WO2022165693A1 - 结核杆菌的检测方法与试剂 - Google Patents
结核杆菌的检测方法与试剂 Download PDFInfo
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- WO2022165693A1 WO2022165693A1 PCT/CN2021/075197 CN2021075197W WO2022165693A1 WO 2022165693 A1 WO2022165693 A1 WO 2022165693A1 CN 2021075197 W CN2021075197 W CN 2021075197W WO 2022165693 A1 WO2022165693 A1 WO 2022165693A1
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- Prior art keywords
- interferon
- interleukin
- mycobacterium tuberculosis
- factors
- detection
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- 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
- G01N2333/435—Assays involving biological materials from specific organisms or of a specific nature from animals; from humans
- G01N2333/52—Assays involving cytokines
- G01N2333/555—Interferons [IFN]
- G01N2333/57—IFN-gamma
Definitions
- the present invention relates to microbiology, in particular to a method for detecting microorganisms such as a method for detecting Mycobacterium tuberculosis and corresponding reagents
- Tuberculosis is a chronic infectious disease caused by Mycobacterium tuberculosis (Mtb) infection that can invade various organs of the human body, but mainly invades the lungs. It has always been a global public health concern. In 2019, approximately 10 million cases and 1.41 million deaths worldwide were attributed to tuberculosis, making it the leading cause of death from infectious diseases. China has the third highest TB burden globally, after India and Indonesia. With effective control strategies, the incidence of TB in China has continued to decline over the past few decades.
- Mtb Mycobacterium tuberculosis
- Interferon-gamma release assays are the main method for diagnosing latent tuberculosis infection by detecting the secretion of IFN-gamma by Mtb-specific T cells [Pai M, Zwerling A, Menzies D: Systematic review: T-cell-based assays for the diagnosis of latent tuberculosis infection:an update.Ann Intern Med 2008,149(3):177-184.], because IGRASs are more specific than tuberculin skin tests in the BCG (Bacille Calmette-Guerin) vaccinated population.
- BCG Bacille Calmette-Guerin
- IGRASs interferon-gamma release assays
- Negative IGRASs in particular are an indicator of exclusion of active TB; however, previous observational studies have shown that approximately 8%-19% of patients with culture-positive TB have negative IGRAS results [Sester M, Sotgiu G, Lange C, Giehl C, Girardi E, Migliori GB, Bossink A, Dheda K, Diel R, Dominguez J et al: Interferon-gamma release assays for the diagnosis of active tuberculosis: a systematic review and meta-analysis. Eur Respir J 2011, 37(1): 100-111.]. As a result, there is a growing concern that inappropriate interpretation of these false-negative results will lead to misdiagnosis in the diagnosis of active TB, especially during disease diagnosis and initial treatment.
- IRASs interferon-gamma release assays
- the present invention provides a diagnostic marker comprising a series of inflammatory factors, which can be used to diagnose whether a patient is infected with Mycobacterium tuberculosis in a test sample or a test site, the inflammatory factors The combination of one or two or more factors selected from cytokines, C-reactive protein, and white blood cell count. Further, the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- Interleukin Interleukin
- IFN interferon
- TNF tumor necrosis factor
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the diagnostic marker of the present invention comprises the inflammatory factor IL10; further preferably, the diagnostic marker of the present invention comprises the inflammatory factor IL10 and IFN- ⁇ .
- the present invention provides an auxiliary diagnostic marker for assisting IGRAs in diagnosing Mycobacterium tuberculosis infection in patients
- the auxiliary diagnostic marker contains an inflammatory factor
- the inflammatory factor is selected from one of cytokines, C-reactive protein, and white blood cell count or A combination of two or more factors.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the auxiliary diagnostic marker of the present invention comprises inflammatory factor IL10; more preferably, the auxiliary diagnostic marker of the present invention comprises inflammatory factor IL10 and IFN- ⁇ .
- the present invention provides a differential diagnosis marker for identifying whether a patient with negative IGRAs detection has Mycobacterium tuberculosis infection
- the differential diagnosis marker contains an inflammatory factor
- the inflammatory factor is selected from cytokines, C-reactive protein, and white blood cell count.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the differential diagnostic marker of the present invention comprises the inflammatory factor IL10; more preferably, the differential diagnostic marker of the present invention comprises the inflammatory factor IL10 and IFN- ⁇ .
