공하는데 있다.Therefore, the purpose of the present invention is to provide a composition for diagnosing non-tuberculous acid-fast bacterial infection diseases and a diagnostic method using the same.
본 발명의 다른 목적 및 이점은 하기의 발명의 상세한 설명, 청구범위 및 도면에 의해 보다 명확하게 된다.Other objects and advantages of the present invention will become clearer from the following detailed description, claims, and drawings.
본 발명의 일 양태에 따르면, 본 발명은 리소포스파티딜콜린(Lysophosphatidylcholine; LPC), 리소포스파티딜에탄올아민(Lysophosphatidylethanolamine; LPE), 포스파티딜콜린(Phosphatidylcholine; PC), 포스파티딜에탄올아민(Phosphatidylethanolamine; PE), 스핑고마이엘린(Sphingomyeline; SM) 및 트리아실글리세롤(Triacylglycerol; TAG)로 구성된 군으로부터 선택되는 하나 이상의 대사체를 측정하는 제제를 유효성분으로 포함하는 비결핵 항산균의 감염 질환의 진단용 조성물을 제공한다.According to one aspect of the present invention, the present invention provides lysophosphatidylcholine (LPC), lysophosphatidylethanolamine (LPE), phosphatidylcholine (PC), phosphatidylethanolamine (PE), and sphingomyelin ( Provided is a composition for diagnosing non-tuberculous mycobacterial infectious diseases, comprising as an active ingredient an agent for measuring one or more metabolites selected from the group consisting of sphingomyeline (SM) and triacylglycerol (TAG).
본 발명자들은 객관적이고 신뢰성 높은 진단 마커의 개발이 어려운 비결핵 항산균(Nontuberculous mycobacteria; NTM), 특히 인간에게 매우 흔하게 폐 질환을 마일으키는 마이코박테리움 아비움 복합체(Mycobacterium avium complex; MAC)에 감염된 환자를 건강한 대상체로부터 구별하기 위한 진단 표지자 발굴을 위하여 예의 연구 노력하였다. 그 결과, 비결핵 항산균 감염환자와 비감염 대상체를 명확히 구분할 수 있는 진단 표지자로서 24종의 지질 대사체를 발굴하였다. The present inventors investigated non-tuberculous mycobacteria (NTM), for which it is difficult to develop objective and reliable diagnostic markers, and in particular, Mycobacterium avium complex (MAC), which very commonly causes lung disease in humans. Extensive research efforts were made to discover diagnostic markers to distinguish patients from healthy subjects. As a result, 24 types of lipid metabolites were discovered as diagnostic markers that can clearly distinguish between non-tuberculous mycobacterial infection patients and non-infected subjects.
본 명세서에서 용어 “비결핵 항산균”은 결핵균이 아닌 항산균을 의미하며 구체적으로는 결핵 및 나병을 유발하지 않는 모든 마이코박테리아를 포함하는 의미이다. 항산균은 일반적인 세균들과 달리 염색과정에서 산(acid)을 첨가해도 용해되지 않고 견딜 수 있는 능력을 가지는 균주를 의미한다. 이런 항산균들 중 대표적인 것이 바로 결핵균이며, 결핵균이 이외의 항산균을 비결핵항산균(Nontuberculous mycobacteria; NTM)이라고 하고, 거의 매년 새로운 비결핵항산균이 발견되고 있다.As used herein, the term “non-tuberculous acid-fast bacteria” refers to acid-fast bacteria other than tuberculosis bacteria, and specifically includes all mycobacteria that do not cause tuberculosis and leprosy. Unlike general bacteria, acid-fast bacteria refer to strains that have the ability to withstand the addition of acid during the dyeing process without being dissolved. The most representative of these acid-fast bacteria is Mycobacterium tuberculosis, and acid-fast bacteria other than Mycobacterium tuberculosis are called Nontuberculous mycobacteria (NTM), and new non-tuberculous mycobacteria are discovered almost every year.
본 명세서에서 용어 “진단”은 특정 질병 또는 질환에 대한 한 객체의 감수성(susceptibility)을 판정하는 것, 한 객체가 특정 질병 또는 질환을 현재 가지고 있는 지 여부를 판정하는 것(예컨대, 비결핵 항산균 감염), 특정 질병 또는 질환에 걸린 한 객체의 예후(prognosis)를 판정하는 것, 또는 테라메트릭스(therametrics)(예컨대, 치료 효능에 대한 정보를 제공하기 위하여 객체의 상태를 모니터링하는 것)을 포함한다. 구체적으로는 본 발명의 취지상 본 명세서의 용어 진단은 한 객체가 특정 질병 또는 질환을 현재 가지고 있는지 여부를 판정하는 것을 의미한다.As used herein, the term “diagnosis” refers to determining an object's susceptibility to a specific disease or disorder, determining whether an object currently has a specific disease or condition (e.g., non-tuberculous acid-fast bacilli). infection), determining the prognosis of a subject with a particular disease or condition, or therametrics (e.g., monitoring the condition of a subject to provide information about the efficacy of treatment). . Specifically, for the purpose of the present invention, the term diagnosis herein means determining whether an object currently has a specific disease or condition.
본 명세서에서 용어“진단용 조성물”은 대상체의 비결핵 항산균의 감염질환의 발병 여부를 판단하거나 발병 가능성을 예측하기 위해 리소포스파티딜콜린(Lysophosphatidylcholine), 리소포스파티딜에탄올아민(Lysophosphatidylethanolamine), 포스파티딜콜린(Phosphatidylcholine), 포스파티딜에탄올아민(Phosphatidylethanolamine), 스핑고마이엘린(Sphingomyeline) 및 트리아실글리세롤(Triacylglycerol)의 대사체 농도 측정수단을 포함하는 통합적인 혼합물(mixture) 또는 장비(device)를 의미하며, 이에“진단용 키트”로 표현될 수도 있다. 본 발명의 진단용 조성물은 본 발명에서 발굴된 대사체를 측정하기 위한 수단이 포함되므로, 용어“진단용 조성물”은 대사체의“정량 장치”로 표현될 수도 있다. As used herein, the term “diagnostic composition” refers to Lysophosphatidylcholine, Lysophosphatidylethanolamine, Phosphatidylcholine, and phosphatidylcholine to determine whether or predict the possibility of developing a non-tuberculous acid-fast bacterial infectious disease in a subject. It refers to an integrated mixture or device containing means for measuring the concentration of metabolites of Phosphatidylethanolamine, Sphingomyeline, and Triacylglycerol, and is therefore referred to as a “diagnostic kit.” It can also be expressed. Since the diagnostic composition of the present invention includes a means for measuring the metabolites discovered in the present invention, the term “diagnostic composition” may also be expressed as a “quantitative device” for metabolites.
본 명세서에서 용어 "대사체(metabolite)"는 대사물질 또는 대사산물이라고도 불리우며, 물질 대사의 중간 생성물 또는 생성물이다. 이러한 대사체는 연료, 구조, 신호전달, 효소에 대한 촉진 및 저해 효과, 그 자신의 촉매 활성(일반적으로 효소에 대한 보조 인자로서), 방어, 다른 생물체와의 상호작용(예: 색소, 방향 화합물, 페로몬)을 포함하는 다양한 기능을 가지고 있다. 1차 대사체는 정상적인 생장, 발생 및 생식에 직접적으로 관여한다. 2차 대사체는 이러한 과정들에 직접적으로 관여하지 않지만, 대개 중요한 생태학적 기능을 가지고 있다.As used herein, the term “metabolite” is also called a metabolite or metabolite, and is an intermediate product or product of metabolism. These metabolites provide fuel, structure, signaling, stimulatory and inhibitory effects on enzymes, their own catalytic activity (usually as cofactors for enzymes), defense, and interactions with other organisms (e.g. pigments, aroma compounds). , pheromones). Primary metabolites are directly involved in normal growth, development, and reproduction. Although secondary metabolites are not directly involved in these processes, they often have important ecological functions.
