CN113156140A - Application of C-type lectin-like receptor-1 as treatment marker of fungal keratitis - Google Patents
Application of C-type lectin-like receptor-1 as treatment marker of fungal keratitis Download PDFInfo
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- CN113156140A CN113156140A CN202110246216.6A CN202110246216A CN113156140A CN 113156140 A CN113156140 A CN 113156140A CN 202110246216 A CN202110246216 A CN 202110246216A CN 113156140 A CN113156140 A CN 113156140A
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Abstract
本发明公开了C型凝集素样受体‑1作为真菌性角膜炎中治疗标志物的应用，并提供一种用于在治疗真菌性角膜炎的过程中评估使用糖皮质激素类药物的用药时机的试剂盒。C型凝集素样受体‑1可作为一种生物标志物简便而安全的判断真菌性角膜炎时糖皮质激素类药物的使用时机，在指导临床决策方面具有重要的意义。
The invention discloses the application of C-type lectin-like receptor-1 as a treatment marker in fungal keratitis, and provides a method for evaluating the timing of using glucocorticoid drugs in the process of treating fungal keratitis the kit. C-type lectin-like receptor-1 can be used as a biomarker to easily and safely determine the timing of glucocorticoid use in fungal keratitis, which is of great significance in guiding clinical decision-making.
Description
Technical Field
The invention belongs to the technical field of biology, and particularly relates to application of C-type lectin-like receptor-1 (C-type lectin-like receptor-1, CLEC-1) as a therapeutic marker for fungal keratitis.
Background
Fungal Keratitis (FK) is a serious infectious ocular disease worldwide, and currently, due to the lack of clinically effective therapeutic means, serious complications of the eye often occur, and serious patients can finally cause permanent vision loss. China is a developing country mainly taking agriculture as a main part, and is a high incidence area of fungal keratitis, and particularly, plant corneal trauma becomes a main cause of the disease during farming. Although many fungal keratitis drugs have been used clinically in recent years, the curative effects of these drugs are poor, and fungi gradually develop drug resistance, especially to azole drugs. Due to the lack of effective treatment, many patients require corneal transplants and even removal of the eye.
After fungal infection of the cornea, mutual recognition of pattern recognition receptors in the cornea and pathogen-associated molecular patterns on the fungal surface initiates an innate immune response of the cornea to clear fungal pathogens. Glucocorticoids, however, inhibit phagocytosis and processing of antigens by the macrophage membrane and cellular immune processes. Various pathogenic factors of the fungi can assist the fungi to adhere to the host cells and decompose phospholipids in the cell membranes, so that the cell membranes are damaged, hyphae can penetrate the host cells more effectively, and the chemotaxis of neutrophils and the phagocytic function of macrophages are reduced. Blindly applying glucocorticosteroids can lead to disease progression, and in severe cases can lead to corneal perforation.
After the cornea innate immune response is initiated, a large number of neutrophils and chemokines accumulate, causing corneal edema and inflammatory infiltration, and even causing corneal ulceration and even perforation. Therefore, too strong an immune response damages corneal tissue while controlling extrinsic infection, making it difficult to restore transparency of the cornea, and causing severe damage to the patient's vision. Recent studies have demonstrated that the use of glucocorticosteroids in the later stages of the disease can reduce corneal haze and help the cornea maintain good transparency. Therefore, it is important to grasp the time point of use of the glucocorticoid drug.
Disclosure of Invention
Aiming at the problems in the prior art, the invention provides a therapeutic marker for fungal keratitis and application thereof.
The C-type lectin-like receptor family codes for the centromeric part of the human chromosome 12 Natural Killer (NK) gene complex, recognizing various ligands and performing various functions. However, no literature discloses or indicates the association between the C-type lectin-like receptor family and fungal keratitis.