- the present invention provides a diagnostic kit for diagnosing whether a patient is infected with Mycobacterium tuberculosis, for quickly, conveniently and timely diagnosing whether a patient is at risk of being infected with Mycobacterium tuberculosis, the diagnostic kit comprising: Detection reagents and/or detection devices for detecting inflammatory factors.
- the inflammatory factor is selected from one or a combination of two or more factors selected from cytokines, C-reactive protein, and white blood cell count.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the diagnostic kit of the present invention for diagnosing whether a patient is infected with Mycobacterium tuberculosis comprises a detection reagent and/or a detection device for detecting inflammatory factor IL10; further preferably, the diagnostic kit of the present invention for diagnosing whether a patient is infected with Mycobacterium tuberculosis
- a detection reagent and/or detection device for detecting inflammatory factors IL10 and IFN- ⁇ are included.
- the present invention provides a differential diagnosis kit for identifying whether a patient with negative IGRAs detection has Mycobacterium tuberculosis infection, the differential diagnosis kit comprising detection reagents and/or detection devices for detecting inflammatory factors.
- the inflammatory factor is selected from one or a combination of two or more factors selected from cytokines, C-reactive protein, and white blood cell count.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the differential diagnosis kit of the present invention for identifying whether a patient with negative IGRAs detection has Mycobacterium tuberculosis infection comprises a detection reagent and/or a detection device for detecting inflammatory factor IL10; further preferably, the present invention is used for identifying whether a patient with negative IGRAs detection is infected or not.
- the differential diagnosis kit for Mycobacterium tuberculosis infection includes detection reagents and/or detection devices for the detection of inflammatory factors IL10 and IFN- ⁇ .
- the present invention provides a method for detecting whether a patient is infected with Mycobacterium tuberculosis, the method comprising detecting an inflammatory factor selected from one or both of cytokines, C-reactive protein, and white blood cell counts combination of more than one factor.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the method for detecting infection with Mycobacterium tuberculosis of the present invention comprises the detection of inflammatory factor IL10; further preferably, the method for detecting infection with Mycobacterium tuberculosis of the present invention comprises the detection of inflammatory factor IL10 and IFN- ⁇ .
- the present invention provides a detection method for assisting IGRAs in detecting whether a patient is infected with Mycobacterium tuberculosis, the method comprising detecting an inflammatory factor selected from one of cytokines, C-reactive protein, and white blood cell count or A combination of two or more factors.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the detection method for detecting whether a patient is infected with Mycobacterium tuberculosis by the auxiliary IGRAs of the present invention comprises the detection of inflammatory factor IL10; further preferably, the detection method for detecting whether a patient is infected with Mycobacterium tuberculosis by the auxiliary IGRAs of the present invention comprises the detection of inflammatory factors IL10 and IFN - Detection of gamma.
- the present invention provides a detection method for identifying whether a patient with negative IGRAs detection is infected with Mycobacterium tuberculosis, the method includes detection of an inflammatory factor selected from cytokines, C-reactive protein, and white blood cell counts. A combination of one or more factors. Further, the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- Interleukin Interleukin
- IFN interferon
- TNF tumor necrosis factor
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the detection method of the present invention for identifying whether a patient with negative IGRAs detection is infected with Mycobacterium tuberculosis comprises the detection of inflammatory factor IL10; further preferably, the detection method of the present invention for identifying whether a patient with negative IGRAs detection is infected with Mycobacterium tuberculosis comprises the detection of inflammatory factor IL10. Detection of factors IL10 and IFN- ⁇ .
- the present invention provides use of an inflammatory factor in preparing a diagnostic kit for detecting whether a patient is infected with Mycobacterium tuberculosis, the diagnostic kit comprising a detection reagent and/or a detection device for detecting an inflammatory factor.
- the inflammatory factor is selected from one or a combination of two or more factors selected from cytokines, C-reactive protein, and white blood cell count.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the inflammatory factor used for preparing a diagnostic kit for detecting whether a patient is infected with Mycobacterium tuberculosis of the present invention comprises IL10; more preferably, it comprises IL10 and IFN- ⁇ .
