Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight

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Early detection of M. bovis is crucial for its effective management because of its immune evasion strategies and resistance to antimicrobial therapies. In this review, we systematically assessed the diagnostic potential of P48 protein, an immunodominant lipoprotein of M. bovis, along with other potential biomarkers. The aim was to provide a comprehensive understanding of P48’s diagnostic utility through both literature analysis and computational insights. A literature search across major databases identified 243 relevant articles, 20 of which were selected based on predefined inclusion criteria. These studies consistently highlight P48’s diagnostic value due to its stability, immunodominance, and strong antibody response in infected cattle. In addition, a molecular analysis using the Expasy ProtParam tool reveals that P48 exhibits favorable properties for diagnostics, including a theoretical isoelectric point (pI) of 7.14, an instability index of 23.64 (classifying it as stable), and an aliphatic index of 83.40, indicating significant thermostability. The review also considers other diagnostic proteins, such as Variable Surface Proteins (VSPs), MbovP proteins, and MilA, although their variable nature and lesser validation across assays limit their broader application. In contrast, P48 is a reliable and specific marker, particularly in serological assays, for the early and accurate detection of M. bovis infections. This study confirms P48’s diagnostic efficacy over other biomarkers, and advocates its inclusion in diagnostic protocols." } { "@context": "http://schema.org", "@type": "BreadcrumbList", "itemListElement": [ { "@type": "ListItem", "position": "1", "item": { "@id": "https://f1000research.com/", "name": "Home" } }, { "@type": "ListItem", "position": "2", "item": { "@id": "https://f1000research.com/browse/articles", "name": "Browse" } }, { "@type": "ListItem", "position": "3", "item": { "@id": "https://f1000research.com/articles/14-497/v1", "name": "Systematic identification of P48 as an advantageous diagnostic protein..." } } ] } Home Browse Systematic identification of P48 as an advantageous diagnostic protein... ALL Metrics - Views Downloads Get PDF Get XML Cite How to cite this article Fasogbon IV, Ondari EN, Tusubira D et al. Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.12688/f1000research.163124.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. Close Copy Citation Details Export Export Citation Sciwheel EndNote Ref. Manager Bibtex ProCite Sente EXPORT Select a format first Track Share ▬ ✚ Systematic Review Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] Ilemobayo Victor Fasogbon https://orcid.org/0000-0003-4362-9004 1 , Erick Nyakundi Ondari https://orcid.org/0000-0002-1498-6486 2 , Deusdedit Tusubira https://orcid.org/0000-0002-4698-424X 3 , [...] Angela Mumbua Musyoka https://orcid.org/0009-0001-4444-256X 1 , Bashiru Ibrahim 4 , Kabiru Haliru Ahmad https://orcid.org/0000-0002-6135-553X 5 , Tonny Kabuuka https://orcid.org/0000-0001-5363-6254 6 , Loganathan Rangasamy 7 , Patrick Maduabuchi Aja https://orcid.org/0009-0006-2450-9460 1 Ilemobayo Victor Fasogbon https://orcid.org/0000-0003-4362-9004 1 , Erick Nyakundi Ondari https://orcid.org/0000-0002-1498-6486 2 , [...] Deusdedit Tusubira https://orcid.org/0000-0002-4698-424X 3 , Angela Mumbua Musyoka https://orcid.org/0009-0001-4444-256X 1 , Bashiru Ibrahim 4 , Kabiru Haliru Ahmad https://orcid.org/0000-0002-6135-553X 5 , Tonny Kabuuka https://orcid.org/0000-0001-5363-6254 6 , Loganathan Rangasamy 7 , Patrick Maduabuchi Aja https://orcid.org/0009-0006-2450-9460 1 PUBLISHED 15 May 2025 Author details Author details 1 Department of Biochemistry, Kampala International University, Ishaka, Uganda 2 Department of Biological Sciences, School of Pure & Applied Sciences, Kisii University, Kisii, Kisii County, Kenya 3 Department of Biochemistry, Mbarara University of Science and Technology, Mbarara, Western Region, Uganda 4 Biochemistry, Ahmadu Bello University, Zaria, Kaduna, Nigeria 5 Department of Veterinary Microbiology, Ahmadu Bello University, Zaria, Kaduna, Nigeria 6 National Livestock Resources Research Institute (NaLIRRI), Infectious Animal Diseases Laboratory,, National Agricultural Research Organisation(NARO), Totoro, Central Region, Uganda 7 Drug Discovery Unit, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore, Tamil Nadu, India Ilemobayo Victor Fasogbon Roles: Conceptualization, Data Curation, Funding Acquisition, Methodology, Resources, Writing – Original Draft Preparation Erick Nyakundi Ondari Roles: Resources, Supervision, Writing – Review & Editing Deusdedit Tusubira Roles: Resources, Supervision, Writing – Review & Editing Angela Mumbua Musyoka Roles: Data Curation, Methodology, Writing – Original Draft Preparation Bashiru Ibrahim Roles: Validation, Writing – Review & Editing Kabiru Haliru Ahmad Roles: Validation, Writing – Review & Editing Tonny Kabuuka Roles: Resources, Validation, Writing – Review & Editing Loganathan Rangasamy Roles: Validation, Writing – Review & Editing Patrick Maduabuchi Aja Roles: Conceptualization, Data Curation, Supervision, Writing – Review & Editing OPEN PEER REVIEW DETAILS REVIEWER STATUS This article is included in the Pathogens gateway. Abstract Mycoplasma bovis (M. bovis) is a significant pathogen in cattle that causes respiratory disease, mastitis, and arthritis, leading to substantial economic losses globally. Early detection of M. bovis is crucial for its effective management because of its immune evasion strategies and resistance to antimicrobial therapies. In this review, we systematically assessed the diagnostic potential of P48 protein, an immunodominant lipoprotein of M. bovis , along with other potential biomarkers. The aim was to provide a comprehensive understanding of P48’s diagnostic utility through both literature analysis and computational insights. A literature search across major databases identified 243 relevant articles, 20 of which were selected based on predefined inclusion criteria. These studies consistently highlight P48’s diagnostic value due to its stability, immunodominance, and strong antibody response in infected cattle. In addition, a molecular analysis using the Expasy ProtParam tool reveals that P48 exhibits favorable properties for diagnostics, including a theoretical isoelectric point (pI) of 7.14, an instability index of 23.64 (classifying it as stable), and an aliphatic index of 83.40, indicating significant thermostability. The review also considers other diagnostic proteins, such as Variable Surface Proteins (VSPs), MbovP proteins, and MilA, although their variable nature and lesser validation across assays limit their broader application. In contrast, P48 is a reliable and specific marker, particularly in serological assays, for the early and accurate detection of M. bovis infections. This study confirms P48’s diagnostic efficacy over other biomarkers, and advocates its inclusion in diagnostic protocols. READ ALL READ LESS Keywords Mycoplasma bovis, Diagnosis, Biomarker, P48 protein. Corresponding Author(s) Ilemobayo Victor Fasogbon ( [email protected] ) Close Corresponding author: Ilemobayo Victor Fasogbon Competing interests: No competing interests were disclosed. Grant information: This study was financially supported by the African German Network of Excellence in Science (AGNES) through an AGNES Intra-Africa Mobility Grant for Junior Researchers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Copyright: © 2025 Fasogbon IV et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. How to cite: Fasogbon IV, Ondari EN, Tusubira D et al. Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.12688/f1000research.163124.1 ) First published: 15 May 2025, 14 :497 ( https://doi.org/10.12688/f1000research.163124.1 ) Latest published: 15 May 2025, 14 :497 ( https://doi.org/10.12688/f1000research.163124.1 ) Introduction Mycoplasma bovis (M. bovis) is a significant opportunistic pathogen responsible for causing various diseases and economic losses in cattle worldwide, affecting both dairy and beef industries ( Ammar et al ., 2021 ; Ohtsuka et al ., 2019 ; James et al ., 2013 ). This bacterium is known for its ability to cause a wide range of clinical manifestations, including bovine respiratory disease (BRD), mastitis, arthritis, and otitis media, affecting cattle of all ages. Initially, M. bovis was considered to be a harmless commensal microorganism found in the lungs of healthy cattle. However, over time, it has emerged as one of the primary pathogens contributing to multiorgan infections in cattle, with serious implications for animal welfare and farm productivity ( Maunsell & Chase, 2019 ). The ability of the pathogen to cause chronic, often subclinical, infections and its capacity for immune evasion complicates its management and control ( Buchenau et al ., 2010 ; Rosengarten et al ., 1994 ). This is further exacerbated by its resistance to common antimicrobial treatments and the lack of an effective vaccine, making rapid and accurate diagnostic methods essential for managing M. bovis infections ( Fasogbon et al ., 2024 ; Zengin et al ., 2024 ; Hasoon et al ., 2023 ). Despite the availability of diagnostic tools, current methods often fail to provide accurate, early detection, which hinders effective disease management and control measures ( Shirani et al ., 2020 ; Fu et al ., 2014c ). The identification of diagnostic biomarkers is essential to improve the detection and management of M. bovis infections. Such biomarkers can be proteins, antigens, or nucleotides that indicate disease conditions. Proteins and protein antigens offer compelling advantages as diagnostic biomarkers because they directly reflect biological activity. Proteins actively participate in physiological processes, meaning that changes in their levels can provide real-time insights into the presence or progression ( Lino et al ., 2022 ). Additionally, many proteins undergo post-translational modifications, which can serve as highly specific indicators of certain conditions, offering a level of detail that is not available with DNA or RNA biomarkers ( Chu et al ., 2021 ). Moreso proteins are often more easily detectable in accessible body fluids, such as blood or urine, making them practical for routine diagnostics ( Lino et al ., 2022 ). Various molecular methods, including polymerase chain reaction (PCR), enzyme-linked immunosorbent assay (ELISA), and proteomic approaches, have been employed to identify potential protein and gene markers specific to M. bovis ( Kumar et al ., 2014 ; Zubair et al ., 2020 ). However, variability in these markers, such as variable surface proteins (Vsp) and nucleomodulins, has introduced complexities in achieving consistent and reliable diagnostics ( Lu et al ., 2024 ; Behrens et al ., 1994 ). This study aimed to consolidate the available literature on potential diagnostic proteins and protein antigens of M. bovis. By evaluating the identification methods and diagnostic efficacy of these proteins, we sought to bridge the gap between bench research and clinical applications, thereby offering insights into the most promising candidates for future diagnostic tools ( Ayan et al ., 2023 ; Dawood et al ., 2023 ). Methods Search strategy and outcome A comprehensive literature search was conducted on 31 st August, 2024 to identify the diagnostic proteins relevant to M. bovis. The search targeted the major scientific databases Scopus , Web of Science (WoS) , and PubMed, using the search terms Mycoplasma bovis, diagnosis/detection, and protein. The search fields were the title, abstract, and keywords. Boolean operators (AND/OR/NOT) were used to develop search strategies ( Table 1 ) tailored to each database ( Fasogbon et al ., 2023 , 2024 ; Mitaki et al ., 2024 ). No date limits were applied, and the search was restricted to original, peer-reviewed articles published in English . The search yielded 243 articles from the three databases. This included 115 articles from Scopus, 88 from the Web of Science, and 40 from PubMed. Table 1. Search strategy. Database Search strategy Search field Scopus “Mycoplasma bovis” AND (diagnos* OR detect*) AND protein Title/Abstract/Keywords WoS “Mycoplasma bovis” AND (diagnos* OR detect*) AND protein Topic PubMed (( Mycoplasma bovis [Title/Abstract]) AND ((diagnos*[Title/Abstract]) OR (detect*[Title/Abstract])) AND (protein [Title/Abstract])) Title/Abstract Selection criteria and process The paper selection process followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 guidelines ( Page et al ., 2021 ; Swase et al ., 2025 ). The inclusion and exclusion criteria ( Table 2 ) were used to select articles to be reviewed in the study. A total of 101 duplicate articles were removed owing to duplicated entries from the databases, resulting in 142 unique articles for screening. The titles and abstracts of the remaining 142 articles were screened to determine their relevance to the research objective. The screening was done by two independent reviewers (Ilemobayo Victor Fasogbon and Angela Mumbua Musyoka) via an online platform, Rayyan ( https://new.rayyan.ai/ ) ( Johnson & Phillips, 2018 ) to ensure objectivity. As illustrated in Figure 1 , after screening, 52 articles were selected for the full-text review. A thorough review of the full text of the 52 articles was conducted. After excluding irrelevant articles based on the inclusion criteria, 20 articles were deemed eligible for inclusion in the systematic review, as outlined in Table 2 . Table 2. Selection criteria. Inclusion criteria Exclusion criteria Studies that focused on identifying diagnostic proteins specific to M. bovis. Studies focused on Mycobacterium bovis or other pathogens. Studies reporting proteins or protein antigens that aid the detection of M. bovis in bovine samples . Studies that report other diagnostic biomarkers aside proteins or protein antigens. Original peer-review articles were included. Non-research articles such as reviews, conference abstracts, or grey literature were excluded. Studies published in English language. Non-English publications were excluded. Figure 1. PRISMA flowchart of screening process. Data extraction Two independent reviewers (Ilemobayo Victor Fasogbon and Angela Mumbua Musyoka) extracted the following data from each of the 20 included articles: • Diagnostic proteins or protein antigens : Specific protein or protein antigens