Alpha-2-Macroglobulin as a New Promising Biomarker Improving the Diagnostic Sensitivity of Bovine Paratuberculosis

Park, Hyun-Eui; Park, Jin-Sik; Park, Hong-Tae; Choi, Jeong-Gyu; Shin, Jeong-Ih; Jung, Myunghwan; Kang, Hyung-Lyun; Baik, Seung‐Chul; Kim, Donghyuk; Yoo, Han Sang; Shin, Min-Kyoung

doi:10.3389/fvets.2021.637716

Cited by 7 publications

(3 citation statements)

References 43 publications

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“…Host biomarkers have been postulated as tools to develop novel diagnostic methods for PTB. − Some have been validated for detection of naturally infected cattle in various stages of Map infection. − Several proteomic studies to investigate the host proteome response to mycobacterial infections and specifically to Map infection have been performed to identify biomarkers of Map infection for development of new diagnostic tools. These studies might also help to identify potential candidate genes for selective breeding programs to enhance resistance or tolerance to PTB .…”

Section: Introductionmentioning

confidence: 99%

Proteomic Serum Profiling of Holstein Friesian Cows with Different Pathological Forms of Bovine Paratuberculosis Reveals Changes in the Acute-Phase Response and Lipid Metabolism

Navarro León,

Muñoz,

Iglesias

et al. 2023

J. Proteome Res.

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The lack of sensitive diagnostic methods to detect Mycobacterium avium subsp. paratuberculosis (Map) subclinical infections has hindered the control of paratuberculosis (PTB). The serum proteomic profiles of naturally infected cows presenting focal and diffuse pathological forms of PTB and negative controls (n = 4 per group) were analyzed using TMT-6plex quantitative proteomics. Focal and diffuse are the most frequent pathological forms in subclinical and clinical stages of PTB, respectively. One (focal versus (vs.) control), eight (diffuse vs. control), and four (focal vs. diffuse) differentially abundant (DA) proteins (q-value < 0.05) were identified. Ingenuity pathway analysis of the DA proteins revealed changes in the acute-phase response and lipid metabolism. Six candidate biomarkers were selected for further validation by specific ELISA using serum from animals with focal, multifocal, and diffuse PTB-associated lesions (n = 108) and controls (n = 56). Overall, the trends of the serum expression levels of the selected proteins were consistent with the proteomic results. Alpha-1-acid glycoprotein (ORM1)-based ELISA, insulin-like growth factor-binding protein 2 (IGFBP2)-based ELISA, and the anti-Map ELISA had the best diagnostic performance for detection of animals with focal, multifocal, and diffuse lesions, respectively. Our findings identify potential biomarkers that improve diagnostic sensitivity of PTB and help to elucidate the mechanisms involved in PTB pathogenesis.

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Section: Introductionmentioning

confidence: 99%

Proteomic Serum Profiling of Holstein Friesian Cows with Different Pathological Forms of Bovine Paratuberculosis Reveals Changes in the Acute-Phase Response and Lipid Metabolism

Navarro León,

Muñoz,

Iglesias

et al. 2023

J. Proteome Res.

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“…The authors concluded that these molecules could show potential as putative biomarkers of PTB infection, especially for identification of subclinical animals showing pathological forms related to latency or resistance to the development of advance lesions. Park et al ( 89 ) identified alpha-2-macroglobulin (A2M) as a new promising biomarker improving the diagnostic sensitivity of bovine PTB. They showed that serum A2M levels were significantly higher in Map-exposed ( n = 20), subclinical shedder ( n = 27), subclinical non-shedder ( n = 50) and clinical shedder ( n = 18) groups that in the healthy control group ( n = 11, from a PTB free farm, negative by fecal PCR and IDEXX and ID Vet ELISA).…”