본 발명에 따르면, 상기 대사체는 생체 기원의 시료, 즉 생물학적 시료로부터 수득한 대사 물질을 말하는 것으로, 상기 생물학적 시료는 생물학적 체액, 조직 또는 세포를 의미하는 것이다.According to the present invention, the metabolite refers to a sample of biological origin, that is, a metabolite obtained from a biological sample, and the biological sample refers to a biological body fluid, tissue, or cell.
본 발명에 따르면, 상기 대사체는 혈액, 구체적으로는 혈청 기원의 액상 시료로부터 수득한 대사물질일 수 있다.According to the present invention, the metabolite may be a metabolite obtained from a liquid sample of blood, specifically serum origin.
본 발명의 구체적인 구현예에 따르면, 상기 리소포스파티딜콜린은 LPC (18:0) 및 LPC (20:5)로 구성된 군으로부터 선택되는 하나 이상의 리소포스파티딜콜린이다.According to a specific embodiment of the present invention, the lysophosphatidylcholine is one or more lysophosphatidylcholine selected from the group consisting of LPC (18:0) and LPC (20:5).
본 발명의 구체적인 구현예에 따르면, 상기 리소포스파티딜에탄올아민은 LPE (18:2) 및 LPE (20:4)로 구성된 군으로부터 선택되는 하나 이상의 리소포스파티딜에탄올아민이다.According to a specific embodiment of the present invention, the lysophosphatidylethanolamine is one or more lysophosphatidylethanolamines selected from the group consisting of LPE (18:2) and LPE (20:4).
본 발명의 구체적인 구현예에 따르면, 상기 포스파티딜콜린은 PC 36:5(20:5/16:0), PC 28:0(14:0/14:0), PC 30:0(14:0/16:0), PC 32:2(18:2/14:0), PC 33:2(18:2/15:0), PC 34:2(18:2/16:0), PC 34:3(16:1/18:2), PC 36:4(20:4/16:0), PC O36:3(O18:1/18:2), PC O36:5(O16:1/20:4) 및 PC O36:5(O16:1/20:4)로 구성된 군으로부터 선택되는 하나 이상의 포스파티딜콜린이다.According to a specific embodiment of the present invention, the phosphatidylcholine is PC 36:5 (20:5/16:0), PC 28:0 (14:0/14:0), PC 30:0 (14:0/16) :0), PC 32:2(18:2/14:0), PC 33:2(18:2/15:0), PC 34:2(18:2/16:0), PC 34:3 (16:1/18:2), PC 36:4(20:4/16:0), PC O36:3(O18:1/18:2), PC O36:5(O16:1/20:4) ) and PC O36:5 (O16:1/20:4).
본 발명의 구체적인 구현예에 따르면, 상기 포스파티딜에탄올아민은 PENME 34:1(18:1/16:0)이다.According to a specific embodiment of the present invention, the phosphatidylethanolamine is PENME 34:1 (18:1/16:0).
본 발명의 구체적인 구현예에 따르면, 상기 스핑고마이엘린은 SM d34:1(d18:1/16:0), SM d42:1(d18:1/24:0) 및 SM d42:2(d18:1/24:1)로 구성된 군으로부터 선택되는 하나 이상의 스핑고마이엘린이다.According to a specific embodiment of the present invention, the sphingomyelin is SM d34:1 (d18:1/16:0), SM d42:1 (d18:1/24:0), and SM d42:2 (d18: 1/24:1) is one or more sphingomyelins selected from the group consisting of
본 발명의 구체적인 구현예에 따르면, 상기 트리아실글리세롤은 TAG 54:5(18:1/18:1/18:3), TAG 55:7(21:5/18:2/16:0), TAG 58:11(22:6/20:5/16:0), TAG 60:11(22:6/20:4/18:1) 및 TAG 60:12(22:6/22:6/16:0)로 구성된 군으로부터 선택되는 하나 이상의 트리아실글리세롤이다.According to a specific embodiment of the present invention, the triacylglycerol is TAG 54:5 (18:1/18:1/18:3), TAG 55:7 (21:5/18:2/16:0), TAG 58:11(22:6/20:5/16:0), TAG 60:11(22:6/20:4/18:1), and TAG 60:12(22:6/22:6/16) :0) is one or more triacylglycerols selected from the group consisting of
본 발명의 구체적인 구현예에 따르면, 상기 리소포스파티딜콜린, 포스파티딜콜린, 스핑고마이엘린 또는 트리아실글리세롤의 농도가 정상 대조군 대비 증가한 경우, 비결핵 항산균에 의해 감염된 것으로 예측한다.According to a specific embodiment of the present invention, when the concentration of lysophosphatidylcholine, phosphatidylcholine, sphingomyelin, or triacylglycerol increases compared to the normal control group, infection by non-tuberculous acid-fast bacteria is predicted.
본 발명에 따르면, 상기 "대조군"이란 비결핵 항산균에 의해 감염되지 않은 정상 개체를 의미한다. According to the present invention, the “control group” refers to a normal individual not infected by non-tuberculous acid-fast bacteria.
본 발명의 구성 중“진단용 조성물”을 언급하면서 사용되는 용어“농도의 증가”는 마이코박테리움에 감염되지 않은 정상인에 비해 감염환자 혈청 내 대세체 농도가 유의하게 높은 경우를 의미하며, 구체적으로는 상기 정상인과 대조군과 비교하여 약 10% 이상 증가, 약 20% 이상 증가, 약 30% 이상 증가, 약 40% 이상 증가 또는 약 50% 이상 증가를 의미하고, 보다 구체적으로는 약 40% 이상 증가한 경우를 의미하며, 이를 벗어나는 범위를 제외하는 것은 아니다.Among the components of the present invention, the term “increase in concentration” used while referring to the “diagnostic composition” refers to a case where the concentration of the major body in the serum of an infected patient is significantly higher than that of a normal person not infected with Mycobacterium, and specifically, means an increase of about 10% or more, an increase of about 20% or more, an increase of about 30% or more, an increase of about 40% or more, or an increase of about 50% or more compared to the normal and control groups, and more specifically, an increase of about 40% or more. It means a case, and does not exclude the scope beyond this.
본 발명의 구체적인 구현예에 따르면, 리소포스파티딜에탄올아민, 포스파티딜콜린 또는 포스파티딜에탄올아민의 농도가 정상 대조군 대비 감소한 경우, 비결핵 항산균에 의해 감염된 것으로 예측한다.According to a specific embodiment of the present invention, when the concentration of lysophosphatidylethanolamine, phosphatidylcholine, or phosphatidylethanolamine decreases compared to the normal control, it is predicted that the patient is infected with non-tuberculous acid-fast bacteria.
