WO2017039359A1 - Composition permettant le diagnostic de maladies infectieuses ou de complications infectieuses à l'aide d'une tryptophanyl arnt synthétase, et procédé de détection de marqueur de diagnostic - Google Patents

Composition permettant le diagnostic de maladies infectieuses ou de complications infectieuses à l'aide d'une tryptophanyl arnt synthétase, et procédé de détection de marqueur de diagnostic Download PDF

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WO2017039359A1
WO2017039359A1 PCT/KR2016/009802 KR2016009802W WO2017039359A1 WO 2017039359 A1 WO2017039359 A1 WO 2017039359A1 KR 2016009802 W KR2016009802 W KR 2016009802W WO 2017039359 A1 WO2017039359 A1 WO 2017039359A1
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Prior art keywords
tryptophanyl
wrs
expression level
synthase
protein
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PCT/KR2016/009802
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English (en)
Korean (ko)
Inventor
김성훈
진미림
안영하
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제이더블유바이오사이언스 주식회사
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Priority claimed from KR1020160025329A external-priority patent/KR20170027258A/ko
Application filed by 제이더블유바이오사이언스 주식회사 filed Critical 제이더블유바이오사이언스 주식회사
Priority to JP2018530462A priority Critical patent/JP6732914B2/ja
Priority to ES16842325T priority patent/ES2911270T3/es
Priority to PL16842325T priority patent/PL3346270T3/pl
Priority to EP16842325.9A priority patent/EP3346270B1/fr
Priority to CN201680050793.5A priority patent/CN108449999B/zh
Publication of WO2017039359A1 publication Critical patent/WO2017039359A1/fr
Priority to US15/908,568 priority patent/US10788493B2/en

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/40—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against enzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q1/00—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions
    • C12Q1/68—Measuring or testing processes involving enzymes, nucleic acids or microorganisms; Compositions therefor; Processes of preparing such compositions involving nucleic acids
    • C12Q1/6876—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes
    • C12Q1/6883—Nucleic acid products used in the analysis of nucleic acids, e.g. primers or probes for diseases caused by alterations of genetic material
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Y—ENZYMES
    • C12Y601/00—Ligases forming carbon-oxygen bonds (6.1)
    • C12Y601/01—Ligases forming aminoacyl-tRNA and related compounds (6.1.1)
    • C12Y601/01002—Tryptophan-tRNA ligase (6.1.1.2)
    • 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
    • G01N33/573—Immunoassay; Biospecific binding assay; Materials therefor for enzymes or isoenzymes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/112—Disease subtyping, staging or classification
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12Q—MEASURING OR TESTING PROCESSES INVOLVING ENZYMES, NUCLEIC ACIDS OR MICROORGANISMS; COMPOSITIONS OR TEST PAPERS THEREFOR; PROCESSES OF PREPARING SUCH COMPOSITIONS; CONDITION-RESPONSIVE CONTROL IN MICROBIOLOGICAL OR ENZYMOLOGICAL PROCESSES
    • C12Q2600/00—Oligonucleotides characterized by their use
    • C12Q2600/158—Expression markers
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2333/00—Assays involving biological materials from specific organisms or of a specific nature
    • G01N2333/90—Enzymes; Proenzymes
    • G01N2333/9015—Ligases (6)
    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N2800/00—Detection or diagnosis of diseases
    • G01N2800/26—Infectious diseases, e.g. generalised sepsis
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
    • Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
    • Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
    • Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Definitions

  • the present invention relates to a composition for diagnosing an infectious disease using tryptophanyl-tRNA synthetase (WRS) and a method for detecting a diagnostic marker, and more particularly, to tryptophanyl thialene synthase protein or mRNA.
  • the present invention relates to a composition for diagnosing an infectious disease, a diagnostic kit, and a method for detecting WRS for providing information necessary for diagnosing an infectious disease, and a method for determining a death risk for an infectious disease using the WRS. .
  • Infectious disease is a disease that occurs when foreign organisms such as bacteria, bacteria, and viruses start to live in the blood, body fluids, and tissues, and can cause life loss if they are not correctly identified and treated properly. to be.
  • the threat of infectious diseases with fatal consequences is increasing.
  • Current diagnostic tools for infections include polymerase chain react ion (PCR) to identify the infected organs and direct microbial culture from blood and urine, as well as empirical judgment by the clinician based on the patient's symptoms. ).
  • systemic inflammation reactions differ depending on the cause, and the rapid diagnosis of systemic c inf lammatory response caused by a non-infectious cause and inflammation reaction caused by a pathogen infection is necessary for proper treatment. very important. This diagnosis is essential for the survival of acute infectious inflammatory patients, especially since it is important for patients with infectious inflammatory diseases caused by an infectious disease to begin appropriate antibiotic treatment as soon as possible, such as death.
  • CRP C-reactive protein
  • the present inventors have found that the level of tryptophany® tRNA synthetase (TrpRS or WRS, hereinafter WRS) in the body during infection infection caused by bacteria, virus, or fungi infection is rapid from the beginning of infection.
  • WRS tryptophany® tRNA synthetase
  • the level of WRS is significantly higher than that of normal people, especially in the case of infectious inflammatory diseases, and in the case of non-infectious inflammatory diseases, the level of WRS, which is not related to WRS levels, can rapidly and rapidly infect infectious diseases and their complications.
  • the present invention has been completed by discovering that it can be used as a marker for accurate diagnosis.