reported in the study were identified. • Method of identification : Techniques involved in the identification of proteins or protein antigens, such as PCR , ELISA , proteomic analysis, or western blotting . • Diagnostic evaluation : The study assessed the diagnostic sensitivity and specificity of the identified proteins or protein antigens. • Author, year of study and other meta-data : The identity of the study and year of study were also identified from the 20 included records. Molecular properties of P48 protein prediction The primary sequence of the P48 protein was downloaded from the UniProt database with the ID A0A1S6K889. Protein properties were predicted using the Expasy ProtParam tool ( Gasteiger et al ., 2005 ). The server was used to predict the number and composition of amino acids in the sequence, molecular weight (Da), theoretical isoelectric point (pI), instability index, aliphatic index, GRAVY (Grand Average of Hydropathicity), total number of negatively charged residues (Asp + Glu), total number of positively charged residues (Arg + Lys), extinction coefficient (M −1 cm −1 , assuming all pairs of Cys residues form cystines), extinction coefficient (M −1 cm −1 , assuming all Cys residues are reduced), estimated half-life (mammalian reticulocytes, in vitro ), estimated half-life (yeast, in vivo ), and estimated half-life ( Escherichia coli , in vivo ) of the protein. Results Identified proteins and protein antigens This systematic review analyzed 20 studies that focused on identifying diagnostic proteins and protein antigens for M. bovis proteins. These proteins have varying levels of diagnostic potential, and have been identified through diverse methods such as PCR, recombinant protein expression, proteomics, and ELISA. Table 3 presents a summary of the diagnostic molecules identified in the 20 studies along with their detection methods and evaluation of diagnostic efficacy. Table 3. Identified putative diagnostic protein of Mycoplasma bovis. Putative diagnostic protein Detection methods Diagnostic evaluation References P48 Recombinant protein expression, PCR, ELISA, ELAA Yes James et al . (2013) , Fu et al . (2014a , 2014b) , Robino et al . (2005) Variable Surface Proteins Monoclonal antibodies, SDS-PAGE, Western blotting, PCR Yes Behrens et al . (1994) , Brank et al . (1999) , Buchenau et al . (2010) MbovP Proteins Proteomics, 2D Gel Electrophoresis, MALDI-TOF-MS, Immunoinformatics Yes Zhang et al . (2021) , Zubair et al . (2020) , Shirani et al . (2020) , Lysnyansky et al . (1996) MilA Protein Phage-based ELISA, Western Blotting Yes Wawegama et al . (2014) , Farzaneh et al . (2022) Interleukin-17A Proteomic Analysis Yes Ohtsuka et al . (2019) Pyruvate Dehydrogenase E1 2D Gel Electrophoresis, Immunoblotting, MALDI-TOF-MS Yes Sun et al . (2014) Cyclooxygenase-2 & Immunohistochemical Labeling No Rodriguez et al . (2015) GAPDH Protein RFLP, PCR No Perez-Casal and Prysliak (2007) Alpha Enolase Cloning, Expression, Purification, Immunofluorescence Labeling No Song et al . (2012) Haptoglobin & Serum Amyloid A - Yes Saher et al . (2024) uvrC PCR Yes Subramaniam et al . (1998) Description of the diagnostic proteins • P48 protein : The P48 protein is one of the most frequently reported diagnostic biomarkers for M. bovis. P48 is a well-established immunodominant lipoprotein in M. bovis and is used as a specific marker for infection, with consistent results showing a high sensitivity and specificity ( James et al ., 2013 ; Fu et al ., 2014c ). Detection methods such as PCR , competitive ELISA, and ELAA have been used to accurately identify P48 in infected cattle. These findings strongly support the inclusion of P48 in routine diagnostic assays for M. bovis because of its comparative advantages ( Figure 2 ) . • Variable Surface Proteins (VSPs) : VSPs (including VspA, VspB, and VspC) are a group of surface-expressed proteins in M. bovis that undergo antigenic variations. They play a key role in immune evasion but are useful for diagnostics because they trigger immune responses. Their variability allows for the differentiation between strains and can aid in epidemiological tracking. They are often detected using techniques like Western blotting and SDS-PAGE ( Behrens et al ., 1994 ; Brank et al ., 1999 ). However, their variability poses challenges for standardization of diagnostic assays. • MbovP proteins: The MbovP proteins, including MbovP274, MbovP570, and others, were identified primarily using proteomic approaches. These proteins are surface-exposed and are involved in pathogen-host interactions. MbovP proteins are valuable biomarkers for detecting M. bovis because of their role in stimulating host immune responses, making them potential targets for serodiagnostic tools. These proteins are increasingly recognized as promising biomarkers owing to their high antigenicity and unique expression patterns in M. bovis ( Zhang et al ., 2021 ; Zubair et al ., 2020 ). MALDI-TOF-MS and immunoinformatic approaches have significantly enhanced the identification of these proteins, leading to their potential inclusion in future diagnostic assays. • MilA protein: The MilA protein, an immunogenic lipase, was shown to demonstrate strong reactivity in phage-based ELISA assays ( Wawegama et al ., 2014 ; Farzaneh et al ., 2022 ). MilA is a putative virulence factor whose diagnostic relevance is tied to its immunogenicity, making it an excellent candidate for inclusion in serological diagnostics of M. bovis. • Interleukin-17A: IL-17A is a cytokine involved in the immune response and has been identified as a putative diagnostic marker. In M. bovis infections, elevated levels of IL-17A may indicate an active inflammatory response, making it a potential marker of immune system involvement in disease progression. ( Ohtsuka et al ., 2019 ). • Pyruvate dehydrogenase E1: Pyruvate dehydrogenase E1 (PDH E1) component beta subunit (PDHB) in M. bovis has been identified as an immunogenic protein with high immune reactivity. It shows potential for diagnostic applications owing to its ability to elicit a strong immune response, making it a candidate for assays such as indirect ELISA ( Sun et al ., 2014 ). • Cyclooxygenase-2 (COX-2) and GAPDH protein: COX-2 are involved in the inflammatory response. Elevated COX-2 expression during M. bovis infection may indicate inflammation, whereas M. bovis GAPDH results in a strong humoral immune response; hence, it is a putative candidate for diagnostics and vaccine development ( Rodriguez et al ., 2015 ; Perez-Casal and Prysliak, 2007 ). • Alpha enolase: Alpha-enolase in M. bovis diagnosis plays a crucial role as an adhesion-related factor in M. bovis diagnosis. It facilitates adherence by binding to the host plasminogen, aiding in the pathogen’s colonization and evasion of host defenses ( Song et al ., 2012 ). This protein, found on the bacterial surface and in membrane fractions, is essential for understanding the pathogenicity of M. bovis . • Haptoglobin & Serum Amyloid A (SAA): Haptoglobin is an acute-phase protein that responds to inflammation and infection, making it useful for detecting the early stages of the disease. For an accurate diagnosis, monitoring haptoglobin levels alongside other biomarkers, such as serum amyloid A, enhances