The applicant of the invention fully proves that C-type lectin-like receptor-1 (CLEC-1) as a member of a C-type lectin-like receptor family has reduced expression in the acute inflammation stage and increased expression in the recovery stage of fungal keratitis through in vivo experiments and in vitro experiments. The expression of CLEC-1 decreased after treatment of fungal keratitis with natamycin. Upon upregulation of CLEC-1 expression, Myeloperoxidase (MPO) levels are reduced, neutrophil recruitment is reduced, IL-1 β expression is reduced, and fungal burden is increased.
The invention adopts quantitative polymerase chain reaction (qRT-PCR) and immunofluorescence to detect the expression of CLEC-1 in the cornea of patients with fungal keratitis. Then, in vitro and in vivo experiments are carried out on THP-1 macrophage and C57BL/6 mouse models respectively, and the expression of CLEC-1 is detected by qRT-PCR, western blot and immunofluorescence. The result shows that the expression of CLEC-1 is reduced in the acute inflammation stage of the fungal keratitis, and the expression in the convalescent stage is increased. The expression of CLEC-1 decreased after treatment of fungal keratitis with natamycin. The mouse cornea and THP-1 macrophage over-express CLEC-1 by utilizing a virus vector, and experiments such as slit lamp photography, clinical scoring, Colony Forming Unit (CFU), bioluminescence imaging system image acquisition, MPO detection, immunofluorescence staining, qRT-PCR, western blot and the like prove that after the CLEC-1 expression is up-regulated, the MPO level is reduced, the recruitment of neutrophils is reduced, the IL-1 beta expression is reduced, and the fungal load is increased.
Based on the above research results, the first aspect of the present invention provides the use of C-type lectin-like receptor-1 as a therapeutic marker for fungal keratitis.
In the use provided by the first aspect of the present invention, the fungal keratitis is aspergillus fumigatus keratitis.
In the use provided by the first aspect of the invention, the therapeutic marker is used to indicate the timing of administration of a glucocorticoid drug.
Further, in the use provided by the first aspect of the present invention, when the expression of C-type lectin-like receptor-1 is increased in vivo, the timing of administration of the glucocorticoid drug is indicated.
A second aspect of the invention provides a kit for assessing the timing of administration of a glucocorticoid drug in the treatment of fungal keratitis, the kit comprising reagents for detecting C-type lectin-like receptor-1 levels in the cornea.
In the kit provided by the second aspect of the present invention, the fungal keratitis is aspergillus fumigatus keratitis.
Further, the second aspect of the present invention provides a kit wherein the reagent enables detection of C-type lectin-like receptor-1 levels based on immunoblotting techniques.
Drawings
FIG. 1 is a graph showing the results of CLEC-1mRNA expression in normal corneas and human corneas infected with Aspergillus fumigatus keratitis as measured by qRT-PCR in example 1;
FIG. 2 is a graph showing the results of detecting CLEC-1 protein expression in normal corneas and human corneas infected with Aspergillus fumigatus keratitis in example 1 using immunofluorescence staining;
FIG. 3 is a photograph under a slit lamp microscope of the mouse model of Aspergillus fumigatus keratitis of example 2 after 1/2, 1, 2, 3, 5, 7, 10, 14 days;
FIG. 4 is a graph showing the results of detecting CLEC-1mRNA expression in mouse cornea by qRT-PCR method after 1/2, 1, 2, 3, 5, 7, 10, and 14 days of establishment of the mouse model of Aspergillus fumigatus keratitis in example 2;
FIG. 5 is a graph showing the results of detecting the expression of CLEC-1 protein in the mouse cornea by the western blot method after 1/2, 1, 2, 3, 5, 7, 10, and 14 days are established in the mouse model of the A.fumigatus keratitis in example 2;
FIG. 6 is a graph showing the results of detecting CLEC-1 protein expression in the mouse cornea by immunofluorescence staining after 5 days from the establishment of the mouse model for Aspergillus fumigatus keratitis in example 2;
FIG. 7 is a photograph under a slit lamp microscope of the Aspergillus fumigatus infection group and the Aspergillus fumigatus infection combined natamycin treatment group for 1, 3, 5 days of mice of example 2;