  • an object of the present invention is to provide an expression level of tryptophany 1-tRNA synthetase protein or tryptophanyl thialen synthase mRNA. It is to provide a composition for diagnosis of an infectious disease comprising an agent for measuring the. It is another object of the present invention to provide a kit for diagnosing an infectious disease comprising an agent for measuring the expression level of tryptophanyl thialN synthase protein or tryptophanyl thialA synthase mRNA.
  • a further object of the present invention comprises the steps of providing a sample of W (a) the test body in order to provide information necessary for the diagnosis of infectious diseases; (b) measuring the expression level of tryptophany tRNA synthetase in the sample; And (c) comparing the level of the tryptophanyl thiANA synthase to a normal person and determining that the subject has an increased expression level of tryptophanyl thiANA synthase as having an infectious disease. To provide a method for detecting tryptophanyl tRNA synthetase.
  • Still another object of the present invention is to provide a composition for determining the risk of death due to an infectious disease, including an agent for measuring the expression level of tryptophanyl thialN synthase protein or tryptophanyl thialN synthase mRNA.
  • Another object of the present invention is to provide a sample of the subject (a); (b) measuring the expression level of tryptophanyl-tRNA synthetase in the sample; And (c) to provide a method for determining the risk of death due to infectious diseases comprising the step of determining that the higher the level of the tryptophanyl ThialN synthase is higher risk of death.
  • Another object of the present invention is the use of an agent for measuring the expression level of tryptophany tRNA synthetase protein or tryptophanyl TN synthase mRNA for the preparation of a diagnostic agent for infectious diseases. To provide it.
  • Another object of the present invention is to measure the level of expression of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-NA synthase mRNA in a subject's sample. It provides a way to diagnose the problem.
  • Another object of the present invention is to measure the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl-thial-NA synthase mRNA for preparing an agent for determining the risk of death due to an infectious disease. It is to provide a use of the formulation.
  • the present invention is an infection comprising an agent for measuring the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-A synthesis synthetic mRNA It provides a diagnostic composition for the disease.
  • the present invention also provides a composition for diagnosing an infectious disease consisting of an agent for measuring the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-A synthase mRNA.
  • the present invention provides a composition for diagnosing an infectious disease consisting essentially of an agent for measuring the expression level of tryptophany tRNA synthetase protein or tryptophanyl thiARNA synthase mRNA.
  • the present invention provides a kit for diagnosing an infectious disease comprising an agent for measuring the expression level of tryptophanyl thiaL synthase protein or tryptophanyl thiaL synthase mRNA. .
  • the present invention provides a kit for diagnosing an infectious disease consisting of an agent for measuring the expression level of tryptophanyl thialN synthase protein or tryptophanyl thialA synthase mRNA.
  • the present invention provides a kit for diagnosing an infectious disease, consisting essentially of an agent for measuring the expression level of tryptophanyl thiaL synthase protein or tryptophanyl thiaL synthase mRNA.
  • the present invention comprises the steps of (a) providing a sample of the subject to provide information necessary for the diagnosis of an infectious disease; (b) measuring the expression level of tryptophanyl tRNA synthetase ( ⁇ 01) 11 ⁇ 1 1 13 ⁇ 41 ⁇ 2 synthetase in the sample; And (c) comparing the level of the tryptophanyl thiANA synthase with a normal person and determining that a subject having an increased expression level of tryptophanyl thiANA synthase is infected with an infectious disease.
  • the present invention in the diagnosis of infectious diseases.
  • A providing a sample of the subject to provide the necessary information;
  • the trip Tryptophanyl tRNA synthetase comprising comparing the level of topanyl thial-A synthase with a normal person and determining that the subject with an increased expression level of tryptophanyl T-A synthase compared to a normal person is infected with an infectious disease Provides a way to hide it.
  • the present invention essentially provides a sample of a subject to provide information necessary for the diagnosis of an infectious disease; (b) measuring the expression level of tryptophany tRNA synthetase in the sample; And (c) comparing the level of the tryptophanyl thiANA synthase with a normal person and determining that the subject has an increased expression level of tryptophanyl thiANA synthase as having an infectious disease. It provides a method for detecting the tryptophanyl tRNA synthetase.
  • the present invention provides a risk of death from an infectious disease comprising an agent for measuring the expression level of tryptophanyl thialene or the expression level of this synthase protein or tryptophanyl thialene synthase niRNA. It provides a composition for determination. In addition, the present invention provides a composition for determining the risk of death by an infectious disease consisting of an agent for measuring the expression level of tryptophanyl thialN synthase protein or tryptophanyl thialN synthase mRNA.
  • the present invention provides a composition for determining the risk of death due to an infectious disease consisting essentially of an agent for measuring the expression level of tryptophanyl thialN synthase protein or tryptophanyl thialN synthase mRNA.
  • the present invention comprises the steps of (a) providing a sample of the subject; (b) measuring the expression level of tryptophany tRNA synthetase in the sample; And (c) provides a method for determining the risk of death due to infectious diseases comprising the step of determining that the higher the level of the tryptophanyl Thialase synthase is higher risk of death.
  • the present invention comprises the steps of (a) providing a sample of the subject; (b) measuring the expression level of tryptophanyl—tRNA synthetase in the sample; And (c) determining that the higher the level of the tryptophanyl TNA synthase is, the higher the risk of death is.
  • the present invention is essentially (a) ⁇ system for providing a sample of the subject; (b) above Measuring the expression level of tryptophany tRNA synthetase in the sample; And (c) determining that the higher the level of the tryptophanyl thiA-N synthase is, the higher the risk of death is.