본 발명의 구성 중“진단용 조성물”을 언급하면서 사용되는 용어“농도의 감소”는 마이코박테리움에 감염되지 않은 정상인에 비해 감염환자 혈청 내 대세체 농도가 유의하게 낮은 경우를 의미하며, 구체적으로는 상기 정상인과 대조군과 비교하여 약 10% 이상 감소, 약 20% 이상 감소 또는 약 30% 이상 감소를 의미하고, 보다 구체적으로는 약 40% 이상 감소한 경우를 의미하며, 이를 벗어나는 범위를 제외하는 것은 아니다.The term “reduction in concentration” used while referring to the “diagnostic composition” of the present invention refers to a case where the concentration of the major body in the serum of an infected patient is significantly lower than that of a normal person not infected with Mycobacterium, and specifically, means a decrease of about 10% or more, a decrease of about 20% or more, or a decrease of about 30% or more compared to the above normal and control group, and more specifically, it means a decrease of about 40% or more, excluding the range beyond this. no.
본 발명의 구체적인 구현예에 따르면, 상기 대사체는 전혈(whole blood), 백혈구(leukocytes), 말초혈액 단핵 세포(peripheral blood mononuclear cells), 백혈구 연층(buffy coat), 혈장(plasma), 혈청(serum), 객담(sputum), 눈물(tears), 점액(mucus), 세비액(nasal washes), 비강 흡인물(nasal aspirate), 호흡(breath), 소변(urine), 정액(semen), 침(saliva), 복강 세척액(peritoneal washings), 복수(ascites), 낭종액(cystic fluid), 뇌척수막 액(meningeal fluid), 양수(amniotic fluid), 선액(glandular fluid), 췌장액(pancreatic fluid), 림프액(lymph fluid), 흉수(pleural fluid), 유두 흡인물(nipple aspirate), 기관지 흡인물(bronchial aspirate), 활액(synovial fluid), 관절 흡인물(joint aspirate), 기관 분비물(organ secretions), 세포(cell), 세포 추출물(cell extract) 및 뇌척수액(cerebrospinal fluid) 내 존재한다. 구체적으로는 혈청일 수 있으나, 이에 제한되는 것은 아니다.According to a specific embodiment of the present invention, the metabolite is extracted from whole blood, leukocytes, peripheral blood mononuclear cells, buffy coat, plasma, and serum. ), sputum, tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva ), peritoneal washings, ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid. ), pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cells, It is present in cell extract and cerebrospinal fluid. Specifically, it may be serum, but is not limited thereto.
보다 구체적으로는 상기 대사체를 검출하기 위해 전혈, 혈장 또는 혈청을 전처리할 수 있다. 예를 들어, 여과, 증류, 추출, 분리, 농축, 방해 성분의 불활성화, 시약의 첨가 등을 포함할 수 있다. 또한, 상기 대사체는 대사 및 대사 과정에 의해 생산된 물질 또는 생물학적 효소 및 분자에 의한 화학적 대사작용으로 발생한 물질 등을 포함할 수 있다.More specifically, whole blood, plasma, or serum can be pretreated to detect the metabolites. For example, it may include filtration, distillation, extraction, separation, concentration, inactivation of interfering components, addition of reagents, etc. Additionally, the metabolites may include substances produced through metabolism and metabolic processes or substances generated through chemical metabolism by biological enzymes and molecules.
본 발명의 구체적인 구현예에 따르면, 상기 비결핵 항산균은 마이코박테리움 아비움(M. avium), 마이코박테리움 압세수스(M. abscessus), 마이코박테리움 플라베센스(M. flavescence), 마이코박테리움 아프리카눔(M. africanum), 마이코박테리움 보비스(M. bovis), 마이코박테리움 첼로네(M. chelonae), 마이코박테리움 셀라툼(M. celatum), 마이코박테리움 포르투이툼(M. fortuitum), 마이코박테리움 고르도네(M. gordonae), 마이코박테리움 가스트리(M. gastri), 마이코박테리움 헤모필룸(M. haemophilum), 마이코박테리움 인트라셀루라레(M. intracellulare), 마이코박테리움 칸사시이(M. kansasii), 마이코박테리움 말모엔스(M. malmoense), 마이코박테리움 마리눔(M. marinum), 마이코박테리움 스줄가이(M. szulgai), 마이코박테리움 테레(M. terrae), 마이코박테리움 스크로풀라세움(M. scrofulaceum), 마이코박테리움 울서란스(M. ulcerans), 마이코박테리움 시미애(M. simiae) 및 마이코박테리움 제노피(M. xenopi)로 구성된 군으로부터 선택될 수 있으나, 이에 제한되는 것은 아니다.According to a specific embodiment of the present invention, the non-tuberculous acid-fast bacteria include Mycobacterium avium ( M. avium ), Mycobacterium abscessus ( M. abscessus ), and Mycobacterium flavescens ( M. flavescence ), Mycobacterium africanum ( M. africanum ), Mycobacterium bovis ( M. bovis ), Mycobacterium chelonae ( M. chelonae ), Mycobacterium celatum ( M. celatum ), Mycobacterium fortuitum ( M. fortuitum ), Mycobacterium gordonae ( M. gordonae ), Mycobacterium gastri ( M. gastri ), Mycobacterium haemophilum ( M. haemophilum), Mycobacterium gordonae (M. gordonae ) Cobacterium intracellulare ( M. intracellulare ), Mycobacterium kansasii ( M. kansasii ), Mycobacterium malmoense ( M. malmoense ), Mycobacterium marinum ( M. marinum ), Mycobacterium Terium szulgai ( M. szulgai ), Mycobacterium terre ( M. terrae ), Mycobacterium scrofulaceum ( M. scrofulaceum ), Mycobacterium ulcerans ( M. ulcerans ), Mycobacterium It may be selected from the group consisting of M. simiae and Mycobacterium xenopi , but is not limited thereto.
본 발명의 구체적인 구현예에 따르면, 상기 비결핵 항산균의 감염 질환은 폐 질환, 림프절염, 피부·연조직·골감염증 또는 파종성 질환인 것이다.According to a specific embodiment of the present invention, the non-tuberculous acid-fast bacterial infection disease is lung disease, lymphadenitis, skin, soft tissue, bone infection, or disseminated disease.
본 발명에 따르면, 상기 비결핵 항산균 감염 질환은 비결핵 항산균의 감염에 의해 나타나는 모든 임상적 증상을 포함한다.According to the present invention, the non-tuberculous mycobacterial infection disease includes all clinical symptoms caused by infection with non-tuberculous mycobacteria.
본 발명의 다른 양태에 따르면, 본 발명은 리소포스파티딜콜린(Lysophosphatidylcholine), 리소포스파티딜에탄올아민(Lysophosphatidylethanolamine), 포스파티딜콜린(Phosphatidylcholine), 포스파티딜에탄올아민(Phosphatidylethanolamine), 스핑고마이엘린(Sphingomyeline) 및 트리아실글리세롤(Triacylglycerol)로 구성된 군으로부터 선택되는 하나 이상의 대사체를 측정하는 단계를 포함하는 비결핵 항산균의 감염 질환을 진단하기 위한 정보방법을 제공한다.According to another aspect of the present invention, the present invention provides lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine, phosphatidylethanolamine, sphingomyeline, and triacylglycerol. ) Provides an information method for diagnosing an infectious disease caused by non-tuberculous acid-fast bacteria, including the step of measuring one or more metabolites selected from the group consisting of.
본 발명에서 진단하고자 하는 비결핵 항산균 및 진단 표지자인 대사체에 대해서는 이미 상술하였으므로, 과도한 중복을 피하기 위해 그 기재를 생략한다.Since the non-tuberculous acid-fast bacteria to be diagnosed in the present invention and the metabolites that are diagnostic markers have already been described in detail, their description is omitted to avoid excessive duplication.
