Bovine Intelectin 2 Expression as a Biomarker of Paratuberculosis Disease Progression

Vázquez, Cristina Blanco; Balseiro, Ana; Alonso‐Hearn, Marta; Juste, Ramón A.; Iglesias, Natàlia; Canive, María; Casáis, Rosa

doi:10.3390/ani11051370

Cited by 8 publications

(9 citation statements)

References 70 publications

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“…Likewise, the individual mean expression levels of ABCA13 in the focal, multifocal and diffuse groups was significantly higher than in the control group (see Figure 1, Table 2). This expression pattern across pathological forms was similar to that observed for intelectin 2 (ITLN2) in the ileocecal valve (ICV) in a recently published study (81). These findings validated our initial study where RNA-seq results showed that the ABCA13 and ITLN2 genes were overexpressed in peripheral blood (log2 fold change = 3.7) and ICV (log2 fold change 10.6) of animals with focal lesions compared to control animals without lesions (35).…”

Section: Discussionsupporting

confidence: 89%

“…A total of 704 Holstein-Friesian cows, with an average age of 5.2 years ranging from 0.5 to 13.4, were included in this study. The positive reference group consisted of 566 cows from 8 different regions of Spain (Basque Country, Catalonia, Navarra, Aragón, Cantabria, Castilla y León, La Rioja and Asturias) commercially slaughtered in five abattoirs located in the Basque Country and Asturias ( 23 , 36 , 81 ). The negative reference group consisted of 138 live cows from 4 PTB-free farms of Asturias.…”

Section: Methodsmentioning

confidence: 99%

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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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Section: Discussionsupporting

confidence: 89%

Section: Methodsmentioning

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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“…Animals are infected early in life through the fecal-oral route but clinical onset appears when animals are 18 months or older. Current diagnostic tests, ELISA and fecal PCR, often fail to detect MAP-infected cattle early in the course of infection ( 3 , 4 ). According to their extension, cellular infiltrate, and amount of MAP, PTB-associated histological lesions have been classified into the following categories: focal, multifocal, and diffuse (diffuse paucibacillary, diffuse intermediate, and diffuse multibacillary) ( 5 ).…”

Section: Introductionmentioning

confidence: 99%

A Genome-Wide Association Study for Tolerance to Paratuberculosis Identifies Candidate Genes Involved in DNA Packaging, DNA Damage Repair, Innate Immunity, and Pathogen Persistence

et al. 2022

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Although the genetic susceptibility to diseases has been extensively studied, the genetic loci and the primary molecular and cellular mechanisms that control disease tolerance are still largely unknown. Bovine paratuberculosis (PTB) is an enteritis caused by Mycobacterium avium subsp. paratuberculosis (MAP). PTB affects cattle worldwide and represents a major issue on animal health. In this study, the associations between host genetic and PTB tolerance were investigated using the genotypes from 277 Spanish Holstein cows with two distinct phenotypes: cases) infected animals with positive PCR and bacteriological culture results but without lesions in gut tissues (N= 24), and controls) animals with negative PCR and culture results but with PTB-associated lesions (N= 253). DNA from peripheral blood of the study population was genotyped with the Bovine EuroG MD Bead Chip, and the corresponding genotypes were imputed to whole-genome sequencing (WGS) data. A genome-wide association study was performed using the WGS data and the defined phenotypes in a case-control approach. A total of 142 single nucleotide polymorphisms (SNPs) were associated (false discovery rate ≤ 0.05, P values between 1.5 × 10-7 and 5.7 × 10-7) with tolerance (heritability= 0.55). The 40 SNPs with P-values < 5 × 10-7 defined 9 QTLs and 98 candidate genes located on BTA4, BTA9, BTA16, BTA25, and BTA26. Some of the QTLs identified in this study overlap with QTLs previously associated with PTB, bovine tuberculosis, mastitis, somatic cell score, bovine diarrhea virus persistent infection, tick resistance, and length of productive life. Two candidate genes with important roles in DNA damage response (ERCC4 and RMI2) were identified on BTA25. Functional analysis using the 98 candidate genes revealed a significant enrichment of the DNA packaging process (TNP2/PRMI1/PRM2/PRM3). In addition, the TNF-signaling (bta04668; TRAF5/CREB5/CASP7/CHUK) and the toxoplasmosis (bta05145; TGFβ2/CHUK/CIITA/SOCS1) pathways were significantly enriched. Interestingly, the nuclear Factor NF-κβ Inhibitor Kinase Alpha (CHUK), a key molecule in the regulation of the NF-κB pathway, was enriched in both pathways. Taken together, our results define a distinct immunogenetic profile in the PTB-tolerant animals designed to control bacterial growth, modulate inflammation, limit tissue damage and increase repair, thus reducing the severity of the disease.