  • the present invention provides an expression of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-A synthase mRNA for the preparation of a diagnostic agent for infectious diseases. Provide the use of the agent to determine the level.
  • the present invention provides a method for measuring the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-A synthase mRNA in a sample of a subject. It provides a method for diagnosing an infectious disease, characterized in that.
  • the present invention is a tryptophanyl-tRNA synthetase protein or tryptophanyl thialene for preparing an agent for determining the risk of death by infectious diseases
  • the use of an agent to measure the expression level of A synthase mRNA is provided.
  • the present invention will be described in detail.
  • the present invention provides a composition for diagnosing an infectious disease comprising an agent for measuring the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-NA synthase tnRNA.
  • WRS increased rapidly from the beginning of infection due to bacterial, viral or fungi infection, and significantly increased than normal controls when complications such as pneumonia or sepsis appeared as infection complications. It was confirmed for the first time.
  • WRS expression levels are highly correlated with the severity and prognosis of sepsis, and because WRS increases only in infectious inflammation, it is possible to quickly and accurately distinguish between infectious and non-infectious inflammatory diseases.
  • Uh it was confirmed that the value as a diagnostic marker in new infectious diseases and infectious complications is very high.
  • the inventors have confirmed in connection with the diagnosis of WRS and infectious diseases in detail as follows.
  • WRS was found to increase significantly in infections caused by bacteria, viruses, or fungi.
  • PBMCs peripheral blood mononuclear cells
  • PR8 WRS secreted out of these cells from these PBMCs early in the infection and at least 1 hour after infection. The level increases rapidly.
  • the amount of WRS in the sera of patients with viral pneumonia was increased compared to the control group.
  • the amount of WRS was significantly increased in the serum of sepsis or sepsis shock patients due to bacterial or fungi infection, compared to the serum of a healthy control group.
  • GRS and KRS another type of aminoacyl tRNA synthetase (ARS) that are secreted out of cells, do not differ between sepsis patients and normal controls, and the increase in WRS due to infection is not a general phenomenon. It was found to be WRS specific.
  • Gram-negative bacteria, Gram-positive bacteria, and Gomstone infections did not appear to be statistically significant in increasing trends in WRS in patients with sepsis due to infection. It was confirmed that both can be usefully used for diagnosing sepsis. In addition, there was no significant difference in blood WRS levels between patients with single infection and patients with multiple infections. Therefore, it could be useful for diagnosing sepsis due to single infection or multiple infections.
  • the amount of WRS was higher than that of normal control group. There was no statistically significant difference. Therefore, the expression level of WRS was not increased in all inflammatory reactions, but only specifically in inflammatory reactions caused by bacterial, viral or fungi infection. In addition, the level of WRS was more increased in patients with septic shock than in patients with sepsis, and the expression level of WRS was related to the severity of sepsis. In other words, the higher the expression level of WRS, the more severe sepsis symptoms. You can judge that.
  • SIRS systemi c inf l ammat ion react ive symptom
  • the sensitivity (sensi t ivi ty) and accuracy (speci f i ci ty) were excellent in diagnosing the inflammation caused by the WRS through the ROC curve boom of the WRS.
  • the correlation between the severity of sepsis expressed by SOFA score and WRS was higher than that of CRP. In other words, the higher the level of expression of WRS and the higher the SOFA score, the higher the probability of organ failure caused by sepsis.
  • WRS levels in sepsis patients who died 28 days after sepsis diagnosis were significantly higher than those in surviving sepsis, further demonstrating that WRS correlates well with sepsis severity and prognosis.
  • the higher the expression level of WRS the higher the severity of sepsis and the poorer the prognosis.
  • the clinical trials were performed on serum of 120 normal persons, 18 SIRS patients (due to infectious diseases), 166 sepsis patients and 160 septic shock patients.
  • the results of WRS are related to the results of procalcitonin, but WRS is specifically detected and detected only for complications of infectious diseases. , It could be confirmed that the screening of death patients is also possible.
  • WRS increases specifically in sepsis and rapidly increases in the early stages of infection, thereby quickly distinguishing between infectious and non-infectious inflammatory diseases, thereby preventing early Daewoong delays caused by not knowing the cause of inflammation.
  • the patient can be given the most appropriate treatment.
  • the present invention provides a composition for diagnosing an infectious disease, including an agent for measuring the expression level of WRS, that is, WRS protein or WRS mRNA level.
  • 'WRS' refers to tryptophanyl thialene synthase ⁇ ! ⁇ ⁇ ⁇ ⁇ synthetase, also known as tryptophan thialene ligase (t ryptophan-tRNA l igase), TrpRS, WARS, etc. have.
  • WRS is an enzyme that mediates the aminoacyl at ion reaction of amino acid tryptophan and tRNA.
  • WRS is encoded by the WARS gene in humans, and the amino acid and mRNA nucleotide sequences of the protein accession number NP_004175.2 (protein), Genbank access i on number NM_004184.3 (mRNA sequence).
  • WRS has two subtypes (i soform): cytoplasmic c form (WARS or tryptophanyl-tRNA synthetase, cytoplasmic c) and mi tochondrial form (WARS2 or tryptophanyl-tRNA synthetase, mi tochondrial).
  • WRS in is preferably cytopl asmi c form.
  • the expression means that the protein or nucleic acid is produced in the cell.