sensitivity ( Saher et al ., 2024 ). Their increase during M. bovis infection makes them non-specific but valuable indicators of ongoing inflammation and disease severity. • uvrC product: Deoxyribodipyrimidine photolyase, encoded by uvrC, plays a crucial role in the repair of DNA damage caused by UV light in M. bovis. This enzyme is a part of the excision DNA repair system, making it a specific target for genetic detection. In diagnostic applications, the uvrC gene is utilized for PCR-based assays to detect and identify M. bovis efficiently ( Subramaniam et al ., 1998 ). Figure 2. Advantages of P48 protein as diagnostic target of M. bovis infection. Molecular properties and stability of the P48 protein The P48 protein was found to possess excellent molecular properties, as predicted by the Expasy ProtParam tool, thus corroborating the findings of this systematic review. The theoretical isoelectric point (pI) of the P48 protein was calculated to be 7.14 ( Table 4 ), suggesting that it carries no net charge at near-neutral pH, which is a common feature of proteins that interact in a neutral physiological environment. A key indicator of protein stability is its instability index, calculated as 23.64. This value categorizes the P48 protein as stable, which is advantageous for its potential use in biosensor applications, where structural integrity over time is critical. Furthermore, the aliphatic index (83.40 points to a high level of thermostability, which is particularly beneficial for a protein that may be exposed to varying environmental conditions during diagnostic assays. The grand average hydrophobicity (GRAVY) score of -0.349 indicates that the P48 protein is mildly hydrophilic, which may influence its solubility and interaction with other biomolecules in aqueous environments. The protein extinction coefficient, a critical parameter for determining protein concentration via absorbance at 280 nm, is 40,340 M −1 cm −1 , assuming that all cysteine residues form disulfide bonds. This same value applies if cysteine residues are reduced, which is consistent with the minimal presence of cysteine. The calculated absorbance at 280 nm for a 0.1% solution of the protein was 0.981, providing a useful measure for quantifying proteins in laboratory settings. Regarding the protein’s turnover, the estimated half-life varies significantly across different biological systems: 5.5 hours in mammalian reticulocytes ( in vitro ), 3 minutes in yeast ( in vivo ), and 2 minutes in Escherichia coli ( in vivo ). These differences highlight the varying stability of the P48 protein across different cellular environments, which could influence its function and longevity during infection or when used as a diagnostic tool. The amino acid (all amino acids named in this work and their 3-letter representation are presented in supplementary file 2) ( Fasogbon et al. , 2025 ). composition of P48 ( Table 5 ) provides further insight into its structure and function. Alanine (Ala) and lysine (Lys) were the most abundant residues, comprising 10.6% of the total amino acids. This high lysine content may contribute to the ability of the protein to interact with negatively charged molecules such as DNA or acidic polysaccharides. The presence of cysteine (Cys), although minimal at 0.3%, is significant for the formation of disulfide bonds, which could further stabilize the structure of the protein. The atomic composition, represented by 1853 carbon, 2901 hydrogen, 485 nitrogen, 568 oxygen, and 2 sulfur atoms, contributed to the overall structural and functional attributes of the protein, resulting in a chemical formula of C 1853 H 2901 N 485 O 568 S 2 . Table 4. Molecular properties of P48 protein. Property Value Number of amino acids 377 Molecular weight (Da) 41125.45 Theoretical pI 7.14 Instability index 23.64 Aliphatic index 83.4 GRAVY (Grand Average of Hydropathicity) -0.349 Total number of negatively charged residues (Asp + Glu) 47 Total number of positively charged residues (Arg + Lys) 47 Extinction coefficient (M -1 cm -1 , assuming all pairs of Cys residues form cystines) 40340 Extinction coefficient (M -1 cm -1 , assuming all Cys residues are reduced) 40340 Estimated half-life (Mammalian reticulocytes, in vitro ) 5.5 hours Estimated half-life (Yeast, in vivo ) 3 minutes Estimated half-life ( Escherichia coli , in vivo ) 2 minutes Table 5. Amino acid composition of the P48 protein. Amino acid Composition (%) Amino acid Composition (%) Ala (A) 10.6 Leu (L) 6.4 Arg (R) 1.9 Lys (K) 10.6 Asn (N) 5.6 Met (M) 0.3 Asp (D) 5.8 Phe (F) 4.8 Cys (C) 0.3 Pro (P) 3.2 Gln (Q) 3.4 Ser (S) 7.4 Glu (E) 6.6 Thr (T) 4.8 Gly (G) 8.2 Trp (W) 0.8 His (H) 1.3 Tyr (Y) 4.2 Ile (I) 8 Val (V) 5.8 Given these detailed molecular properties, P48 has emerged as a robust candidate for diagnostic applications, particularly in the context of M. bovis infection. The stability and specific molecular characteristics of P48 make it an ideal target for the development of peptide aptamers and biosensors. Discussion The P48 protein emerged as a highly valuable diagnostic biomarker for M. bovis infection because of its distinct immunological characteristics. One of the most significant advantages of P48 is immunodominance. Several studies, including those by Robino et al . (2005) and Fu et al . (2014c) , have demonstrated that P48 elicits a strong and consistent antibody response in infected cattle, making it a reliable target for diagnostic assays, such as ELISA and Western blotting. Unlike the variable surface proteins (VSPs) of M. bovis , which are known for their high-frequency phase variation, P48 remains structurally and antigenically conserved across different field isolates of M. bovis ( Robino et al ., 2005 ). This stability makes P48 a more reported candidate for diagnostic applications than VSPs, which may evade detection due to their variability ( Behrens et al ., 1994 ). In their development of a direct competitive ELISA (Dc-ELISA), Fu et al . (2014c) confirmed that P48 showed no cross-reactivity with other pathogens such as Mycoplasma agalactiae or Mycoplasma bovirhinis , further enhancing its diagnostic specificity. The stability and immunodominance of P48 enable it to serve as a reliable biomarker for detecting M. bovis infections at various stages of the disease, from early to chronic phases. The P48 protein has been utilized in the development of diagnostic assays that offer high sensitivity and specificity. For example, Fu et al . (2014c) developed a monoclonal antibody-based competitive ELISA that specifically detected M. bovis antibodies with a cut-off inhibition value of 32%, providing significantly higher sensitivity than other commercial ELISA kits. Additionally, a study by Robino et al . (2005) showed that recombinant P48 (rP48) can detect both IgM and IgG antibodies, with IgM antibodies appearing within 6–9 days of infection. This early antibody response position, P48, is an effective marker for early-stage detection, offering a diagnostic window for many other proteins, such as IL-17A ( Robino et al ., 2005 ; Ohtsuka et al ., 2019 ). Specificity of the P48 protein for M. bovis is another critical advantage that distinguishes it from other proteins used in diagnostic assays. As demonstrated by Fu et al . (2014c) , the P48 protein does not cross-react with other common pathogens, such as bovine viral diarrhea virus or infectious bovine rhinotracheitis virus, ensuring that diagnostic assays based on P48 can confidently distinguish M. bovis infections from other respiratory pathogens common in cattle populations. In contrast, proteins such as GAPDH and COX-2, although useful in some contexts, may lack the same level of specificity for M. bovis ( Perez-Casal & Prysliak, 2007 ). P48 has proven to be a versatile protein for the development of various serological assays, including indirect ELISA, sandwich ELISA, and competitive ELISA ( Fu et al ., 2014c ; Robino et al ., 2005 ). The ability to incorporate P48 into different assay formats allows its application in both research and clinical settings. For example, Enzyme-Linked Aptamer Assays (ELAA) using P48 have demonstrated high sensitivity and have the potential to replace traditional antibody-based assays because of the ease of aptamer production and stability under various conditions ( Fu et al ., 2014c ; Zhang et al ., 2012 ). When compared to other diagnostic molecules, such as variable surface proteins (VSPs), MbovP proteins, or IL-17A, P48 stands out because of its consistency and robust immune response. Although variable surface proteins are valuable in distinguishing chronic infections, they are prone to antigenic variation, which can reduce the reliability of diagnostic assays based on these proteins ( Behrens et al ., 1994 ; Buchenau et al ., 2010 ). Similarly, while MbovP proteins have shown promise in proteomic studies, they lack broad validation across multiple diagnostic platforms that P48 has achieved ( Zhang et al ., 2021 ; Zubair et al ., 2020 ). Additionally, P48 has been shown to be highly effective when combined with recombinant protein expression systems, allowing easy production and purification for large-scale diagnostic applications. This systematic review highlights the diagnostic potential of the P48 protein for Mycoplasma bovis infections in cattle, supported by its immunodominance, stability, and high specificity in serological assays. However, limitations include the small number of included studies (n = 20), methodological heterogeneity across diagnostic techniques, and a lack of longitudinal data assessing P48’s performance over time. The review also did not formally evaluate study bias, and its computational predictions require experimental validation. Despite these constraints, the findings advocate for P48 as a promising biomarker, encouraging the development of P48-based diagnostic tools like ELISA and lateral flow tests. Future research should focus on large-scale validation and comparative studies with other biomarkers to optimize M. bovis detection and improve cattle disease management. Conclusion This study establishes P48 as a more reported diagnostic protein for Mycoplasma bovis detection, based on systematic literature evaluation and computational analysis. Compared to alternative biomarkers, such as VSPs, MbovP proteins, and MilA, P48 consistently demonstrated higher specificity, stability, and immunodominance in infected cattle. Computational analysis confirms P48’s structural and physicochemical advantages, including stability (instability index: 23.64), thermostability (aliphatic index: 83.40), and moderate hydrophilicity (GRAVY score: -0.349). These properties make P48 a reliable target for serological assays, biosensors, and recombinant antigen-based diagnostics. Given these findings, we strongly recommend further experimental validation and development of P48-based diagnostic tools for early, accurate, and cost-effective M. bovis detection. Future research should explore P48’s integration into next-generation biosensors to improve their diagnostic efficiency in veterinary medicine. Ethics and consent Ethics and consent were not required. Data availability statement Open Science Framework: Systematic Identification of P48 as An Advantageous Diagnostic Protein for Mycoplasma Bovis Infections: A Literature Survey and Computational Insight. ( https://doi.org/10.17605/OSF.IO/2NK6H ) ( Fasogbon et al. , 2025 ). This project contains the following extended data: • Flowchart of selection.docx • Supplementary file 1.docx (PRISMA checklist) • Supplementary file 2.docx Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Reporting guidelines Open Science Framework: PRISMA checklist and flowchart for “Systematic Identification of P48 as An Advantageous Diagnostic Protein for Mycoplasma Bovis Infections: A Literature Survey and Computational Insight” https://doi.org/10.17605/OSF.IO/2NK6H ( Fasogbon et al. , 2025 ). Data are available under the terms of the Creative Commons Zero “No rights reserved” data waiver (CC0 1.0 Public domain dedication). Acknowledgements The authors acknowledge the African German Network of Excellence in Science (AGNES Intra-Africa Mobility Grant for Junior Researchers.) for financially supporting this work. References Ammar A, El-Hamid A, Marwa I, et al. : Mycoplasma bovis: Taxonomy, characteristics, pathogenesis and antimicrobial resistance. Zagazig Vet. J. 2021; 49 (4): 444–461. Publisher Full Text Ayan A, De Brito LGM, Roy P, et al. : P48 as a diagnostic candidate for Mycoplasma bovis detection. Vet. Microbiol. 2023; 256 : 108983. 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Publisher Full Text Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 15 May 2025 ADD YOUR COMMENT Comment Author details Author details 1 Department of Biochemistry, Kampala International University, Ishaka, Uganda 2 Department of Biological Sciences, School of Pure & Applied Sciences, Kisii University, Kisii, Kisii County, Kenya 3 Department of Biochemistry, Mbarara University of Science and Technology, Mbarara, Western Region, Uganda 4 Biochemistry, Ahmadu Bello University, Zaria, Kaduna, Nigeria 5 Department of Veterinary Microbiology, Ahmadu Bello University, Zaria, Kaduna, Nigeria 6 National Livestock Resources Research Institute (NaLIRRI), Infectious Animal Diseases Laboratory,, National Agricultural Research Organisation(NARO), Totoro, Central Region, Uganda 7 Drug Discovery Unit, Centre for Biomaterials, Cellular and Molecular Theranostics (CBCMT), Vellore Institute of Technology, Vellore, Tamil Nadu, India Ilemobayo Victor Fasogbon Roles: Conceptualization, Data Curation, Funding Acquisition, Methodology, Resources, Writing – Original Draft Preparation Erick Nyakundi Ondari Roles: Resources, Supervision, Writing – Review & Editing Deusdedit Tusubira Roles: Resources, Supervision, Writing – Review & Editing Angela Mumbua Musyoka Roles: Data Curation, Methodology, Writing – Original Draft Preparation Bashiru Ibrahim Roles: Validation, Writing – Review & Editing Kabiru Haliru Ahmad Roles: Validation, Writing – Review & Editing Tonny Kabuuka Roles: Resources, Validation, Writing – Review & Editing Loganathan Rangasamy Roles: Validation, Writing – Review & Editing Patrick Maduabuchi Aja Roles: Conceptualization, Data Curation, Supervision, Writing – Review & Editing Competing interests No competing interests were disclosed. Grant information This study was financially supported by the African German Network of Excellence in Science (AGNES) through an AGNES Intra-Africa Mobility Grant for Junior Researchers. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Article Versions (1) version 1 Published: 15 May 2025, 14:497 https://doi.org/10.12688/f1000research.163124.1 Copyright © 2025 Fasogbon IV et al . This is an open access article distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Download Export To Sciwheel Bibtex EndNote ProCite Ref. Manager (RIS) Sente metrics Views Downloads F1000Research - - PubMed Central info_outline Data from PMC are received and updated monthly. - - Citations open_in_new 0 open_in_new 0 open_in_new SEE MORE DETAILS CITE how to cite this article Fasogbon IV, Ondari EN, Tusubira D et al. Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.12688/f1000research.163124.1 ) NOTE: If applicable, it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS track receive updates on this article Track an article to receive email alerts on any updates to this article. TRACK THIS ARTICLE Share Open Peer Review Current Reviewer Status: ? Key to Reviewer Statuses VIEW HIDE Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Version 1 VERSION 1 PUBLISHED 15 May 2025 Views 0 Cite How to cite this report: Mehmood K. Reviewer Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r417826 ) The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-417826 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 13 Oct 2025 Khalid Mehmood , Islamia University of Bahawalpur, Bahawalpur, Pakistan Approved with Reservations VIEWS 0 https://doi.org/10.5256/f1000research.179424.r417826 General Comments: The review acknowledge the importance of the topic and the potential value of a systematic review to identify the most reliable diagnostic biomarker for Mycoplasma bovis . However, significant concerns were raised regarding the literature search strategy, potential for ... Continue reading READ ALL General Comments: The review acknowledge the importance of the topic and the potential value of a systematic review to identify the most reliable diagnostic biomarker for Mycoplasma bovis . However, significant concerns were raised regarding the literature search strategy, potential for selection bias, and the resulting conclusions. The rationale for the review is weakened by the use of inappropriate references. Specifically, citing Ohtsuka et al. (2019)—a paper focused on cytokine levels in infected calves—to support the broad statement that M. bovis is a significant global pathogen is not fitting. This calls into question the authors' foundational understanding of the literature and their ability to systematically synthesize it. The structure of the manuscript and the handling of the cited literature raise doubts about the authors' qualifications to conduct a rigorous systematic review on this specific topic. The review, as presented, does not meet the expected standard for a systematic analysis. The primary weakness of this review is a significant selection bias. The search strategy appears to have been skewed towards identifying studies on P48, while overlooking a substantial body of recent literature on other diagnostic antigens. A critical omission is the failure to include the extensive body of work (over 10 papers) on the MilA protein developed over the past decade. The conclusion that P48 is "advantageous" and more reliable than other biomarkers is not justified by the data presented. Since P48 was one of the first antigens described, it has rarely been directly compared in contemporary studies with newer candidates like MilA or the MbovP proteins. By failing to review these newer studies, the authors cannot make a valid comparative claim. The conclusion is therefore based on an incomplete and potentially biased dataset. While the methods are described, the significant variation in detection techniques across the included small number of studies (n=20) makes a unified conclusion about P48's performance challenging. The computational analysis of P48's properties is sound but is presented as corroborating the review's conclusion. However, since the literature review itself is considered flawed and biased, the computational insights cannot rescue the overarching claim. The conclusions should be moderated to reflect the actual findings of the revised review. Instead of stating P48 is "advantageous," the conclusion could highlight that P48 remains a stable and useful diagnostic antigen, while acknowledging the promising role of other biomarkers and the need for more direct comparative studies. Scrutinize all references, particularly in the introduction, to ensure they are appropriately used to support the statements made and add below mentioned recent references to strengthen the study. Raza et al., 2024. Molecular detection and phylogenetic analysis of Mycoplasma bovis in bovine calves. Pak Vet J, 44(3): 889-895. http://dx.doi.org/10.29261/pakvetj/2024.232 Ghazvineh et al. Molecular detection of selective virulence factors of Mycoplasma bovis local isolates involved in bovine mastitis. Kafkas Univ Vet Fak Derg, 30 (5): 631-639, 2024. DOI: 10.9775/kvfd.2024.32118 Abdalhamed et al., 2024. Detecting Mycoplasma bovis by sybr green-based real-time quantitative PCR and loop-mediated isothermal amplification methods. Pak Vet J, 44(3): 847-853. http://dx.doi.org/10.29261/pakvetj/2024.192 Hayajneh et al., 2024. Epidemiological investigations of Mycoplasma bovis-associated mastitis in dairy animals along with analysis of interleukin-6 (IL-6) as a potential diagnostic marker. International Journal of Veterinary Science 13(1): 120-126. https://doi.org/10.47278/journal.ijvs/2023.072 Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Veterinary Medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Mehmood K. Reviewer Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r417826 ) The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-417826 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Ninković M. Reviewer Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r412045 ) The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-412045 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 23 Sep 2025 Milan Ninković , Scientific Institute of Veterinary Medicine of Serbia, Belgrade, Serbia Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.179424.r412045 Dear Editor and Authors The research is interesting and is within the scope of the journal. Considering the structure of the review paper, the literature used and the references cited, I believe that the paper cannot be indexed in ... Continue reading READ ALL Dear Editor and Authors The research is interesting and is within the scope of the journal. Considering the structure of the review paper, the literature used and the references cited, I believe that the paper cannot be indexed in its current form. Considering the structure of the paper, the authors state the incorrect readings in the introduction to the research review. Introduction: Mycoplasma bovis (M. bovis) is a significant opportunistic pathogen responsible for causing various diseases and economic losses in cattle worldwide, affecting both dairy and beef industries ( Ammar et al ., 2021 ; Ohtsuka et al ., 2019 ; James et al ., 2013 ). Reference : Ohtsuka H, Nakazono M, Kondoh T, et al. : Cytokine levels of peripheral blood