FIG. 8 is the corneal clinical scores for 3 days and 5 days of the group treated with natamycin in combination with the group treated with Aspergillus fumigatus infection in mice of example 2;
FIG. 9 is a graph showing the results of qRT-PCR detection of CLEC-1mRNA expression in the mouse Aspergillus fumigatus infection group and the Aspergillus fumigatus infection combined natamycin treatment group in example 2;
FIG. 10 is a graph showing the results of detecting the expression of CLEC-1 protein in the A.fumigatus infection group and the A.fumigatus infection combined natamycin treatment group in mice using western blot in example 2;
FIG. 11 is a photograph of the expression of EGFP in mouse cornea taken with a fluorescence microscope in example 3;
FIG. 12 is a graph showing the results of detecting CLEC-1mRNA overexpression using qRT-PCR in example 3;
FIG. 13 is a graph showing the results of detecting overexpression of CLEC-1 protein using western blot in example 3;
FIG. 14 is a photograph of corneas of the control group mice and CLEC-1 overexpression group mice 1 day after infection with A.fumigatus keratitis in example 3;
FIG. 15 is the corneal clinical scores of the control group mice and the CLEC-1 overexpression group mice 1 day after infection with A.fumigatus keratitis in example 3;
FIG. 16 is a graph showing the results of corneal CFU in the control group and CLEC-1 overexpression group of mice 1 day after infection with A.fumigatus keratitis in example 3;
FIG. 17 is a photograph showing the mean bioluminescence of the corneas of the control group and the CLEC-1 overexpression group of mice 1 day after infection with A.fumigatus keratitis in example 3;
FIG. 18 is a graph showing the results of corneal MPO in the control group of mice and the CLEC-1 overexpression group of mice after infection with A.fumigatus keratitis for 1 day in example 3;
FIG. 19 is a graph showing the results of measuring the distribution of neutrophils in the corneas of the control group of mice and the CLEC-1 overexpression group of mice 1 day after the infection of the A.fumigatus keratitis by the immunofluorescence method in example 3;
FIG. 20 is a graph showing the results of example 3 using qRT-PCR to detect CLEC-1mRNA expression in the corneas of normal mice, mice infected with Aspergillus fumigatus keratitis, CLEC-1 overexpressing mice, and CLEC-1 overexpressing mice in combination with Aspergillus fumigatus keratitis;
FIG. 21 is a graph showing the results of detecting the expression of CLEC-1 protein in the corneas of normal mice, mice infected with Aspergillus fumigatus keratitis, CLEC-1 overexpressing mice, and CLEC-1 overexpressing mice in combination with Aspergillus fumigatus keratitis in example 3 using a western blot method;
FIG. 22 is a graph showing the results of qRT-PCR method for detecting CLEC-1mRNA expression in normal THP-1 macrophages, Aspergillus fumigatus-treated THP-1 macrophages, CLEC-1 overexpressing THP-1 macrophages, and CLEC-1 overexpressing combined with Aspergillus-treated THP-1 macrophages in example 3;
FIG. 23 is a graph showing the results of example 3 using the western blot method to detect CLEC-1 protein expression in normal THP-1 macrophages, Aspergillus fumigatus-treated THP-1 macrophages, CLEC-1 overexpressing THP-1 macrophages, and CLEC-1 overexpressing combined with Aspergillus-treated THP-1 macrophages.
Detailed Description
In order to make the objects, technical solutions and advantages of the present invention more apparent, embodiments of the present invention will be described in detail below. However, it will be appreciated by those of ordinary skill in the art that numerous technical details are set forth in order to provide a better understanding of the present application in various embodiments of the present invention. However, the technical solutions claimed in the claims of the present application can be implemented without these technical details and with various changes and modifications based on the following embodiments.
The invention provides a method for guiding clinical treatment by taking C-type lectin-like receptor-1 of a patient with fungal keratitis as a marker for using a glucocorticoid medicament and evaluating the medication time of using the glucocorticoid medicament based on the level of the C-type lectin-like receptor-1 in cornea.