- the present invention provides the use of an inflammatory factor in the preparation of an auxiliary diagnosis kit for assisting IGRAs to detect whether a patient is infected with Mycobacterium tuberculosis, wherein the inflammatory factor is selected from one or both of cytokines, C-reactive protein and white blood cell count. combination of more than one factor.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the inflammatory factor used in the preparation of an auxiliary diagnostic kit for detecting whether a patient is infected with Mycobacterium tuberculosis of the present invention comprises IL10; more preferably, the inflammatory factor comprises IL10 and IFN- ⁇ .
- the present invention provides the use of an inflammatory factor in the preparation of a differential diagnosis kit for identifying whether a patient with negative IGRs detection is infected with Mycobacterium tuberculosis
- the inflammatory factor is selected from one of cytokines, C-reactive protein, and white blood cell counts. combination of one or more factors.
- the cytokine is selected from one or a combination of two or more factors selected from interleukin (Interleukin, IL), interferon (Interferon, IFN), tumor necrosis factor (Tumor-Necrosis Factor, TNF) and the like.
- the interleukin is selected from: IL-1 ⁇ , IL-1 ⁇ , IL-4, IL10, IL11, IL12A, etc.;
- the interferon is selected from: IFNA1, IFNA2, IFNA3, IFNA4, IFNB, IFN- ⁇ , etc.;
- the tumor necrosis factor is selected from: TNF, TNF ⁇ , TNF ⁇ and the like.
- the inflammatory factor used in the preparation of a differential diagnosis kit for detecting whether a patient is infected with Mycobacterium tuberculosis of the present invention comprises IL10; more preferably, the inflammatory factor IL10 and IFN- ⁇ .
- the use of the detection reagent and the detection method of the present invention can significantly reduce the occurrence of false negatives of the IGRAs test, thereby improving the efficacy of the IGRAs test for diagnosing tuberculosis.
- Figure 1 The expression of IL-10 is up-regulated in peripheral blood mononuclear cells of IGRAs-negative tuberculosis patients
- A-C mRNA expression levels of IL-10, TGF- ⁇ and IL-4 after Mtb antigen stimulated PBMC;
- Mtb antigen stimulates the level of IL-10 in PBMC supernatant.
- the patients described in the present invention are mammals, including humans, livestock, pets, laboratory animals, etc., wherein humans include patients of various age groups and gender characteristics, and further are patients who have been detected for the first time or have been detected for multiple times by Mycobacterium tuberculosis.
- the detection samples of inflammatory factors described in the present invention are blood, liquid in body cavity, and the body cavity is selected from abdominal cavity, pelvic cavity, joint cavity, thoracic cavity environment and/or brain cavity, etc.; the liquid in the body cavity is selected from Fluid in the abdominal, pelvic, joint, thoracic environment and/or cerebrospinal fluid.
- the sites where Mycobacterium tuberculosis invades in the present invention include lungs, pleura, meninges, peritoneum, intestines, skin, bones, lymph and other sites.
- the detection method of the inflammatory factor used in the present invention is the existing detection method in the prior art, including the detection of the secretion level of the inflammatory factor or the detection of the expression level of the nucleic acid of the inflammatory factor, and further including the detection of the mRNA expression level of the inflammatory factor.
- Specific examples include Real-time fluorescence quantitative detection method, ELISA analysis of inflammatory factor protein level, liquid chip method, flow cytometry analysis method, etc.
- the content of the inflammatory factor is greater than 1.5 pg/mL, preferably greater than 1.7 pg/mL, more preferably greater than 2.0 pg/mL.
- tuberculosis detection reagent product and method of the present invention In order to further illustrate the effect of the tuberculosis detection reagent product and method of the present invention, the following example is given, which is only an example of the method of the present invention, and does not constrain the protection subject and scope of the present invention. Other equivalent techniques within the scope of the inventive concept also belong to the scope of the present invention.
- Example 1 PBMCs isolation and TB antigen peptide costimulation
- tuberculosis patients patients with positive evidence of Mycobacterium tuberculosis etiology (smear, culture, xpert) and IGRAS positive, no other serious medical history;
- IGRAs(-) tuberculosis patients patients with positive evidence of Mycobacterium tuberculosis etiology (smear, culture, xpert) and negative IGRAs, no other serious medical history;
- Exclusion criteria HIV coinfected individuals and other comorbidities, and anyone showing an indeterminate response to IGRAs.