본 발명의 구체적인 구현예에 따르면, 상기 대사체의 농도를 측정하는 단계는 크로마토그래피 또는 질량분석기인 정량 장치를 이용할 수 있으나, 이에 제한되는 것은 아니다.According to a specific embodiment of the present invention, the step of measuring the concentration of the metabolite may use a quantitative device such as a chromatography or mass spectrometer, but is not limited thereto.
본 발명에서 이용되는 크로마토그래피는 고성능 액체 크로마토그래피(High Performance Liquid Chromatography, HPLC), 액체-고체 크로마토그래피(Liquid-Solid Chromatography, LSC), 종이크로마토그래피(Paper Chromatography, PC), 박층 크로마토그래피(Thin-Layer Chromatography, TLC), 기체-고체 크로마토그래피(Gas-Solid Chromatography, GSC), 액체-액체 크로마토그래피(Liquid-Liquid Chromatography, LLC), 포말 크로마토그래피(Foam Chromatography, FC), 유화 크로마토그래피(Emulsion Chromatography, EC), 기체-액체 크로마토그래피(Gas-Liquid Chromatography, GLC), 이온 크로마토그래피(Ion Chromatography, IC), 겔 여과 크로마토그래피(Gel Filtration Chromatograhy, GFC) 또는 겔 투과 크로마토그래피(Gel Permeation Chromatography, GPC)를 포함될수 있으나, 이에 제한되지 않고 당업계에서 통상적으로 사용되는 모든 정량용 크로마토그래피를 사용할 수 있다.Chromatography used in the present invention is High Performance Liquid Chromatography (HPLC), Liquid-Solid Chromatography (LSC), Paper Chromatography (PC), and Thin Layer Chromatography (Thin Layer Chromatography). -Layer Chromatography (TLC), Gas-Solid Chromatography (GSC), Liquid-Liquid Chromatography (LLC), Foam Chromatography (FC), Emulsion Chromatography (Emulsion) Chromatography (EC), Gas-Liquid Chromatography (GLC), Ion Chromatography (IC), Gel Filtration Chromatography (GFC), or Gel Permeation Chromatography (GFC) GPC) may be included, but is not limited thereto, and any quantitative chromatography commonly used in the art may be used.
본 발명에서 상기 질량분석기는 특별한 제한없이 종래 공지된 질량 분석기를 이용할 수 있지만, 구체적으로 예를 들면, 푸리에 변환 질량분석기(FTMS, Fourier transform mass spectrometer), 말디토프 질량분석기(MALDI-TOF MS), Q-TOF MS 또는 LTQ-Orbitrap MS일 수 있으나, 이에 제한되는 것은 아니다.In the present invention, the mass spectrometer may be a conventionally known mass spectrometer without particular restrictions, but specifically, for example, a Fourier transform mass spectrometer (FTMS), a MALDI-TOF MS, It may be Q-TOF MS or LTQ-Orbitrap MS, but is not limited thereto.
본 발명의 특징 및 이점을 요약하면 다음과 같다:The features and advantages of the present invention are summarized as follows:
(a) 본 발명은 혈액 내 특정 지질대사체를 측정함으로써, 비결핵 항산균의 감염 여부를 정확히 판정하는 진단용 조성물을 제공한다.(a) The present invention provides a diagnostic composition that accurately determines infection by non-tuberculous acid-fast bacteria by measuring specific lipid metabolites in the blood.
(b) 본 발명은 비결핵 항산균(NTM), 특히 객관적이고 신뢰도 높은 진단 표지자가 부족한 마이코박테리움 아비움 복합체(MAC)에 있어서, 상기 대사체들을 신속 정확하며 신뢰도 높은 측정을 위한 바이오마커로 적용함으로써, 비결핵 항산균 감염 질환의 보다 효율적인 진단에 유용하게 이용될 수 있다. (b) The present invention provides a biomarker for rapid, accurate, and reliable measurement of the metabolites in non-tuberculous mycobacteria (NTM), especially Mycobacterium avium complex (MAC), which lacks objective and reliable diagnostic markers. By applying it, it can be useful for more efficient diagnosis of non-tuberculous acid-fast bacterial infection diseases.
도 1a는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 리소포스파티딜콜린(Lysophosphatidylcholine; LPC 18:0)의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1b는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 리소포스파티딜콜린(Lysophosphatidylcholine; LPC 20:5)의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1c는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 36:5(20:5/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1d는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 스핑고마이엘린(Sphingomyeline; SM d34:1(d18:1/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1e는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 스핑고마이엘린(Sphingomyeline; SM d42:1(d18:1/24:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1f는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 스핑고마이엘린(Sphingomyeline; SM d42:2(d18:1/24:1))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1g는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 트리아실글리세롤(Triacylglycerol; TAG 54:5(18:1/18:1/18:3))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1h는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 트리아실글리세롤(Triacylglycerol; TAG 55:7(21:5/18:2/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1i는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 트리아실글리세롤(Triacylglycerol; TAG 58:11(22:6/20:5/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1j는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 트리아실글리세롤(Triacylglycerol; TAG 60:11(22:6/20:4/18:1))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 1k는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 트리아실글리세롤(Triacylglycerol; TAG 60:12(22:6/22:6/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2a는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 리소포스파티딜에탄올아민(Lysophosphatidylethanolamine; LPE 18:2)의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2b는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 리소포스파티딜에탄올아민(Lysophosphatidylethanolamine; LPE 20:4)의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2c는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 28:0(14:0/14:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2d는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 30:0(14:0/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2e는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 32:2(18:2/14:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2f는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 33:2(18:2/15:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2g는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 34:2(18:2/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2h는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 34:3(16:1/18:2))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2i는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC 36:4(20:4/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2j는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC O36:3(O18:1/18:2))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2k는 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC O36:5(O16:1/20:4))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2l은 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜콜린(Phosphatidylcholine; PC O38:5(O18:1/20:4))의 발현 수준을 비교한 그래프를 나타낸 것이다.
도 2m은 본 발명의 일 실시예에서 항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 혈청 시료에서 포스파티딜에탄올아민(Phosphatidylethanolamine; PENME 34:1(18:1/16:0))의 발현 수준을 비교한 그래프를 나타낸 것이다.Figure 1a compares the expression level of lysophosphatidylcholine (LPC 18:0) in serum samples of patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in an embodiment of the present invention. It shows a graph.
Figure 1b compares the expression levels of lysophosphatidylcholine (LPC 20:5) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in an embodiment of the present invention. It shows a graph.
Figure 1c shows phosphatidylcholine (PC 36:5 (20:5/16:0) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 1D shows sphingomyeline (SM d34:1(d18:1/ This shows a graph comparing the expression levels of 16:0)).
Figure 1e shows sphingomyeline (SM d42:1(d18:1/ This shows a graph comparing the expression levels of 24:0)).
Figure 1f shows sphingomyeline (SM d42:2(d18:1/ This is a graph comparing the expression levels of 24:1)).
Figure 1g shows triacylglycerol (TAG 54:5 (18:1/18) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. :1/18:3)) shows a graph comparing the expression levels.
Figure 1h shows triacylglycerol (TAG 55:7 (21:5/18)) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in an embodiment of the present invention. This is a graph comparing the expression levels of :2/16:0)).
Figure 1i shows triacylglycerol (TAG 58:11 (22:6/20) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. This is a graph comparing the expression levels of :5/16:0)).