The experimental protocol and results established for the embodiments of the present invention are as follows:
the corneas of 6 patients with aspergillus fumigatus keratitis and 6 healthy patients were collected for immunofluorescence and qRT-PCR detection, and the specimens were confirmed by fungus culture and morphology. The purpose and method of the study is elaborated on the patient, who takes samples after obtaining informed consent. The results show that the expression of CLEC-1 is significantly increased in infected corneas compared to normal corneas. When the disease course of the patient is less than 1 month, the expression of the CLEC-1mRNA has no obvious change, but when the disease course is more than 1 month, the expression of the CLEC-1mRNA is obviously increased.
In vivo experiments, a mouse model of fungal keratitis was established using intrastromal injection, and the mouse cornea was observed daily with a slit lamp microscope and photographs taken. After infection, 1/2, 1, 2, 3, 5, 7, 10 and 14 days, the cornea is taken for western blot and qRT-PCR detection, and the eyeball is taken for immunofluorescence staining after 5 days. The degree of corneal infection was observed, clinical scores were recorded, and the expression of CLEC-1 was measured on day 3 and day 5 using qRT-PCR and western blot. CLEC-1 was overexpressed in mouse corneas by intrastromal injection of CLEC-1 adeno-associated virus (AAV) vectors. One eye was randomly selected from each mouse to receive subconjunctival injections of 5. mu.l of 1011vg vector. Two weeks later, enhanced green fluorescent protein was examined with fluorescence stereomicroscope to determine the uniform distribution of the virus in the corneal stroma. And detecting the over-expression of CLEC-1 by adopting qRT-PCR and western blot. The cornea was taken 1 day after infection for MPO detection, immunofluorescence staining, western blot and qRT-PCR. The result shows that the expression of CLEC-1 is reduced in the acute inflammation stage of the fungal keratitis, and the expression in the convalescent stage is increased. The expression of CLEC-1 decreased after treatment of fungal keratitis with natamycin. Following up-regulation of CLEC-1 expression, MPO levels are reduced, neutrophil recruitment is reduced, IL-1 β expression is reduced, and fungal burden is increased.
In an in vitro experiment, a lentiviral vector CLEC-1 is pretreated in THP-1 macrophages for 24 hours, then the THP-1 macrophages are infected by aspergillus fumigatus conidia for 16 hours, and the THP-1 macrophages are collected for western blot and qRT-PCR detection. The results are consistent with those of the mouse keratitis model, with decreased MPO levels, decreased neutrophil recruitment, decreased IL-1 β expression, and increased fungal burden following up-regulation of CLEC-1 expression. Note: all figures indicate P <0.05 and P < 0.01.
Example 1 CLEC-1 expression increases in the cornea of patients with Aspergillus fumigatus keratitis
1. Experimental Material
1.1 Collection of human corneal specimens
Corneas of 6 patients with aspergillus fumigatus keratitis and 6 healthy patients were collected, and specimens were confirmed by fungal culture and morphology. The purpose and method of the study is elaborated on the patient, who, after obtaining informed consent, collected a sample. Patients with any form of immunosuppression or topical steroid therapy or acute or chronic systemic disease were excluded.
1.2 test fungi
Aspergillus fumigatus 3.0772 strain (China general microbiological culture collection management center)
2. Experimental methods
The corneas of 6 patients with aspergillus fumigatus keratitis and 6 healthy patients were collected for immunofluorescence and qRT-PCR detection.
3. Results of the experiment
FIG. 1 is a graph showing the results of CLEC-1mRNA expression in normal corneas tested by qRT-PCR and human corneas infected with A.fumigatus keratitis. FIG. 2 is a graph showing the results of detecting CLEC-1 protein expression in normal corneas and human corneas infected with Aspergillus fumigatus keratitis using immunofluorescence staining.