mononuclear cells in the clinical cases of Holstein calves infected with Mycoplasma bovis. J. Vet. Med. Sci. 2019; 82 (1):27–30 Reading this the paper, there are many doubts regarding the structure and qualifications of the authors for systematising data related to the P48 protein M. bovis. Decline submission. Are the rationale for, and objectives of, the Systematic Review clearly stated? No Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Not applicable Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests: No competing interests were disclosed. Reviewer Expertise: Epidemiology of Mycoplasma bovis I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Ninković M. Reviewer Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r412045 ) The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-412045 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Views 0 Cite How to cite this report: Browning GF. Reviewer Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r412053 ) The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-412053 NOTE: it is important to ensure the information in square brackets after the title is included in this citation. Close Copy Citation Details Reviewer Report 12 Sep 2025 Glenn F Browning , Asia-Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Australia Not Approved VIEWS 0 https://doi.org/10.5256/f1000research.179424.r412053 This review indicates that the intent was to systematically assess the value of P48 as a diagnostic antigen for detection of infections with Mycoplasma bovis . However, the approach to reviewing the literature was very significantly biased towards selection of papers describing ... Continue reading READ ALL This review indicates that the intent was to systematically assess the value of P48 as a diagnostic antigen for detection of infections with Mycoplasma bovis . However, the approach to reviewing the literature was very significantly biased towards selection of papers describing the use of P48, and the vast majority of papers describing other diagnostic antigens were not reviewed. As P48 was one of the first diagnostic antigens described, it has rarely been compared directly with the more recently described antigens. Given the failure to assess much of the recent literature, including the extensive studies (over 10 papers) performed using assays based on the MilA protein over the last 10 years, the conclusion of the paper is not justified. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? No Are the conclusions drawn adequately supported by the results presented in the review? No If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests: No competing interests were disclosed. Reviewer Expertise: mycoplasmology, veterinary microbiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. Close READ LESS CITE CITE HOW TO CITE THIS REPORT Browning GF. Reviewer Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r412053 ) The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-412053 NOTE: it is important to ensure the information in square brackets after the title is included in all citations of this article. COPY CITATION DETAILS Report a concern Respond or Comment COMMENT ON THIS REPORT Comments on this article Comments (0) Version 1 VERSION 1 PUBLISHED 15 May 2025 ADD YOUR COMMENT Comment keyboard_arrow_left keyboard_arrow_right Open Peer Review Reviewer Status info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Reviewer Reports Invited Reviewers 1 2 3 Version 1 15 May 25 read read read Glenn F Browning , The University of Melbourne, Parkville, Australia Milan Ninković , Scientific Institute of Veterinary Medicine of Serbia, Belgrade, Serbia Khalid Mehmood , Islamia University of Bahawalpur, Bahawalpur, Pakistan Comments on this article All Comments (0) Add a comment Sign up for content alerts Sign Up You are now signed up to receive this alert Browse by related subjects keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Mehmood K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 13 Oct 2025 | for Version 1 Khalid Mehmood , Islamia University of Bahawalpur, Bahawalpur, Pakistan 0 Views copyright © 2025 Mehmood K. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Approved With Reservations info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions General Comments: The review acknowledge the importance of the topic and the potential value of a systematic review to identify the most reliable diagnostic biomarker for Mycoplasma bovis . However, significant concerns were raised regarding the literature search strategy, potential for selection bias, and the resulting conclusions. The rationale for the review is weakened by the use of inappropriate references. Specifically, citing Ohtsuka et al. (2019)—a paper focused on cytokine levels in infected calves—to support the broad statement that M. bovis is a significant global pathogen is not fitting. This calls into question the authors' foundational understanding of the literature and their ability to systematically synthesize it. The structure of the manuscript and the handling of the cited literature raise doubts about the authors' qualifications to conduct a rigorous systematic review on this specific topic. The review, as presented, does not meet the expected standard for a systematic analysis. The primary weakness of this review is a significant selection bias. The search strategy appears to have been skewed towards identifying studies on P48, while overlooking a substantial body of recent literature on other diagnostic antigens. A critical omission is the failure to include the extensive body of work (over 10 papers) on the MilA protein developed over the past decade. The conclusion that P48 is "advantageous" and more reliable than other biomarkers is not justified by the data presented. Since P48 was one of the first antigens described, it has rarely been directly compared in contemporary studies with newer candidates like MilA or the MbovP proteins. By failing to review these newer studies, the authors cannot make a valid comparative claim. The conclusion is therefore based on an incomplete and potentially biased dataset. While the methods are described, the significant variation in detection techniques across the included small number of studies (n=20) makes a unified conclusion about P48's performance challenging. The computational analysis of P48's properties is sound but is presented as corroborating the review's conclusion. However, since the literature review itself is considered flawed and biased, the computational insights cannot rescue the overarching claim. The conclusions should be moderated to reflect the actual findings of the revised review. Instead of stating P48 is "advantageous," the conclusion could highlight that P48 remains a stable and useful diagnostic antigen, while acknowledging the promising role of other biomarkers and the need for more direct comparative studies. Scrutinize all references, particularly in the introduction, to ensure they are appropriately used to support the statements made and add below mentioned recent references to strengthen the study. Raza et al., 2024. Molecular detection and phylogenetic analysis of Mycoplasma bovis in bovine calves. Pak Vet J, 44(3): 889-895. http://dx.doi.org/10.29261/pakvetj/2024.232 