  • 'Protein' is used interchangeably with 'polypeptide' or 'peptide' and refers to a polymer of amino acid residues, for example as commonly found in natural proteins.
  • 'Polynucleotide' or ' 1 nucleic acid' refers to deoxyribonucleotides (DNA) or ribonucleotides (RNA) in the form of single- or double-strands. Unless otherwise limited, known analogues of natural nucleotides are also included which are localized to nucleic acids in a manner similar to naturally occurring nucleotides.
  • 'mRNA' is RNA that transfers genetic information (gene-specific nucleotide sequences) to ribosomes that specify amino acid sequences from specific genes during protein synthesis.
  • the diagnosis in the present invention measures the expression level of the WRS gene, that is, the level of the WRS protein or WRS mRNA, to determine the presence or pathology of an infectious disease. To confirm.
  • the agent for measuring the expression level of the WRS protein may be an antibody that specifically binds to the WRS protein.
  • the WRS protein may be derived from a mammal including a human, and may preferably include a human WRS amino acid sequence represented by SEQ ID NO: 1.
  • the antibody in the present invention is an antibody that specifically binds only to WRS protein without reacting with other proteins including other kinds of aminoacyl thiA-N synthase other than WRS.
  • WRS antibodies can be produced by cloning the WRS gene into an expression vector to obtain a protein encoded by the gene, and from the protein obtained according to conventional methods in the art. Fragments of WRS proteins comprising WRS antigenic sites can also be used to prepare WRS protein specific antibodies.
  • the form of the antibody of the present invention is not particularly limited and includes a polyclonal ant ibody or a monoclonal ant ibody.
  • the antibody of the present invention includes all kinds of immunoglobulin antibodies that specifically bind to WRS.
  • immunoglobulin antibodies that specifically bind to WRS.
  • the antibodies of the present invention also include recombinant antibodies and special antibodies such as humanized antibodies and chimeric antibodies as long as they can specifically bind to WRS proteins.
  • WRS protein in the present invention preferably comprises a human WRS amino acid sequence represented by SEQ ID NO: 1, the antibody specifically binding to the WRS protein in the present invention, preferably the amino acid represented by SEQ ID NO: 1 It may be an antibody that specifically binds to a protein having a sequence.
  • the diagnostic composition of the present invention comprising the WRS-specific antibody as an agent for measuring the expression level of WRS may further include an agent necessary for a method for detecting a known protein, and using the present composition, a known protein may be used. Any method of detection can be used to determine the level of WRS protein in the subject.
  • the agent for measuring the expression level of WRS mRNA may be a probe or primer set that specifically binds to WRS mRNA.
  • the WRS mRNA may be derived from a mammal including a human, and preferably may include a human WRS mRNA nucleotide sequence represented by SEQ ID NO: 2.
  • the diagnostic composition of the present invention comprising the WRS mRNA specific probe or primer set as an agent for measuring the expression level of WRS may further include an agent required for a method for detecting a known RNA.
  • the present composition can be used to measure the level of WRS mRNA in a subject using any known method of detecting RNA.
  • the 'primer' is a single stranded oligonucleotide that acts as a starting point for DNA synthesis.
  • the primer specifically binds to a polynucleotide that is a template at suitable buffer and temperature conditions, and the DNA polymerase is linked to the primer by adding nucleoside triphosphate having a base complementary to the template DNA. DNA is synthesized by this.
  • Primers typically consist of 15 to 30 nucleotide sequences, and vary in base composition and length. The temperature at which they bind to the mold strand (melting temperature, Tm) varies.
  • the sequence of the primer need not have a sequence that is completely complementary to some nucleotide sequences of the template, and it is sufficient to have sufficient complementarity within a range that can be hybridized with the template to perform primer-specific functions. Therefore, the primers for measuring the expression level of the WRS mRNA in the present invention does not need to have a sequence completely complementary to the WRS gene sequence, and the amount of WRS mRNA by amplifying a specific section of the WRS mRNA or WRS cDNA through DNA synthesis. It is sufficient to have a length and complementarity for the purpose to be measured.
  • the primer for amplification reaction consists of a set (pair) of complementary binding to the template (or sense) and the opposite (antisense, ant i sense) at each end of a specific section of the WRS mRNA to be amplified do. Primers can be easily designed by those skilled in the art with reference to WRS mRNA or cDNA sequences.
  • the primer of the present invention may be preferably a set or a pair specifically binding to the WRS mRNA nucleotide sequence represented by SEQ ID NO: 2, and most preferably represented by the nucleotide sequences of SEQ ID NO: 3 and SEQ ID NO: 4 It may be a primer set.
  • Probe is a fragment of a polynucleotide, such as RNA or DNA, from short to several hundred bases in length that can specifically bind to mRNA or cDNA (complementary DNA) of a specific gene. Meaning, it is labeled (l abel ing) can be confirmed whether the presence of the target mRNA or cDNA to bind, expression amount and the like.
  • probes complementary to WRS mRNA can be used to diagnose infectious inflammatory diseases by measuring the expression level of WRS mRNA by performing a hybr idi zat ion with a sample of a subject. The choice and probe conditions of the probe can be appropriately selected according to techniques known in the art.
  • primers or probes of the present invention can be synthesized chemically using phosphoramidite solid support synthesis or other well known methods.