Figures 1, 2 show that CLEC-1mRNA and protein expression is significantly increased in human corneas infected with aspergillus fumigatus keratitis compared to healthy corneas. And when the disease course is longer than 1 month, the expression of CLEC-1mRNA is obviously increased.
Example 2CLEC-1 expression decreased in acute inflammatory phase and increased in convalescent phase of A.fumigatus keratitis
1. Experimental Material
1.1 Experimental animals
C57BL/6 mice (from experimental animal breeding of Jinnanpunyue Co., Ltd.)
1.2 test fungi
Aspergillus fumigatus 3.0772 strain (China general microbiological culture collection management center)
2. Experimental methods
2.1 fungal preparation
Inoculating Aspergillus fumigatus strain on Sabouraud's medium, and culturing in a constant-temperature incubator at 37 deg.C for 2-3 days. And (4) scraping hyphae and conidia, putting the hyphae and the conidia into 5ml of sterile PBS to form a mixed solution, and filtering the hyphae through sterile gauze. After centrifugation at 4500rpm for 10 min at 4 ℃, the supernatant was discarded and 5ml of bacterial PBS was added to the pellet for resuspension to form a conidia suspension. The conidia concentration was adjusted to 5X 10 with sterile PBS6cfu/ml。
2.2 model mice
An 8-week-old healthy clean grade C57BL/6 female mouse was selected as the subject. Before the experiment, the slit lamp is used for checking and removing eye diseases, and the right eye is selected as the experimental eye. All procedures for the experimental mice were in accordance with the regulations of the Chinese science and technology department for the humanized treatment guidelines for experimental animals (vGKFCZ-2006-.
2.3 expression of CLEC-1 in mouse cornea
2.3.1 Change in expression of CLEC-1 in the Natural course of the keratitis fumigatus mice
C57BL/6 mice were randomly divided into a control group and an A.fumigatus keratitis group. After anesthetizing the mice by intraperitoneal injection of 8% chloral hydrate, 2.5. mu.l of 2.5X 106The cfu/ml conidium suspension was injected into the corneal stroma of the group of A.fumigatus keratitis mice. After modeling, the mouse cornea is observed by a slit lamp microscope every day and photographed, the cornea is taken out 1/2, 1, 2, 3, 5, 7, 10 and 14 days after infection, the expression of CLEC-1 is detected by western blot and qRT-PCR, and the eyeball is taken out for immunofluorescence staining 5 days. 2.3.2 changes in CLEC-1 expression upon therapeutic intervention in A mouse with Aspergillus fumigatus keratitis
The C57BL/6 mice were randomly divided into two groups, and both of them established a model of A.fumigatus keratitis, one group was not treated after the cornea was infected with A.fumigatus, and the other group was treated with natamycin after the cornea was infected with A.fumigatus. After modeling, the mouse cornea is observed by a slit lamp microscope every day and photographed, clinical scores are recorded, and the mouse cornea is taken on the 3 rd day and the 5 th day and is used for detecting the expression of CLEC-1 by qRT-PCR and western blot.
3. Results of the experiment
3.1 Change in expression of CLEC-1 in the Natural course of the mouse with Aspergillus fumigatus keratitis
FIG. 3 is a slit lamp microscope photomicrograph of the Aspergillus fumigatus keratitis mouse model after 1/2, 1, 2, 3, 5, 7, 10, 14 days; FIG. 4 is a graph showing the results of detecting CLEC-1mRNA expression in mouse cornea by qRT-PCR method after 1/2, 1, 2, 3, 5, 7, 10 and 14 days of establishment of the mouse model of Aspergillus fumigatus keratitis; FIG. 5 is a graph showing the results of detecting CLEC-1 protein expression in mouse cornea by the western blot method after 1/2, 1, 2, 3, 5, 7, 10 and 14 days of establishment of the mouse model of the Aspergillus fumigatus keratitis; FIG. 6 is a graph showing the results of detecting CLEC-1 protein expression in mouse cornea by immunofluorescence staining after 5 days of establishment of the mouse model of Aspergillus fumigatus keratitis.