Ghazvineh et al. Molecular detection of selective virulence factors of Mycoplasma bovis local isolates involved in bovine mastitis. Kafkas Univ Vet Fak Derg, 30 (5): 631-639, 2024. DOI: 10.9775/kvfd.2024.32118 Abdalhamed et al., 2024. Detecting Mycoplasma bovis by sybr green-based real-time quantitative PCR and loop-mediated isothermal amplification methods. Pak Vet J, 44(3): 847-853. http://dx.doi.org/10.29261/pakvetj/2024.192 Hayajneh et al., 2024. Epidemiological investigations of Mycoplasma bovis-associated mastitis in dairy animals along with analysis of interleukin-6 (IL-6) as a potential diagnostic marker. International Journal of Veterinary Science 13(1): 120-126. https://doi.org/10.47278/journal.ijvs/2023.072 Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? Yes Are the conclusions drawn adequately supported by the results presented in the review? Yes If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Veterinary Medicine I confirm that I have read this submission and believe that I have an appropriate level of expertise to confirm that it is of an acceptable scientific standard, however I have significant reservations, as outlined above. reply Respond to this report Responses (0) Mehmood K. Peer Review Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r417826) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-417826 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Ninković M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. 23 Sep 2025 | for Version 1 Milan Ninković , Scientific Institute of Veterinary Medicine of Serbia, Belgrade, Serbia 0 Views copyright © 2025 Ninković M. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The author(s) is/are employees of the US Government and therefore domestic copyright protection in USA does not apply to this work. The work may be protected under the copyright laws of other jurisdictions when used in those jurisdictions. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions Dear Editor and Authors The research is interesting and is within the scope of the journal. Considering the structure of the review paper, the literature used and the references cited, I believe that the paper cannot be indexed in its current form. Considering the structure of the paper, the authors state the incorrect readings in the introduction to the research review. Introduction: Mycoplasma bovis (M. bovis) is a significant opportunistic pathogen responsible for causing various diseases and economic losses in cattle worldwide, affecting both dairy and beef industries ( Ammar et al ., 2021 ; Ohtsuka et al ., 2019 ; James et al ., 2013 ). Reference : Ohtsuka H, Nakazono M, Kondoh T, et al. : Cytokine levels of peripheral blood mononuclear cells in the clinical cases of Holstein calves infected with Mycoplasma bovis. J. Vet. Med. Sci. 2019; 82 (1):27–30 Reading this the paper, there are many doubts regarding the structure and qualifications of the authors for systematising data related to the P48 protein M. bovis. Decline submission. Are the rationale for, and objectives of, the Systematic Review clearly stated? No Are sufficient details of the methods and analysis provided to allow replication by others? Partly Is the statistical analysis and its interpretation appropriate? Not applicable Are the conclusions drawn adequately supported by the results presented in the review? Partly If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Partly Competing Interests No competing interests were disclosed. Reviewer Expertise Epidemiology of Mycoplasma bovis I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Ninković M. Peer Review Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r412045) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-412045 keyboard_arrow_left Back to all reports Reviewer Report 0 Views copyright © 2025 Browning G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. 12 Sep 2025 | for Version 1 Glenn F Browning , Asia-Pacific Centre for Animal Health, Melbourne Veterinary School, Faculty of Science, The University of Melbourne, Parkville, Australia 0 Views copyright © 2025 Browning G. This is an open access peer review report distributed under the terms of the Creative Commons Attribution License , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. format_quote Cite this report speaker_notes Responses (0) Not Approved info_outline Alongside their report, reviewers assign a status to the article: Approved The paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. Not approved Fundamental flaws in the paper seriously undermine the findings and conclusions This review indicates that the intent was to systematically assess the value of P48 as a diagnostic antigen for detection of infections with Mycoplasma bovis . However, the approach to reviewing the literature was very significantly biased towards selection of papers describing the use of P48, and the vast majority of papers describing other diagnostic antigens were not reviewed. As P48 was one of the first diagnostic antigens described, it has rarely been compared directly with the more recently described antigens. Given the failure to assess much of the recent literature, including the extensive studies (over 10 papers) performed using assays based on the MilA protein over the last 10 years, the conclusion of the paper is not justified. Are the rationale for, and objectives of, the Systematic Review clearly stated? Partly Are sufficient details of the methods and analysis provided to allow replication by others? Yes Is the statistical analysis and its interpretation appropriate? No Are the conclusions drawn adequately supported by the results presented in the review? No If this is a Living Systematic Review, is the ‘living’ method appropriate and is the search schedule clearly defined and justified? (‘Living Systematic Review’ or a variation of this term should be included in the title.) Not applicable Competing Interests No competing interests were disclosed. Reviewer Expertise mycoplasmology, veterinary microbiology I confirm that I have read this submission and believe that I have an appropriate level of expertise to state that I do not consider it to be of an acceptable scientific standard, for reasons outlined above. reply Respond to this report Responses (0) Browning GF. Peer Review Report For: Systematic identification of P48 as an advantageous diagnostic protein for Mycoplasma bovis infections: A literature survey and computational insight [version 1; peer review: 1 approved with reservations, 2 not approved] . F1000Research 2025, 14 :497 ( https://doi.org/10.5256/f1000research.179424.r412053) NOTE: it is important to ensure the information in square brackets after the title is included in this citation. The direct URL for this report is: https://f1000research.com/articles/14-497/v1#referee-response-412053 Alongside their report, reviewers assign a status to the article: Approved - the paper is scientifically sound in its current form and only minor, if any, improvements are suggested Approved with reservations - A number of small changes, sometimes more significant revisions are required to address specific details and improve the papers academic merit. 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