  • primers or probes can be variously modified according to methods known in the art within a range that does not prevent the hybridization with WRS mRNA. Examples of such modifications include methylation, capping, substitution of one or more homologs of natural nucleotides, and modifications between nucleotides, for example, uncharged linkages (e.g., methyl phosphonates, phosphoriesters, phosphoramidates, Carbamate, etc.) or charged linkages (eg, phosphorothioate, phosphorodithioate), and binding of a labeling agent (fluorescence or enzyme).
  • uncharged linkages e.g., methyl phosphonates, phosphoriesters, phosphoramidates, Carbamate, etc.
  • charged linkages eg, phosphorothioate, phosphorodithioate
  • the infection means that one or two or more kinds of exogenous bacteria (including bacteria, Gram-negative bacteria or Gram-positive bacteria), viruses, and bearish (bacteria) enter the body and settle, proliferate, and become parasitic.
  • Infectious diseases can be any disease that results from infection of a pathogen and the resulting reaction in vivo. Reactions resulting from infectious diseases may include inflammation, pain, fever, fatigue, swelling, and lowering blood pressure.
  • the infectious disease of the present invention is salmonellosis, food poisoning, typhoid fever, paratyphoid, pneumonia, pulmonary tuberculosis, tuberculosis, sepsis, septic shock, urinary tract infection, cystitis, pyelonephritis, It may be urethritis, prostatitis, upper respiratory tract infection, otitis media, more preferably salmonelosis, food poisoning, pneumonia, sepsis, septic shock.
  • the sepsis is a systemic inflammatory syndrome, which is a complication of an infectious disease, and when the cause cannot be diagnosed quickly and accurately early, severe sepsis or septic shock, lung, kidney, liver , Multit organ dysfunct ion syndrome (MODS), disseminated endovascular syndrome (DIC), acute respiratory swelling syndrome (ARDS), or acute renal failure (AKI) It is a fatal disease that can progress and die.
  • MODS Multit organ dysfunct ion syndrome
  • DIC disseminated endovascular syndrome
  • ARDS acute respiratory swelling syndrome
  • AKI acute renal failure
  • Sepsis as used herein includes sepsis, severe sepsis, septic shock and sepsis associated with the final stage of sepsis, mult iple organ dysfunct ion syndrome (MODS), disseminated intravascular arch Syndrome (DIC), Acute Respiratory Tension Syndrome (ARDS) or Acute Renal Failure (AKI), including, but not limited to, all stages of sepsis.
  • MODS mult iple organ dysfunct ion syndrome
  • DIC disseminated intravascular arch Syndrome
  • ARDS Acute Respiratory Tension Syndrome
  • Acute Renal Failure Acute Renal Failure
  • the present invention also provides a kit for diagnosing an infectious disease comprising an agent for measuring the expression level of a tryptophanyl-tRNA synthetase (WRS) protein or WRS mRNA.
  • WRS tryptophanyl-tRNA synthetase
  • the diagnostic kit of the present invention includes one or more other component compositions suitable for analytical methods as well as primers or probes that selectively recognize WRS proteins as markers or primers and probes that recognize WRS proteins as markers. Or solutions or devices may be included.
  • the diagnostic kit may be a diagnostic kit comprising essential elements necessary for performing reverse transcription polymerase reaction.
  • the reverse transcription polymerase kit contains individual primer pairs specific for the marker gene. All.
  • the primer is a nucleotide having a sequence specific to the nucleic acid sequence of each marker gene, which is about 7bp to 50bp in length, more preferably about 10bp to 30bp in length. It may also include primers specific for the nucleic acid sequence of the control gene.
  • reverse transcriptase polymer reaction kits include test leuub or other suitable containers, reaction buffers (pH and magnesium concentrations vary), deoxynucleotides (dNTPs), enzymes such as Taq-polymerase and reverse transcriptase, DNAse, RNAse Inhibitor DEPC-water, sterile water, and the like.
  • reaction buffers pH and magnesium concentrations vary
  • dNTPs deoxynucleotides
  • enzymes such as Taq-polymerase and reverse transcriptase
  • DNAse DNAse
  • RNAse Inhibitor DEPC-water sterile water, and the like.
  • the DNA chip kit may include a substrate on which a cDNA or oligonucleotide corresponding to a gene or a fragment thereof is attached, and a reagent, an agent, an enzyme, or the like for preparing a fluorescent probe.
  • the substrate may also include cDNA or ligonucleotide corresponding to the control gene or fragment thereof.
  • ELISA kits contain specific antibodies to the marker protein. Antibodies are antibodies that have high specificity and affinity for each marker protein and have little cross-reactivity to other proteins. They are monoclonal antibodies, polyclonal antibodies, or recombinant antibodies. .
  • the ELISA kit can also include antibodies specific for the control protein.
  • Other ELISA kits may bind to reagents capable of detecting bound antibodies, such as labeled secondary antibodies, chromophores, enzymes (as conjugated to antibodies) and substrates or antibodies thereof. Other substances, and the like.
  • the kit of the present invention may include a washing solution or an eluent capable of removing the enzyme, the substrate to be reacted with, the unbound protein, and the like, and retaining only the bound protein marker.
  • Samples used for analysis include biological samples capable of identifying infectious inflammatory disease specific proteins that can be distinguished from normal states of blood, serum, urine, tears and saliva.
  • a biological liquid sample for example blood, serum, plasma.
  • Samples may be prepared to increase the detection sensitivity of protein markers, for example serum samples obtained from patients may be anion exchange chromatography, affinity chromatography, size exclusion chromatography, liquid chromatography, continuous It may be pretreated using a method such as extractive extract or gel electrophoresis.