Figure 1j shows triacylglycerol (TAG 60:11 (22:6/20) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in an embodiment of the present invention. This is a graph comparing the expression levels of :4/18:1)).
Figure 1k shows triacylglycerol (TAG 60:12 (22:6/22)) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. This is a graph comparing the expression levels of :6/16:0)).
Figure 2a shows the expression level of lysophosphatidylethanolamine (LPE 18:2) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. This shows the comparison graph.
Figure 2b shows the expression level of lysophosphatidylethanolamine (LPE 20:4) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. This shows the comparison graph.
Figure 2c shows phosphatidylcholine (Phosphatidylcholine; PC 28:0 (14:0/14:0) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2d shows phosphatidylcholine (PC 30:0 (14:0/16:0) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2e shows phosphatidylcholine (PC 32:2 (18:2/14:0) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2f shows phosphatidylcholine (Phosphatidylcholine; PC 33:2 (18:2/15:0) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2g shows phosphatidylcholine (Phosphatidylcholine; PC 34:2 (18:2/16:0) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2h shows phosphatidylcholine (PC 34:3 (16:1/18:2) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in an embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2i shows phosphatidylcholine (PC 36:4 (20:4/16:0) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2j shows phosphatidylcholine (PC O36:3 (O18:1/18:2) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2k shows phosphatidylcholine (PC O36:5 (O16:1/20:4) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2l shows phosphatidylcholine (PC O38:5 (O18:1/20:4) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. ))) shows a graph comparing the expression levels.
Figure 2m shows phosphatidylethanolamine (PENME 34:1 (18:1/16) in serum samples from patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment in one embodiment of the present invention. This is a graph comparing the expression levels of :0)).
이하, 실시예를 통하여 본 발명을 더욱 상세히 설명하고자 한다. 이들 실시예는 오로지 본 발명을 보다 구체적으로 설명하기 위한 것으로, 본 발명의 요지에 따라 본 발명의 범위가 이들 실시예에 의해 제한되지 않는다는 것은 당업계에서 통상의 지식을 가진 자에 있어서 자명할 것이다.Hereinafter, the present invention will be described in more detail through examples. These examples are only for illustrating the present invention in more detail, and it will be apparent to those skilled in the art that the scope of the present invention is not limited by these examples according to the gist of the present invention. .
실시예Example
[실험예 1] MAC 감염 환자와 건강한 사람의 시료 수집[Experimental Example 1] Collection of samples from patients with MAC infection and healthy people
2012년 1월부터 2016년 8월까지 기간 동안 대략 6년간 서울 삼성병원에서 수집한 마이코박테리움 아비움 복합체(Mycobacterium avium complex) (avium : 80명, intracellulare : 65명, 총 145명) 감염 환자의 항생제 치료 전의 혈청 샘플 145개와 건강한 사람의 혈청 30개를 준비하였다. Patients infected with Mycobacterium avium complex (avium: 80, intracellulare: 65, total 145) collected at Samsung Hospital in Seoul over a period of approximately 6 years from January 2012 to August 2016. 145 serum samples before antibiotic treatment and 30 serum samples from healthy people were prepared.
[실험예 2] 시료에 대한 전처리[Experimental Example 2] Pretreatment of samples
먼저, 상기 실험예 1에서 얻어진 혈청 시료 (50 μl)에 300 μl 클로로포름, 150 μl 메탄올 (chloroform-methanol, 2:1, v/v, 4 ℃)을 첨가하고 30초 동안 섞어 주었다. 여기에 150 μl 물을 첨가하고 30 초 동안 섞은 뒤 ICE에 넣어 10 분간 방치하여 추출하였다. 이후, 원심분리기기를 이용하여 10 분간 13,000 rpm, 4 ℃에서 원심분리한 뒤 하층액(200 μl) 분리해내어 Speed vacuum (full vacuum, no temp, 1-2hours)을 이용하여 건조하여 이하의 대사체 분석 전까지 -20 ℃에서 보관하였다. 질량 분석기 분석을 위해 건조된 시료를 200 μl 아이소프로판올:아세토니트릴:물(Isopropanol :Acetonitrile:Water)(2:1:1, v/v)에 재용해 후, 존재할 가능성이 있는 불순물 제거를 위하여 필터 튜브(Filter tube)(Costar 8169)를 이용하여 여과한 후 분석을 진행하였다. 기계 품질 관리(Machinery Quality Control; MQC)로, MS/MS 기기상태를 체크하기 위하여 혈청 샘플과 같은 전 처리방법으로 건강한 사람의 혈청을 기계 품질 관리(MQC)의 샘플로 사용하여 배치 당 6회 반복 분석하였다. 시료 품질 관리(Sample Quality Control; SQC)를 위하여 각 배치 안에서 시료 간의 차이를 비교하기 위해 시료 당 10 μl씩 모아 시료 품질 관리를 제작하여 배치 당 6회 반복 분석하였다.First, 300 μl chloroform and 150 μl methanol (chloroform-methanol, 2:1, v/v, 4°C) were added to the serum sample (50 μl) obtained in Experimental Example 1 and mixed for 30 seconds. 150 μl of water was added here, mixed for 30 seconds, placed in ICE, left for 10 minutes, and extracted. Afterwards, centrifugation was performed at 13,000 rpm and 4°C for 10 minutes using a centrifugal separator, and then the lower layer (200 μl) was separated and dried using speed vacuum (full vacuum, no temp, 1-2 hours). Stored at -20°C until sieve analysis. For mass spectrometry analysis, the dried sample was re-dissolved in 200 μl Isopropanol:Acetonitrile:Water (2:1:1, v/v), then filtered to remove impurities that may be present. Analysis was performed after filtration using a filter tube (Costar 8169). Machine Quality Control (MQC): Repeat 6 times per batch using healthy human serum as a sample for Machine Quality Control (MQC), using the same preprocessing method as serum samples to check the condition of the MS/MS instrument. analyzed. For sample quality control (SQC), 10 μl per sample was collected to compare differences between samples within each batch, and sample quality control was created and analyzed six times per batch.