As shown in FIGS. 3 to 6, significant corneal clouding was observed in C57BL/6 mice 1 day after infection with A.fumigatus keratitis and continued for 14 days after infection. With the increase of new blood vessels, keratitis is gradually improved. The corneal CLEC-1 protein level of the mice in the infected group was decreased at 12h after infection and continued until 3d after infection, and the expression of CLEC-1 was significantly increased from day 5 and continued until 14 days after infection, compared with the control group. CLEC-1 has reduced expression in the acute inflammatory phase of mouse aspergillus fumigatus keratitis and increased expression in the convalescent phase.
3.2 Change in CLEC-1 expression upon therapeutic intervention in A.fumigatus keratitis mice
FIG. 7 is a photograph under a slit lamp microscope of a mouse group infected with Aspergillus fumigatus in combination with natamycin treatment groups for 1, 3, 5 days; FIG. 8 is the corneal clinical scores for 3 days and 5 days of the mice group with Aspergillus fumigatus infection in combination with natamycin treatment; FIG. 9 is a graph showing the results of detecting the expression of CLEC-1mRNA in the mouse Aspergillus fumigatus infection group and the Aspergillus fumigatus infection combined natamycin treatment group using qRT-PCR; FIG. 10 is a graph showing the results of detecting the expression of CLEC-1 protein in the A.fumigatus infection group and the A.fumigatus infection combined natamycin treatment group in mice using western blot.
As shown in FIGS. 7-10, natamycin treated the mice with fumagillokeratosis, clinical score decreased and CLEC-1 expression was up-regulated.
Example 3 CLEC-1 overexpression reduces inflammatory response
1. Experimental Material
1.1 Experimental articles
CLEC-1 adenovirus (AAV) vector (Genechem Co., Ltd.)
CLEC-1 lentivirus vector (Genechem corporation)
1.2 test cells
THP-1 macrophage (Chinese Wuhan)
1.3 test fungi
Aspergillus fumigatus 3.0772 strain (China general microbiological culture collection management center)
2. Experimental methods
2.1 in vivo experiments
One eye subconjunctival injection (5 μ l) of 1011vgAAV vector was randomly selected from each mouse. Two weeks later, Enhanced Green Fluorescent Protein (EGFP) was examined with fluorescence stereomicroscope to determine the uniform distribution of the virus in the corneal stroma. And detecting the over-expression of CLEC-1 by adopting qRT-PCR and western blot. The cornea was taken 1 day after infection for MPO detection, immunofluorescence staining, western blot and qRT-PCR.
2.2 in vitro experiments
Human corneal epithelial cells were placed at 37 ℃ in 5% CO2The cells were cultured in the incubator until the cell density reached 80%. CLEC-1 lentiviral vectors were added to THP-1 macrophages for 24 hours of pretreatment. The THP-1 macrophage is infected by aspergillus fumigatus conidium, the infection Multiple (MOI) is 1, and the THP-1 macrophage is collected after 24 hours of treatment to carry out western blot and qRT-PCR detection.