- BMI Body Mass Index. The measurement data conformed to the normal distribution using t test, and the mean ⁇ standard error was expressed; the categorical variable data was tested using the chi-square test. Significance level: p ⁇ 0.05.
- Example 2 Real-time fluorescence quantitative (QRT) PCR detection of IL-10, TGF- ⁇ , IL-4 mRNA expression levels
- RNA of cells was extracted using a cell/bacteria total RNA extraction kit (R1061, Guangzhou Dongsheng Biotechnology Co., Ltd.).
- Reverse transcription reaction system preparation (20 ⁇ l): Add 2x Hifair TM II SuperMix plus to the RNase free eight-row tube, then add 10 ⁇ l of total RNA extracted in step (B), and mix by pipetting gently.
- Example 3 IL-10 levels in the supernatant of PBMCs in peripheral blood of IGRAs positive group and IGRAs negative group after being stimulated by tuberculosis antigen peptide for 24 h.
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Abstract
Description
Claims (8)
- 一种用于诊断患者是否感染结核分支杆菌的诊断标记物,其特征在于:所述诊断标记物包括一系列炎症因子,所述炎症因子选自细胞因子、C反应蛋白、白细胞计数中的一种或两种以上因子的结合,优选所述细胞因子选自白细胞介素(Interleukin,IL)、干扰素(Interferon,IFN)、肿瘤坏死因子(Tumor-Necrosis Factor,TNF)中的一种或两种以上因子的组合。
- 根据权利要求1所述的用于诊断患者是否感染结核分支杆菌的诊断标记物,其特征在于:所述白细胞介素选自:IL-1α、IL-1β、IL-4、IL10、IL11、IL12A;所述干扰素选自:IFNA1、IFNA2、IFNA3、IFNA4、IFNB、IFN-γ;所述肿瘤坏死因子选自:TNF、TNFα、TNFβ。
- 一种用于诊断患者是否感染结核分支杆菌的试剂盒,其特征在于:包含用于检测权利要求1-2中任一项所述标记物的检测试剂和/或检测装置。
- 一种权利要求1-2任一项所述标记物在用于制备诊断患者是否感染结核分支杆菌的检测试剂或检测试剂盒中的用途,所述试剂盒包含用于检测所述标记物的检测试剂或检测装置。
- 一种检测患者是否感染结核分支杆菌的方法,其特征在于:所述方法包括对炎症因子的检测,所述炎症因子选自细胞因子、C反应蛋白、白细胞计数中的一种或两种以上因子的结合,优选所述细胞因子选自白细胞介素(Interleukin,IL)、干扰素(Interferon,IFN)、肿瘤坏死因子(Tumor-Necrosis Factor,TNF)中的一种或两种以上因子的组合。
- 根据权利要求5所述的用于检测患者是否感染结核分支杆菌的方法,其特征在于:所述白细胞介素选自:IL-1α、IL-1β、IL-4、IL10、IL11、IL12A;所述干扰素选自:IFNA1、IFNA2、IFNA3、IFNA4、IFNB、IFN-γ;所述肿瘤坏死因子选自:TNF、TNFα、TNFβ。
- 一种炎症因子在制备检测患者结核杆菌感染的诊断试剂盒中的用途,其特征在于:所述炎症因子选自细胞因子、C反应蛋白、白细胞计数中的一种或两种以上因子的结合,优选,所述细胞因子选自白细胞介素(Interleukin,IL)、干扰素(Interferon,IFN)、肿瘤坏死因子(Tumor-Necrosis Factor,TNF)中的一种或两种以上因子的组合。
- 根据权利要求7所述的炎症因子在制备检测患者结核杆菌感染的诊断试剂盒中的用途,其特征在于:所述白细胞介素选自:IL-1α、IL-1β、IL-4、IL10、IL11、IL12A;所述干扰素选自:IFNA1、IFNA2、IFNA3、IFNA4、IFNB、IFN-γ;所述肿瘤坏死因子选自:TNF、TNFα、TNFβ。
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