[실험예 3] UHPLC-MS(Q-Exactive Orbitrap Plus)를 통한 대사체 분석[Experimental Example 3] Metabolite analysis through UHPLC-MS (Q-Exactive Orbitrap Plus)
혈청에서 처리한 분석 시료 내의 지질대사체를 분석하기 위하여 크로마토그래피-텐덤 질량분석기(UHPLC-MS)를 이용하여 분석을 진행하였다. 사용된 장비는 Thermo Scientific의 Ultimate 3000RS pump UHPLC와 Q-Exactive Orbitrap Plus MS를 이용하였다. 친수성 상호 작용을 위한 크로마토그래피 조건으로는 Acquity UPLC BEH C18(2.1 x 100 mm, 1.7μm, Waters) 컬럼을 이용하여 35 ℃에서 기울기 용리를 이용하여 지질대사체들을 분리하였다. 첫 번째 이동상으로는 (A) 10mM Ammonium formate in 50% ACN + 0.1% Formic acid (v/v)및 (B) 2mM Ammonium formate in ACN/IPA/Water 10:88:2 + 0.02% Formic acid (v/v)을 이용하였으며, 다음 이동상의 기울기 용리는 총 분석 시간을 28분으로 하여 아래 표 1과 동일하게 수행하였다. 전기분무법(Electrospray Ionization, ESI)은 양(positive), 음(negative) 2가지 모드의 이온화방식으로 수행하였으며, Full scan 매스 범위(Mass range)는 250-1200 m/z으로 70,000 해상도(Resolution)를 사용하였으며, 자동 이득 제어(Automatic gain control, AGC) target은 1x106 이온으로 최대 주입 시간(Injection time, IT)는 100ms로 분석하였다. 충돌 에너지(Collision energy, CE)는 20, 30, 40이며 이온화 소스 (Source ionization spray voltage)는 3.0kV, Capillary temperature은 370°C였다. 분석을 통해 얻어진 결과는 Thermo Scientific의 분석소프트웨어(Compound Discoverer)를 통하여 로우 데이터(raw data)를 계산하여 유의성(p-value<0.05)이 높은 지질대사체를 산출하였다.To analyze lipid metabolites in the analysis sample processed from serum, analysis was performed using chromatography-tandem mass spectrometry (UHPLC-MS). The equipment used was Thermo Scientific's Ultimate 3000RS pump UHPLC and Q-Exactive Orbitrap Plus MS. As chromatographic conditions for hydrophilic interaction, lipid metabolites were separated using an Acquity UPLC BEH C18 (2.1 x 100 mm, 1.7 μm, Waters) column using gradient elution at 35°C. The first mobile phase is (A) 10mM Ammonium formate in 50% ACN + 0.1% Formic acid (v/v) and (B) 2mM Ammonium formate in ACN/IPA/Water 10:88:2 + 0.02% Formic acid (v/ v) was used, and gradient elution of the next mobile phase was performed in the same manner as Table 1 below with a total analysis time of 28 minutes. Electrospray Ionization (ESI) was performed using two modes of ionization, positive and negative, and the full scan mass range was 250-1200 m/z with a resolution of 70,000. The automatic gain control (AGC) target was 1x10 6 ion and the maximum injection time (IT) was analyzed as 100ms. Collision energy (CE) was 20, 30, and 40, source ionization spray voltage was 3.0kV, and capillary temperature was 370°C. The results obtained through the analysis were raw data calculated using Thermo Scientific's analysis software (Compound Discoverer) to calculate lipid metabolites with high significance (p-value<0.05).
[실험예 4] 비결핵항산균 감염자의 혈청 시료 내 대사체 분석 결과[Experimental Example 4] Metabolite analysis results in serum samples from non-tuberculous mycobacteria infected patients
항생제 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람의 대사체 농도를 비교하기 위해 다음의 통계 검정 2가지 방법으로 Metaboanalyst(data 통계사이트)와 SPSS 통계 프로그램을 이용하여 그룹간 유의성 있는 (p-value<0.05) 지질대사체를 산출하였고, 그 결과를 이용하여 치료 전의 마이코박테리움 아비움 복합체(MAC) 감염 폐 질환 환자와 건강한 사람을 구분 할 수 있는 질병 관련 대사체 총 24 종(p-value<0.05)을 각각의 p-value와 건강한 사람 대비 발현 수준의 배수 변화(Fold change) 값을 토대로 선정하여 그 결과를 하기 표 2 및 도 1a 내지 2m에 나타내었다. 단, 도 1a 내지 2m에서, HC는 건강한 사람 30명의 혈청 샘플에서 각 대사체의 발현 수준을 나타낸 것이고, Tx0는 항생제 치료 시작전의 마이코박테리움 아비움 복합체(MAC) 감염 환자 145명의 혈청 샘플에서 각 대사체의 발현 수준을 나타낸 것이다. 또한, 유의성 unpaired t-test에서 *P<0.05; **P<0.01; ***P<0.001를 의미한다.To compare the metabolite concentrations of patients with Mycobacterium avium complex (MAC)-infected lung disease and healthy people before antibiotic treatment, the following two statistical tests were used to group group data using Metaboanalyst (data statistics site) and the SPSS statistical program. Lipid metabolites with liver significance (p-value<0.05) were calculated, and the results were used to identify disease-related metabolites that could distinguish patients with Mycobacterium avium complex (MAC)-infected lung disease before treatment from healthy people. A total of 24 species (p-value<0.05) were selected based on each p-value and the fold change value of expression level compared to healthy people, and the results are shown in Table 2 and Figures 1A to 2M. However, in Figures 1a to 2m, HC represents the expression level of each metabolite in serum samples from 30 healthy people, and Tx0 represents the expression level of each metabolite in serum samples from 145 patients with Mycobacterium avium complex (MAC) infection before starting antibiotic treatment. It shows the expression level of each metabolite. Additionally, *P<0.05 in significance unpaired t-test; **P<0.01; ***Means P<0.001.
상기 표 2 및 도 1a 내지 2m에서 보는 바와 같이, 혈액 대사체 중 리소포스파티딜콜린(Lysophosphatidylcholine; LPC 18:0), 리소포스파티딜콜린(LPC 20:5), 포스파티딜콜린(Phosphatidylcholine; PC 36:5(20:5/16:0)), 스핑고마이엘린(Sphingomyeline; SM d34:1(d18:1/16:0)), 스핑고마이엘린(SM d42:1(d18:1/24:0)), 스핑고마이엘린(SM d42:2(d18:1/24:1)), 트리아실글리세롤(Triacylglycerol; TAG 54:5(18:1/18:1/18:3)), 트리아실글리세롤(TAG 55:7(21:5/18:2/16:0)), 트리아실글리세롤(TAG 58:11(22:6/20:5/16:0)), 트리아실글리세롤(TAG 60:11(22:6/20:4/18:1)) 및 트리아실글리세롤(TAG 60:12(22:6/22:6/16:0))은 건강한 사람 대비 비결핵 항산균 감염자에서 유의적으로 그 발현이 증가하였고, 그 외에 리소포스파티딜에탄올아민(Lysophosphatidylethanolamine; LPE 18:2), 리소포스파티딜에탄올아민(LPE 20:4), 포스파티딜콜린(Phosphatidylcholine; PC 28:0(14:0/14:0)), 포스파티딜콜린(PC 30:0(14:0/16:0)), 포스파티딜콜린(PC 32:2(18:2/14:0)), 포스파티딜콜린(PC 33:2(18:2/15:0)), 포스파티딜콜린(PC 34:2(18:2/16:0)), 포스파티딜콜린(PC 34:3(16:1/18:2)), 포스파티딜콜린(PC 36:4(20:4/16:0)), 포스파티딜콜린(PC O36:3(O18:1/18:2)), 포스파티딜콜린(PC O36:5(O16:1/20:4)), 포스파티딜콜린(PC O36:5(O16:1/20:4)) 및 포스파티딜에탄올아민(PENME 34:1(18:1/16:0))은 건강한 사람 대비 비결핵 항산균 감염자에서 유의적으로 그 발현이 감소한 것을 확인할 수 있었다.As shown in Table 2 and Figures 1a to 2m, among blood metabolites, lysophosphatidylcholine (LPC 18:0), lysophosphatidylcholine (LPC 20:5), and phosphatidylcholine (Phosphatidylcholine; PC 36:5 (20:5/20:5) 16:0)), Sphingomyeline (SM d34:1(d18:1/16:0)), Sphingomyeline (SM d42:1(d18:1/24:0)), Sphingomyeline Myelin (SM d42:2(d18:1/24:1)), Triacylglycerol (TAG 54:5 (18:1/18:1/18:3)), Triacylglycerol (TAG 55: 7(21:5/18:2/16:0)), triacylglycerol (TAG 58:11(22:6/20:5/16:0)), triacylglycerol (TAG 60:11(22: 6/20:4/18:1)) and triacylglycerol (TAG 60:12(22:6/22:6/16:0)) were significantly expressed in non-tuberculous mycobacteria infected patients compared to healthy people. increased, and in addition, lysophosphatidylethanolamine (LPE 18:2), lysophosphatidylethanolamine (LPE 20:4), phosphatidylcholine (PC 28:0 (14:0/14:0)), phosphatidylcholine ( PC 30:0(14:0/16:0)), Phosphatidylcholine(PC 32:2(18:2/14:0)), Phosphatidylcholine(PC 33:2(18:2/15:0)), Phosphatidylcholine (PC 34:2(18:2/16:0)), Phosphatidylcholine(PC 34:3(16:1/18:2)), Phosphatidylcholine(PC 36:4(20:4/16:0)), Phosphatidylcholine (PC O36:3(O18:1/18:2)), Phosphatidylcholine (PC O36:5(O16:1/20:4)), Phosphatidylcholine (PC O36:5(O16:1/20:4)) And phosphatidylethanolamine (PENME 34:1(18:1/16:0)) was found to have significantly reduced expression in non-tuberculous mycobacteria infected patients compared to healthy people.