  • the present invention to provide information necessary for the diagnosis of infectious diseases
  • WRS can function as a marker of a novel infectious disease and provide a method of measuring the expression level of WRS to provide information necessary for the diagnosis of an infectious disease.
  • the method of the present invention will be described below step by step.
  • Step (a) of the method of the present invention is a step of providing a sample of a subject.
  • the sample may be used without limitation as long as it is collected from a subject to diagnose an infectious disease, for example, cells or tissues obtained by biopsy, blood, whole blood, serum, plasma, saliva, cerebrospinal fluid, various rainwater, urine. Or can be stool.
  • an infectious disease for example, cells or tissues obtained by biopsy, blood, whole blood, serum, plasma, saliva, cerebrospinal fluid, various rainwater, urine.
  • blood, plasma, or serum are preferably, or serum.
  • Step (b) of the method of the present invention is a step of measuring the expression level of WRS in the sample provided in step (a).
  • the expression level of the WRS may be the expression level of the WRS protein or WRS mRNA.
  • WRS protein specific antibodies are as described in the diagnostic composition of the present invention.
  • Methods for measuring the expression level of the WRS protein can be used without limitation, methods known in the art, such as Western blotting, dot blotting, enzyme immunoassay (enzyme) 1 inked immunosorbent assay (ELISA), radioimmunoassay (RIA), radioimmunoassay, oukteroni immunodiffusion, rocket immunoelectrophoresis, immunohistochemical staining, immunoprecipi tat i on, complement fixation assay, Flow cytometry (FACS) or protein chip methods, but are not limited to these.
  • an ELISA method can be used.
  • WRS mRNA levels can be expressed by amplifying WRS mRNA or cDNA from a sample of a subject using a primer set or probe that specifically binds to WRS mRNA, or by localizing with a probe. The presence and expression of WRS mRNA in the subject sample can be measured using a hybridization ion. Primers and probes of the WRS are as described in the diagnostic composition of the present invention.
  • Determination of WRS mRNA expression level can be used without limitation the conventional expression level confirmation method in the art, and examples of the analysis method is reverse transcript ion polymerase chain react ion (RT-PCR), competitive RT ⁇ PCR ( compet it ive RT-PCR, real-time RT-PCR, RNase protect ion assay (RPA), northern blotting, DNA microarray chip ), RNA sequencing, hybridization using nanostrings, in situ hybridization of tissue sections, and the like, but are not limited thereto.
  • RT-PCR reverse transcript ion polymerase chain react ion
  • competitive RT ⁇ PCR compet it ive ive RT-PCR, real-time RT-PCR, RNase protect ion assay (RPA), northern blotting, DNA microarray chip
  • RNA sequencing hybridization using nanostrings, in situ hybridization of tissue sections, and the like, but are not limited thereto.
  • Step (c) of the method of the present invention is to compare the level of the WRS of the subject sample measured in step (b) with a normal person, and to determine that the subject has an increased infectious disease level compared to the normal person as having an infectious disease. to be.
  • the expression level of the WRS of the subject measured by the method of step (b) described above is compared with the WRS level of the normal person measured by the same method.
  • Subjects with increased levels of expression of WRS compared to healthy normal subjects are determined to have an infectious disease.
  • the infectious disease is sepsis
  • the higher the expression level of WRS it can be determined that sepsis is more severe.
  • the extent of WRS expression level is analyzed by analyzing the correlation between WRS expression level and sepsis severity according to techniques known in the art for the selected method of measuring WRS expression level. In some cases, an appropriate diagnosis may be provided to indicate the severity of sepsis.
  • the expression of WRS in the serum of the deceased patient significantly increased compared to the surviving patient through a clinical trial of the investigator, which is a procalcitonin (marker used conventionally procalci tonin) was indistinguishable.
  • the present invention provides a composition for determining the risk of death by an infectious disease comprising an agent for measuring the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-NA synthase mRNA to provide.
  • the risk of death refers to the risk of death due to an infectious disease, and the death due to infection shows some or all symptoms of inflammatory reaction, high fever pain, difficulty breathing, hypothermia, lowering blood pressure, shock, partial or multiple symptoms. This means death of organs due to organ failure.
  • (C) provides a method for identifying the risk of death due to an infectious disease comprising the step of determining that the higher the level of the tryptophanyl TNA synthase is higher risk of death.
  • the sample and the like in the determination method of the present invention are as described above.
  • the present invention provides a use of an agent for measuring the expression level of tryptophany® tRNA synthetase protein or tryptophanyl thialene synthase mRNA for the preparation of a diagnostic agent for infectious disease.
  • the present invention provides a method for diagnosing an infectious disease characterized by measuring the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-NA synthase mRNA in a sample of a subject. to provide.
  • the present invention is the use of an agent for measuring the expression level of tryptophanyl-tRNA synthetase protein or tryptophanyl thial-A synthase mRNA for the preparation of the agent for determining the risk of death by infectious diseases
  • the subject of the present invention may be an animal, preferably a mammal, particularly an animal including a human, more preferably a human or a patient (pat i ent) in need of diagnosis.
  • the method of diagnosing the perioral disease is to compare the WRS level of the measured subject sample with a normal person and express the protein or mRNA of the WRS compared to the normal person. Increasing levels of a subject are diagnosed as having an infectious disease.
  • the comparison with the normal person is as described above.
  • the term 'comprising' of the present invention is used in the same way as 'containing' or 'featured' and does not exclude additional component elements or method steps that are not mentioned in the composition or method. .