3. Results of the experiment
3.1 in vivo experiments
Fig. 11 is a photograph of EGFP expression in mouse cornea taken with a fluorescence microscope; FIG. 12 is a graph showing the results of detecting CLEC-1mRNA overexpression using qRT-PCR; FIG. 13 is a graph showing the results of detecting the overexpression of CLEC-1 protein using western blot; FIG. 14 is a photograph of corneas of control mice and CLEC-1 overexpression mice 1 day after infection with A.fumigatus keratitis; FIG. 15 is the corneal clinical scores of mice in the control group and mice in the CLEC-1 overexpression group 1 day after infection with A.fumigatus keratitis; FIG. 16 is a graph showing the results of corneal CFU in the control group and CLEC-1 overexpression group of mice 1 day after infection with A.fumigatus keratitis; FIG. 17 is a photograph showing the mean bioluminescence of the cornea of the control group of mice and the CLEC-1 overexpression group of mice 1 day after infection with the A.fumigatus keratitis; FIG. 18 is a graph showing the results of corneal MPO in control mice and CLEC-1 overexpression mice 1 day after infection with A.fumigatus keratitis; FIG. 19 is a graph showing the results of measuring the distribution of neutrophils in the corneas of control mice and CLEC-1 overexpression mice 1 day after infection with A.fumigatus keratitis by immunofluorescence; FIG. 20 is a graph showing the results of detecting CLEC-1mRNA expression in the corneas of normal mice, mice infected with Aspergillus fumigatus keratitis, CLEC-1 overexpressing mice, and CLEC-1 overexpressing combined Aspergillus fumigatus keratitis using the qRT-PCR method; FIG. 21 is a graph showing the results of using a western blot method to detect the expression of CLEC-1 protein in the corneas of normal mice, mice infected with Aspergillus fumigatus keratitis, CLEC-1 overexpression mice, and CLEC-1 overexpression and Aspergillus fumigatus keratitis combined mice.
As shown in FIGS. 11 to 13, overexpression of CLEC-1 was effective. As shown in FIGS. 14-21, following up-regulation of CLEC-1 expression, MPO and CFU levels in the cornea were reduced, neutrophil recruitment was reduced, IL-1 β expression was reduced, fungal burden was increased, and inflammatory response was reduced.
3.2 in vitro experiments
FIG. 22 is a graph showing the results of using qRT-PCR to detect CLEC-1mRNA expression in normal THP-1 macrophages, Aspergillus fumigatus-treated THP-1 macrophages, CLEC-1 overexpressing THP-1 macrophages, and CLEC-1 overexpressing THP-1 macrophages combined with Aspergillus treatment; FIG. 23 is a graph showing the results of detecting CLEC-1 protein expression in normal THP-1 macrophages, Aspergillus fumigatus-treated THP-1 macrophages, CLEC-1 overexpression THP-1 macrophages, and CLEC-1 overexpression combined with Aspergillus-treated THP-1 macrophages using the western blot method.
As shown in FIGS. 22, 23, IL-1. beta. mRNA and protein expression was down-regulated following Aspergillus fumigatus treatment in THP-1 macrophages.
Example 4 kit
Embodiments of the present invention also provide a kit for assessing the timing of administration of a glucocorticoid drug in the treatment of aspergillus fumigatus keratitis. Specifically, the kit comprises a reagent for detecting the CLEC-1 level in the cornea.
Specifically, the kit realizes the detection of the CLEC-1 content based on the immunoblotting technology. The method of use of the kit is briefly described as follows: scraping corneal epithelium of patients with fungal keratitis, and detecting the expression level of CLEC-1 receptor protein in the corneal epithelium by adopting an immunoblotting technology. When significant increase (P < 0.05) occurs in the expression level of CLEC-1 compared with the former expression level, the result is analyzed by using a t test method of two independent samples, namely the time for applying the glucocorticoid medicaments (refer to figure 5).
Based on the molecular biological detection techniques in the art, the detection of the CLEC-1 protein can be achieved by an antigen-antibody immune reaction by a person skilled in the art, for example, by an antibody against the CLEC-1 protein.
The amino acid sequence of the CLEC-1 protein is shown as the following SEQ ID NO. 1:
MQAKYSSTRDMLDDDGDTTMSLHSQGSATTRHPEPRRTEHRAPSSTWRPVALTLLTLCLVLLIGLAALGLLFFQYYQLSNTGQDTISQMEERLGNTSQELQSLQVQNIKLAGSLQHVAEKLCRELYNKAGGYTRNMVPASASSESLRQLPHMGESAAAHRCSPCTEQWKWHGDNCYQFYKDSKSWEDCKYFCLSENSTMLKINKQEDLEFAASQSYSEFFYSYWTGLLRPDSGKAWLWMDGTPFTSELFHIIIDVTSPRSRDCVAILNGMIFSKDCKELKRCVCERRAGMVKPESLHVPPETLGEGD。
the CLEC-1 protein is derived from different individuals and different species, has certain sequence difference, belongs to homologous proteins in nature, and can be used as a marker of glucocorticoid medicaments used in fungal keratitis, so the CLEC-1 can be a protein shown in SEQ ID NO.1 or a protein with homology of at least 95%, 96%, 97%, 98% and 99% with the SEQ ID NO. 1; by detecting CLEC-1 homologous protein, the medication time of glucocorticoid medicaments in fungal keratitis can be determined.