이를 통하여 지질대사체로, 리소포스파티딜콜린(Lysophosphatidylcholine; LPC 18:0), 리소포스파티딜콜린(LPC 20:5), 포스파티딜콜린(Phosphatidylcholine; PC 36:5(20:5/16:0)), 스핑고마이엘린(Sphingomyeline; SM d34:1(d18:1/16:0)), 스핑고마이엘린(SM d42:1(d18:1/24:0)), 스핑고마이엘린(SM d42:2(d18:1/24:1)), 트리아실글리세롤(Triacylglycerol; TAG 54:5(18:1/18:1/18:3)), 트리아실글리세롤(TAG 55:7(21:5/18:2/16:0)), 트리아실글리세롤(TAG 58:11(22:6/20:5/16:0)), 트리아실글리세롤(TAG 60:11(22:6/20:4/18:1)), 트리아실글리세롤(TAG 60:12(22:6/22:6/16:0)), 리소포스파티딜에탄올아민(Lysophosphatidylethanolamine; LPE 18:2), 리소포스파티딜에탄올아민(LPE 20:4), 포스파티딜콜린(Phosphatidylcholine; PC 28:0(14:0/14:0)), 포스파티딜콜린(PC 30:0(14:0/16:0)), 포스파티딜콜린(PC 32:2(18:2/14:0)), 포스파티딜콜린(PC 33:2(18:2/15:0)), 포스파티딜콜린(PC 34:2(18:2/16:0)), 포스파티딜콜린(PC 34:3(16:1/18:2)), 포스파티딜콜린(PC 36:4(20:4/16:0)), 포스파티딜콜린(PC O36:3(O18:1/18:2)), 포스파티딜콜린(PC O36:5(O16:1/20:4)), 포스파티딜콜린(PC O36:5(O16:1/20:4)) 및 포스파티딜에탄올아민(PENME 34:1(18:1/16:0))을 비결핵 항산균에 의한 감염 또는 감염 질환을 진단하기 위한 바이오마커로 사용할 수 있음을 알 수 있었다.Through this, lipid metabolites include Lysophosphatidylcholine (LPC 18:0), Lysophosphatidylcholine (LPC 20:5), Phosphatidylcholine (PC 36:5 (20:5/16:0)), and sphingomyelin ( Sphingomyeline; SM d34:1(d18:1/16:0)), Sphingomyeline (SM d42:1(d18:1/24:0)), Sphingomyeline (SM d42:2(d18:1) /24:1)), triacylglycerol (TAG 54:5(18:1/18:1/18:3)), triacylglycerol (TAG 55:7(21:5/18:2/16) :0)), triacylglycerol (TAG 58:11(22:6/20:5/16:0)), triacylglycerol (TAG 60:11(22:6/20:4/18:1)) , triacylglycerol (TAG 60:12 (22:6/22:6/16:0)), lysophosphatidylethanolamine (LPE 18:2), lysophosphatidylethanolamine (LPE 20:4), phosphatidylcholine ( Phosphatidylcholine; PC 28:0(14:0/14:0)), Phosphatidylcholine(PC 30:0(14:0/16:0)), Phosphatidylcholine(PC 32:2(18:2/14:0)) , Phosphatidylcholine (PC 33:2 (18:2/15:0)), Phosphatidylcholine (PC 34:2 (18:2/16:0)), Phosphatidylcholine (PC 34:3 (16:1/18:2) ), Phosphatidylcholine(PC 36:4(20:4/16:0)), Phosphatidylcholine(PC O36:3(O18:1/18:2)), Phosphatidylcholine(PC O36:5(O16:1/20:4) )), phosphatidylcholine (PC O36:5(O16:1/20:4)), and phosphatidylethanolamine (PENME 34:1(18:1/16:0)) to treat infections or infectious diseases caused by non-tuberculous acid-fast bacteria. It was found that it can be used as a biomarker for diagnosis.
이상으로 본 발명의 특정한 부분을 상세히 기술하였는 바, 당업계의 통상의 지식을 가진 자에게 있어서 이러한 구체적인 기술은 단지 바람직한 구현예일 뿐이며, 이에 본 발명의 범위가 제한되는 것이 아닌 점은 명백하다. 따라서, 본 발명의 실질적인 범위는 첨부된 청구항과 그의 등가물에 의하여 정의된다고 할 것이다.As the specific parts of the present invention have been described in detail above, it is clear to those skilled in the art that these specific techniques are merely preferred embodiments and do not limit the scope of the present invention. Accordingly, the substantial scope of the present invention will be defined by the appended claims and their equivalents.
Claims (14)
상기 조성물은 인간 개체로부터 분리된 시료를 대상으로 하는 것이고,
상기 대사체는 LPC (18:0), LPC (20:5), LPE (18:2), LPE (20:4), PC 36:5(20:5/16:0), PC 28:0(14:0/14:0), PC 30:0(14:0/16:0), PC 32:2(18:2/14:0), PC 33:2(18:2/15:0), PC 34:2(18:2/16:0), PC 34:3(16:1/18:2), PC 36:4(20:4/16:0), PC O36:3(O18:1/18:2), PC O36:5(O16:1/20:4), PC O36:5(O16:1/20:4), PENME 34:1(18:1/16:0), SM d34:1(d18:1/16:0), SM d42:1(d18:1/24:0), SM d42:2(d18:1/24:1), TAG 54:5(18:1/18:1/18:3), TAG 55:7(21:5/18:2/16:0), TAG 58:11(22:6/20:5/16:0), TAG 60:11(22:6/20:4/18:1) 및 TAG 60:12(22:6/22:6/16:0)로 구성된 군으로부터 선택되는 하나 이상의 대사체인 것인, 조성물.