  • the term 'consisting of' excludes additional elements, steps or components, etc., unless otherwise noted.
  • the term 'essentially consisting of' means, in the scope of the composition or method, that the substance or step is included in addition to the substance or step described and does not substantially affect its basic properties. .
  • WRS is increased only in an infectious disease caused by an infection, and thus is distinguished from a non-infectious disease and rapidly increases in the early stage of infection.
  • Levels of WRS also correlate closely with the severity and prognosis of diseases or complications caused by infection.
  • WRS can be used as a faster and more accurate diagnostic marker than markers of existing infectious diseases or complications thereof.
  • Figure 1 shows a Salmonella WRS changes in accordance vs time (5. typhimurium, 57) the first ( ⁇ 10?, Or from 10 FU abdominal peritoneal exudates (peritoneal lavage fluid of mice injected with) after infection as measured by EUSA.
  • the horizontal axis shows the time at which the abdominal effusion was obtained after ST infection (Time after ST innoculat ion (hr)).
  • Figure 2 shows the results of ELISA experiments to measure the WRS secretion pattern following virus infection.
  • FIG. 3A measures the levels of WRS present in serum of healthy thy control (HC), Severe sepsis, and Septic shock patients. Shows the results of the ELISA experiment. 3B and 3C show the results of ELISA experiments measuring the levels of GRS or KRS in serum of healthy normal (HC) and sepsis patients, respectively (Statistical significance of Dunn's comparison test after ruskal wallis test in FIG. 3A). 3B and 3C were judged by a two-tailed Mann-Whitney test, where *** indicates pO.001 and * indicates p ⁇ 0.05. Ns indicates no statistical significance).
  • 4A shows the results of ELISA experiments measuring the levels of WRS present in the serum of healthy normal (H.C) and fungi infected sepsis patients.
  • 4B and 3B and 3C show the results of ELISA experiments measuring levels of GRS or KRS present in serum of healthy normal (HC) and sepsis patients, respectively (statistical significance was determined by the two-tailed Mann-Whitney test). *** denotes pO.001 and * denotes pO.05, ns denotes no statistical significance).
  • FIG. 5A shows the results of an ELISA experiment measuring the level of WRS present in the serum of Gram-negative bacteria infected patients, Gram-positive bacteria infected patients and Gomwang infected patients.
  • Figure 5B shows the results of ELISA experiments to measure the level of WRS present in the serum of single and multi-infected patients (statistical significance was determined by Dunn's comparison test after Kruskal wallis test, *** is ⁇ ⁇ 0 ⁇ 001 , * Indicates p ⁇ 0.05, ns indicates no statistical significance).
  • SIRS systemic inflammatory response syndrome
  • FIG. 6A asthma (asthma, ASA, FIG. 6B), a disease of chronic inflammatory diseases, and rheumatoid arthritis (RA, FIG. 6C) and the results of comparing WRS levels in patients with Sjogren's syndrome (SS, FIG. 6C) with healthy thy control (HC).
  • the experiment was conducted with the permission of the Institutional Review Board (permission number 1502-001-010). Serum samples from healthy controls were collected at the Seoul National University Health Center. Serum samples from 99 sepsis patients were obtained from severe sepsis or septic shock intensive care unit. The patients who provided the serum used in the experiment were admitted to the intensive care unit of a university-affiliated hospital in Seoul. Only patients with confirmed bacterial infection participated in the experiment. Diagnosis of severe sepsis or septic shock was made according to the criteria of the ACCP / SCCM consensus conference (1992). The trial was conducted with informed consent for all patients participating in the trial, in accordance with the review committee's policy. The experiment was also approved by the Review Committee of Seolle Asan Hospital.
  • SIRS patients caused by non-infectious diseases
  • 166 sepsis patients and 160 septic shock patients were informed of all patients participating in the experiment in accordance with the institution's review committee's policy.
  • SIRS systemic inflammatory reaction syndrome
  • sepsis or septic shock was confirmed by the ACCP / SCCM consensus conference (1992). It was made according to the standards.
  • Serum procalcitonin (RayBiotech, USA Cat No: ELH-PROCALC) and WRS (CUSABI0, China, Cat No: CSB-E11789h) levels were measured using the respective ELISA kits and were measured according to the manufacturer's method. .
  • peripheral blood mononuclear cells peripheral blood mononuclear cells
  • PBMC peripheral blood mononuclear cells
  • CPTTM Cell Preparation Tube
  • Bee t onD i ck i nson Cell Preparation Tube
  • Salmonella typJiimur iuwi TCC 14028 was obtained from the Korea Microbial Conservation Center (Seoul). Bacteria were commonly cultured using nutrient broth of BD bioscience. The bacteria were incubated overnight before infection and obtained at a density of 1 ⁇ 10 8 CFU. Bacteria density was estimated using an absorbance of 600 nm and a calibration curve. For PBMC or mouse infection experiments, bacteria were washed with PBS and redispersed in medium or serum without PBS. Enzyme—linked immunosorbent assay (ELISA)
  • WRS ELISA kit was purchased from CusabioCWuhan, China, catalog number CSB-E11789h), and KRS was purchased from USCN (Wuhan, China, catalog number SED002 Hu). Statistics If the probability value (p-value) is less than 0.05, it was determined that there was statistical significance. All statistical calculations were performed using Graphpad prism 5.0 (GraphPad Software).
  • Salmonella typimurium Salmonella typimurium was injected into the mouse abdominal cavity, and the amount of WRS present in the abdominal effusion was checked.