On the basis that the sequence of the CLEC-1 protein to be detected is known, the anti-CLEC-1 protein antibody can be easily obtained by a person skilled in the art, and the detection of the CLEC-1 protein can be realized by any anti-CLEC-1 protein antibody. Based on the fact, the antibody of the CLEC-1 protein with any structure or sequence only needs to be used for detecting the CLEC-1 protein to prepare a kit for guiding the application of glucocorticoid medicaments in fungal keratitis, and the kit belongs to the protection scope of the invention.
The technology for realizing the detection of the CLEC-1 protein through antigen-antibody immunization comprises but is not limited to immunoblotting technology, and the detection of the CLEC-1 protein by other similar methods also belongs to the protection scope of the invention.
It will be understood by those of ordinary skill in the art that the foregoing embodiments are specific examples for carrying out the invention, and that various changes in form and details may be made therein without departing from the spirit and scope of the invention in practice.
SEQUENCE LISTING
<110> affiliated Hospital of Qingdao university
Application of <120> C-type lectin-like receptor-1 as treatment marker of fungal keratitis
<130> 210231CN-CH-I
<160> 1
<170> PatentIn version 3.3
<210> 1
<211> 307
<212> PRT
<213> Homo sapiens
<400> 1
Met Gln Ala Lys Tyr Ser Ser Thr Arg Asp Met Leu Asp Asp Asp Gly
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Asp Thr Thr Met Ser Leu His Ser Gln Gly Ser Ala Thr Thr Arg His
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Pro Glu Pro Arg Arg Thr Glu His Arg Ala Pro Ser Ser Thr Trp Arg
35 40 45
Pro Val Ala Leu Thr Leu Leu Thr Leu Cys Leu Val Leu Leu Ile Gly
50 55 60
Leu Ala Ala Leu Gly Leu Leu Phe Phe Gln Tyr Tyr Gln Leu Ser Asn
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Thr Gly Gln Asp Thr Ile Ser Gln Met Glu Glu Arg Leu Gly Asn Thr
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Ser Gln Glu Leu Gln Ser Leu Gln Val Gln Asn Ile Lys Leu Ala Gly
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Ser Leu Gln His Val Ala Glu Lys Leu Cys Arg Glu Leu Tyr Asn Lys
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Ala Gly Gly Tyr Thr Arg Asn Met Val Pro Ala Ser Ala Ser Ser Glu
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Ser Leu Arg Gln Leu Pro His Met Gly Glu Ser Ala Ala Ala His Arg
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Cys Ser Pro Cys Thr Glu Gln Trp Lys Trp His Gly Asp Asn Cys Tyr
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Gln Phe Tyr Lys Asp Ser Lys Ser Trp Glu Asp Cys Lys Tyr Phe Cys
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Leu Ser Glu Asn Ser Thr Met Leu Lys Ile Asn Lys Gln Glu Asp Leu
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Glu Phe Ala Ala Ser Gln Ser Tyr Ser Glu Phe Phe Tyr Ser Tyr Trp
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Gly Thr Pro Phe Thr Ser Glu Leu Phe His Ile Ile Ile Asp Val Thr
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Ser Pro Arg Ser Arg Asp Cys Val Ala Ile Leu Asn Gly Met Ile Phe
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275 280 285
Gly Met Val Lys Pro Glu Ser Leu His Val Pro Pro Glu Thr Leu Gly
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Claims (7)
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