Lysophosphatidylcholine (LPC), Lysophosphatidylethanolamine (LPE), phosphatidylcholine (PC) PHOSPHATIDYTHANOLAMINE (PE), Sphingomyeline (SM) and Triacylglycerol; A composition for diagnosing infectious diseases caused by non-tuberculous acid-fast bacteria, comprising as an active ingredient an agent for measuring one or more metabolites selected from the group consisting of (TAG),
The composition is intended for samples isolated from human subjects,
The metabolites are LPC (18:0), LPC (20:5), LPE (18:2), LPE (20:4), PC 36:5 (20:5/16:0), PC 28:0 (14:0/14:0), PC 30:0(14:0/16:0), PC 32:2(18:2/14:0), PC 33:2(18:2/15:0) ), PC 34:2(18:2/16:0), PC 34:3(16:1/18:2), PC 36:4(20:4/16:0), PC O36:3(O18) :1/18:2), PC O36:5(O16:1/20:4), PC O36:5(O16:1/20:4), PENME 34:1(18:1/16:0), SM d34:1(d18:1/16:0), SM d42:1(d18:1/24:0), SM d42:2(d18:1/24:1), TAG 54:5(18:1) /18:1/18:3), TAG 55:7(21:5/18:2/16:0), TAG 58:11(22:6/20:5/16:0), TAG 60:11 (22:6/20:4/18:1) and TAG 60:12 (22:6/22:6/16:0).
The method of claim 1, wherein the metabolite includes lysophosphatidylcholine, and further includes one or more selected from the group consisting of lysophosphatidylethanolamine, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and triacylglycerol. A composition made of.
The composition of claim 1, wherein the metabolite includes lysophosphatidylethanolamine and further includes one or more selected from the group consisting of phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and triacylglycerol. .
The composition of claim 1, wherein the metabolite includes phosphatidylcholine and further includes one or more selected from the group consisting of phosphatidylethanolamine, sphingomyelin, and triacylglycerol.
The composition of claim 1, wherein the metabolite includes phosphatidylethanolamine and further includes at least one selected from the group consisting of sphingomyelin and triacylglycerol.
The composition of claim 1, wherein the metabolite includes sphingomyelin and triacylglycerol.
The composition of claim 1, wherein the metabolites include lysophosphatidylcholine, lysophosphatidylethanolamine, phosphatidylcholine, phosphatidylethanolamine, sphingomyelin, and triacylglycerol.
The method of claim 1, wherein the LPC (18:0), LPC (20:5), PC 36:5 (20:5/16:0), SM d34:1 (d18:1/16:0), SM d42:1(d18:1/24:0), SM d42:2(d18:1/24:1), TAG 54:5(18:1/18:1/18:3), TAG 55:7( 21:5/18:2/16:0), TAG 58:11(22:6/20:5/16:0), TAG 60:11(22:6/20:4/18:1), or A composition that predicts that the subject is infected with non-tuberculous acid-fast bacteria when the concentration of TAG 60:12 (22:6/22:6/16:0) increases compared to the normal control group.
The method of claim 1, wherein the LPE (18:2), LPE (20:4), PC 28:0 (14:0/14:0), PC 30:0 (14:0/16:0), PC 32:2(18:2/14:0), PC 33:2(18:2/15:0), PC 34:2(18:2/16:0), PC 34:3(16:1/ 18:2), PC 36:4(20:4/16:0), PC O36:3(O18:1/18:2), PC O36:5(O16:1/20:4), PC O36: A composition that predicts that the subject is infected with non-tuberculous acid-fast bacteria when the concentration of 5(O16:1/20:4), or PENME 34:1(18:1/16:0) is decreased compared to the normal control group.
The method of claim 1, wherein the sample is whole blood, leukocytes, peripheral blood mononuclear cells, leukocyte buffy coat, plasma, serum, sputum ( sputum, tears, mucus, nasal washes, nasal aspirate, breath, urine, semen, saliva, abdominal washes (peritoneal washings), ascites, cystic fluid, meningeal fluid, amniotic fluid, glandular fluid, pancreatic fluid, lymph fluid, pleural fluid ( pleural fluid, nipple aspirate, bronchial aspirate, synovial fluid, joint aspirate, organ secretions, cells, cell extracts extract), or a composition characterized in that it is cerebrospinal fluid.
The method of claim 1, wherein the non-tuberculous acid-fast bacteria are Mycobacterium avium ( M. avium ), Mycobacterium abscessus ( M. abscessus ), Mycobacterium flavescence ( M. flavescence ), Mycobacterium africanum ( M. africanum ), Mycobacterium bovis ( M. bovis ), Mycobacterium chelonae ( M. chelonae ), Mycobacterium celatum ( M. celatum ), Mycobacterium M. fortuitum , Mycobacterium gordonae (M. gordonae), Mycobacterium gastri (M. gastri ), Mycobacterium haemophilum ( M. haemophilum ), Mycobacterium Intracellulare ( M. intracellulare ), Mycobacterium kansasii ( M. kansasii ), Mycobacterium malmoense ( M. malmoense ), Mycobacterium marinum ( M. marinum ), Mycobacterium szul Guy ( M. szulgai ), Mycobacterium terre ( M. terrae ), Mycobacterium scrofulaceum ( M. scrofulaceum ), Mycobacterium ulcerans ( M. ulcerans ), Mycobacterium simiae A composition characterized in that it is selected from the group consisting of ( M. simiae ) and Mycobacterium xenopi ( M. xenopi ).
The composition according to claim 1, wherein the non-tuberculous acid-fast bacterial infection disease is lung disease, lymphadenitis, skin, soft tissue, bone infection, or disseminated disease.
상기 측정은 인간 개체로부터 분리된 시료를 대상으로 하는 것이고,
상기 대사체는 LPC (18:0), LPC (20:5), LPE (18:2), LPE (20:4), PC 36:5(20:5/16:0), PC 28:0(14:0/14:0), PC 30:0(14:0/16:0), PC 32:2(18:2/14:0), PC 33:2(18:2/15:0), PC 34:2(18:2/16:0), PC 34:3(16:1/18:2), PC 36:4(20:4/16:0), PC O36:3(O18:1/18:2), PC O36:5(O16:1/20:4), PC O36:5(O16:1/20:4), PENME 34:1(18:1/16:0), SM d34:1(d18:1/16:0), SM d42:1(d18:1/24:0), SM d42:2(d18:1/24:1), TAG 54:5(18:1/18:1/18:3), TAG 55:7(21:5/18:2/16:0), TAG 58:11(22:6/20:5/16:0), TAG 60:11(22:6/20:4/18:1) 및 TAG 60:12(22:6/22:6/16:0)로 구성된 군으로부터 선택되는 하나 이상의 대사체인 것인, 방법.
One or more metabolites selected from the group consisting of Lysophosphatidylcholine, Lysophosphatidylethanolamine, Phosphatidylcholine, Phosphatidylethanolamine, Sphingomyeline, and Triacylglycerol A method of providing information for diagnosing an infectious disease caused by non-tuberculous acid-fast bacteria, including the step of measuring,
The measurement is performed on samples isolated from human subjects,
The metabolites are LPC (18:0), LPC (20:5), LPE (18:2), LPE (20:4), PC 36:5 (20:5/16:0), PC 28:0 (14:0/14:0), PC 30:0(14:0/16:0), PC 32:2(18:2/14:0), PC 33:2(18:2/15:0) ), PC 34:2(18:2/16:0), PC 34:3(16:1/18:2), PC 36:4(20:4/16:0), PC O36:3(O18) :1/18:2), PC O36:5(O16:1/20:4), PC O36:5(O16:1/20:4), PENME 34:1(18:1/16:0), SM d34:1(d18:1/16:0), SM d42:1(d18:1/24:0), SM d42:2(d18:1/24:1), TAG 54:5(18:1) /18:1/18:3), TAG 55:7(21:5/18:2/16:0), TAG 58:11(22:6/20:5/16:0), TAG 60:11 (22:6/20:4/18:1) and TAG 60:12 (22:6/22:6/16:0).
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