  • WRS secreted by intraperitoneal effusion was secreted from the very early stage after Salmonella infection, and the concentration of Salmonella was increased, and the amount of WRS was almost the highest at 1 hour after infection.
  • PBMCs peripheral blood monocytes
  • RSV respiratory syncytial virus
  • PR8 virus an influenza virus
  • WRS increased significantly in cell culture medium from 30 minutes after infection.
  • FIG. 2A It was confirmed that the level of WRS secreted up to 4 hours after the infection progressed the experiment.
  • H.C normal control
  • the patients with sepsis who participated in the trial were severe sepsis and septic shock patients who had been identified as having a bacterial infection in the intensive care unit of Asan Medical Center. This (fungi) is as described in Table 1.
  • Glycyl-tRNA synthetase Glycyl-tRNA synthetase (GRS)
  • ARS secreted aminoacyl tRNA synthetase
  • KRS Lysyl-tRNA synthetase
  • WRS detected in the serum of systemic inflammatory response syndrome (FIG. 6A), asthma patients (FIG. 6B), rheumatoid arthritis patients (FIG. 6C), and Sjogren's syndrome patients (FIG. 6C) is healthy normal. There was no statistically significant difference compared to the control.
  • ROC curve receiver operating characteristics curve
  • ⁇ 4-2> Comparison of contents according to survival Patients with sepsis and septic shock were divided into survivors and deaths according to their survival after 28 days.
  • the content of WRS and procalcitonin in patient serum of each group was measured quantitatively as in Example ⁇ 4-1>.
  • the procalcytonin was not distinguished between the survivors and the dead among the patients, but the WRS was statistically meaningful to confirm that the screening of the patients of death was possible.
  • Spearman's correlat ion analys i was performed on sepsis patients using measurements from WRS and procalcitonin in order to correlate the diagnosis results of conventionally used procalcitonin and WRS. As a result, as shown in FIG. 10, it was confirmed that Spearman's rho value (r) was 0.127 and p value was 0.022, indicating an association between WRS and procalcitonin.
  • WRS since WRS is increased only in infectious diseases caused by infection, WRS is differentiated from non-infectious diseases and increases rapidly in the early stage of infection. The level of WRS also correlates closely with the severity and prognosis of the disease or complications caused by infection. Thus, WRS can be used as a faster and more accurate diagnostic marker than markers of existing infectious diseases or complications thereof.

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Abstract

La présente invention concerne une composition permettant le diagnostic de maladies infectieuses à l'aide d'une tryptophanyl ARNt synthétase (WRS), et un procédé permettant la détection d'un marqueur de diagnostic, et plus particulièrement : une composition permettant le diagnostic de maladies infectieuses, contenant une préparation mesurant le taux de protéines WRS ou d'expression d'ARNm; un kit de diagnostic; un procédé permettant la détection de la WRS pour fournir des informations requises pour le diagnostic de maladies infectieuses, et un procédé permettant la détermination de risque de mortalité par une maladie infectieuse à l'aide de la WRS. Selon la présente invention, la WRS est accrue uniquement dans des maladies infectieuses induites par une infection, différenciant des maladies non infectieuses de ces dernières, et est rapidement accrue lors du stade précoce de l'infection. De plus, le taux de la WRS est étroitement mis en corrélation avec la gravité et le pronostic de maladies ou de complications induites par une infection. Par conséquent, la WRS peut être utilisée comme marqueur pour un diagnostic plus rapide et précis, par rapport à un marqueur classique contre des maladies infectieuses ou des complications de ces dernières.
PCT/KR2016/009802 2015-09-01 2016-09-01 Composition permettant le diagnostic de maladies infectieuses ou de complications infectieuses à l'aide d'une tryptophanyl arnt synthétase, et procédé de détection de marqueur de diagnostic WO2017039359A1 (fr)

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JP2018530462A JP6732914B2 (ja) 2015-09-01 2016-09-01 トリプトファニルｔＲＮＡ合成酵素を利用した感染症又は感染合併症の診断用組成物と診断マーカー検出方法
ES16842325T ES2911270T3 (es) 2015-09-01 2016-09-01 Composición para diagnosticar enfermedades infecciosas o complicaciones infecciosas mediante el uso de triptofanil-arnt sintetasa y método para detectar el marcador de diagnóstico
PL16842325T PL3346270T3 (pl) 2015-09-01 2016-09-01 KOMPOZYCJA I SPOSÓB WYKRYWANIA MARKERA DIAGNOSTYCZNEGO DO DIAGNOZOWANIA CHORÓB ZAKAŹNYCH LUB POWIKŁAŃ ZAKAŹNYCH Z WYKORZYSTANIEM SYNTETAZY TRYPTOFANYLO-tRNA
EP16842325.9A EP3346270B1 (fr) 2015-09-01 2016-09-01 Composition permettant le diagnostic de maladies infectieuses ou de complications infectieuses à l'aide d'une tryptophanyl arnt synthétase, et procédé de détection de marqueur de diagnostic
CN201680050793.5A CN108449999B (zh) 2015-09-01 2016-09-01 使用色酰胺-tRNA合成酶诊断感染病或其并发症的组合物以及检测诊断标记物的方法
US15/908,568 US10788493B2 (en) 2015-09-01 2018-02-28 Composition for diagnosing infectious diseases or infectious complications by using tryptophanyl-tRNA synthetase and method for detecting diagnostic marker

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