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“…Using RNA-Seq technology we previously identi ed a biomarker of PTB progression, the precursor of the bovine intelectin 2 (ITLN2), which was overexpressed in ICV samples of animals with focal (log 2 fold-change = 10.6) and diffuse (log 2 foldchange = 6.8) lesions compared with animals without visible lesions [31]. More recently, we have demonstrated that the quanti cation of bovine ITLN2 secreting cells by immunohistochemical analysis of ICV sections could constitute a good post-mortem tool, complementary to histopathology, to improve the detection of focal lesions which may sometimes be di cult to detect [32]. In an attempt to test whether the focal lesions were controlled by a speci c genetic, a GWAS comparing animals with focal vs multifocal and focal vs diffuse lesions was performed (data not shown).…”

Section: Discussionmentioning

confidence: 98%

“…Using RNA-Seq, we previously detected that the cholesterol route (bta04977) was dysregulated in the ICV of cows with diffuse lesions versus the control group with four upregulated genes matching this route (APOA1, APOC3, APOA4, APOB) [31]. In addition, the top upregulated gene in peripheral blood of animals with focal lesions versus control cows was the cassette subfamily A member 13 (ABCA13), a gene that accelerates cholesterol internalization and accumulation in intracellular vesicles [31][32]41]. In agreement with our data, recent evidence suggests that MAP-infected macrophages accumulate intracellular cholesterol droplets and depict a foam cell phenotype providing an enriched environment for MAP survival [42][43].…”

Section: Discussionmentioning

confidence: 99%

Host Genetics Underlying Pathological Outcomes to Mycobacterium Avium Subsp. Paratuberculosis Infection is Governed by Distinct Genetic Variants

Canive

Badia-Bringué

Vázquez

et al. 2021

Preprint

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Bovine paratuberculosis (PTB), caused by Mycobacterium avium subsp. paratuberculosis (MAP), is a chronic granulomatous enteritis that affects cattle worldwide. According to their severity and extension, PTB-associated histological lesions have been classified into the following groups; focal, multifocal, and diffuse. It is unknown whether these lesions represent sequential stages or divergent outcomes. In the current study, the associations between host genetics and pathology were explored by genotyping 813 Spanish Holstein cows with no visible lesions (N= 373) and with focal (N=371), multifocal (N=33), and diffuse (N=33) lesions in gut tissues and regional lymph nodes. DNA from peripheral blood samples of these animals was genotyped with the Bovine EuroG MD Bead Chip, and the corresponding genotypes were imputed to whole-genome sequencing (WGS) data using the 1,000 Bull genomes reference population. A genome-wide association study (GWAS) was performed using the WGS data and the presence or absence of each type of histological lesion in a case-control approach. No overlap was seen in the SNPs controlling the three PTB-associated lesions. A total of 192 and 92 SNPs defining 13 and 9 distinct quantitative trait loci (QTLs) were highly-associated (P ≤ 5 x 10-7) with the multifocal (heritability= 0.075) and the diffuse (heritability= 0.189) lesions, respectively. Some of the identified QTLs overlapped with QTLs previously associated with PTB, bovine tuberculosis, mastitis, and IgG levels. Pathway analysis with candidate genes overlapping the identified QTLs revealed a significant enrichment of the keratinization pathway and cholesterol metabolism in the animals with multifocal and diffuse lesions, respectively. While keratin variants may predispose cows to the development of multifocal lesions, cholesterol variants associate with the more severe lesions. Taken together, these findings suggest that the variation in MAP-associated pathological outcomes might be genetically determined and indicative of distinct host responses in genetically predisposed individuals.

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Bovine Intelectin 2 Expression as a Biomarker of Paratuberculosis Disease Progression

Cited by 8 publications

References 70 publications

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

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

A Genome-Wide Association Study for Tolerance to Paratuberculosis Identifies Candidate Genes Involved in DNA Packaging, DNA Damage Repair, Innate Immunity, and Pathogen Persistence

Host Genetics Underlying Pathological Outcomes to Mycobacterium Avium Subsp. Paratuberculosis Infection is Governed by Distinct Genetic Variants

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