Section: Discussionmentioning

confidence: 99%

Use of ATP-Binding Cassette Subfamily A Member 13 (ABCA13) for Sensitive Detection of Focal Pathological Forms of Subclinical Bovine Paratuberculosis

et al. 2022

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Bovine paratuberculosis (PTB) is a chronic enteritis caused by Mycobacterium avium subspecies paratuberculosis (Map) that causes a heavy economic impact worldwide. Map infected animals can remain asymptomatic for years while transmitting the mycobacteria to other members of the herd. Therefore, accurate detection of subclinically infected animals is crucial for disease control. In a previous RNA-Seq study, we identified several mRNAs that were overexpressed in whole blood of cows with different PTB-associated histological lesions compared with control animals without detected lesions. The proteins encoded by two of these mRNAs, ATP binding cassette subfamily A member 13 (ABCA13) and Matrix Metallopeptidase 8 (MMP8) were significantly overexpressed in whole blood of animals with focal histological lesions, the most frequent pathological form in the subclinical stages of the disease. In the current study, the potential of sensitive early diagnostic tools of commercial ELISAs, based on the detection of these two biomarkers, was evaluated in serum samples of 704 Holstein Friesian cows (566 infected animals and 138 control animals from PTB-free farms). For this evaluation, infected animals were classified into three groups, according to the type of histological lesions present in their gut tissues: focal (n = 447), multifocal (n = 59), and diffuse (n = 60). The ELISA based on the detection of ABCA13 was successfully validated showing good discriminatory power between animals with focal lesions and control animals (sensitivity 82.99% and specificity 80.43%). Conversely, the MMP8-based ELISA showed a poor discriminatory power between the different histological groups and non-infected controls. The ABCA13-based ELISA showed a higher diagnostic value (0.822) than the IDEXX ELISA (0.517), the fecal bacterial isolation (0.523) and the real-time PCR (0.531) for the detection of animals with focal lesions. Overall, our results indicate that this ABCA13 ELISA greatly improves the identification of subclinically infected animals with focal lesions that are undetectable using current diagnostic methods.

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“…Recently, attempts have been made to overcome the difficulty of diagnosing MAP in the subclinical stage. Differentially expressed serum proteins were identified by proteomic profiling and ELISA was performed to discover a potential novel biomarker called A2M [ 10 ]. There was also a study using the NanoString nCounter technology that suggested a combination of four miRNAs that are distinguished from the negative control group as biomarkers according to the severity of JD [ 11 ].…”

Section: Introductionmentioning

confidence: 99%

MicroRNA profiling in bovine serum according to the stage of Mycobacterium avium subsp. paratuberculosis infection

et al. 2021

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Mycobacterium avium subsp. paratuberculosis (MAP) is the causative agent of Johne’s disease (JD), and it causes diarrhea and weakness in cattle. During a long subclinical stage, infected animals without clinical signs shed pathogens through feces. For this reason, the diagnosis of JD during the subclinical stage is very important. Circulating miRNAs are attracting attention as useful biomarkers in various veterinary diseases because of their expression changes depending on the state of the disease. Based on current knowledge, circulating miRNAs extracted from bovine serum were used to develop a diagnostic tool for JD. In this study, the animals were divided into 4 groups according to fecal shedding, the presence of antibodies, and clinical signs. Gene expression was analyzed by performing miRNA sequencing for each group, and it was identified that the miRNA expression changed more as the MAP infection progressed. The eight miRNAs that were differentially expressed in all infected groups were selected as biomarker candidates based on their significant differences compared to the control group. These biomarker candidates were validated by qRT-PCR. Considering the sequencing data, two upregulated miRNAs and two downregulated miRNAs showed the same trend in the validation results. Network analysis was also conducted and the results showed that mRNAs (IL-10, TGF-β1) associated with regulatory T cells were predicted to be activated in the subclinical stage. Taken together, our data suggest that two miRNAs (bta-miR-374b, bta-miR-2887) may play major roles in the immune response to MAP infection during the subclinical stage.

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Alpha-2-Macroglobulin as a New Promising Biomarker Improving the Diagnostic Sensitivity of Bovine Paratuberculosis

Cited by 7 publications

References 43 publications

Proteomic Serum Profiling of Holstein Friesian Cows with Different Pathological Forms of Bovine Paratuberculosis Reveals Changes in the Acute-Phase Response and Lipid Metabolism

Proteomic Serum Profiling of Holstein Friesian Cows with Different Pathological Forms of Bovine Paratuberculosis Reveals Changes in the Acute-Phase Response and Lipid Metabolism

Use of ATP-Binding Cassette Subfamily A Member 13 (ABCA13) for Sensitive Detection of Focal Pathological Forms of Subclinical Bovine Paratuberculosis

MicroRNA profiling in bovine serum according to the stage of Mycobacterium avium subsp. paratuberculosis infection

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