Genome-wide association studies for the identification of cattle susceptible and resilient to paratuberculosis

Abstract

Mycobacterium avium subsp. paratuberculosis (MAP) causes Johne's disease or paratuberculosis (PTB), with important animal health and economic implications. There are no therapeutic strategies to control this disease, and vaccination with inactivated vaccines is limited in many countries because it can interfere with the intradermal test used for bovine tuberculosis detection. Thus, infected animals either get culled after a positive ELISA or fecal PCR result or die due to clinical disease. In this study, we review recent studies aimed to discover genetic markers which could help to identify and select cattle less susceptible and more resilient to PTB. In recent years, the genotyping and subsequent imputation to whole-genome sequence (WGS) has allowed the identification of single-nucleotide polymorphisms (SNPs), quantitative trait loci (QTL), and candidate genes in the Bos taurus genome associated with susceptibility to MAP infection. In most of these genome-wide association studies (GWAS), phenotypes were based on ante-mortem test results including serum ELISA, milk ELISA, and detection of MAP by fecal PCR and bacteriological culture. Cattle infected with MAP display lesions with distinct severity but the associations between host genetics and PTB-associated pathology had not been explored until very recently. On the contrary, the understanding of the mechanisms and genetic loci influencing pathogen resistance, and disease tolerance in asymptomatic individuals is currently very limited. The identification of long-time asymptomatic cattle that is able to resist the infection and/or tolerate the disease without having their health and milk production compromised is important for disease control and breeding purposes.

Evaluation of Mycobacterium avium subsp. paratuberculosis isocitrate lyase (IcL) and ABC transporter (BacA) knockout mutants as vaccine candidates

“…Current control strategies focus on preventing the transmission of MAP through management practices ( Barkema et al., 2018 ) by testing and culling positive animals, decreasing the incidence of new infections, preventing spread, and protecting negative herds, and decreasing prevalence in bulk tank milk ( Wolf et al., 2014 ). Identifying and selectively breeding cattle with natural resistance to MAP infection is also an approach recently employed by Canada and some European countries ( Alonso-Hearn et al., 2022 ; Sanchez et al., 2022 ). Despite considerable efforts to control Johne's disease, their effectiveness has been limited mostly due to high costs, suboptimal diagnostics, and incomplete knowledge of MAP pathogenesis ( Nielsen and Toft, 2006 ; Nielsen and Toft, 2008 ).…”

Summary-data based mendelian randomization identifies gene expression regulatory polymorphisms associated with bovine paratuberculosis by modulation of the nuclear factor Kappa β (NF-κß)-mediated inflammatory response

“…Currently, there is not any effective therapeutic treatment to cure bovine PTB and the parenteral vaccination with heat-killed inactivated vaccines is not widely accepted by animal health authorities on the grounds of a slight interference with the diagnosis of bovine tuberculosis (Garrido et al, 2013 13 ). The identi cation and selection of animals naturally less susceptible to MAP infection or with increased resistance to PTB is important for disease control and breeding purposes (Alonso-Hearn et al, 2022 14 ). Genome-wide association studies (GWAS) have allowed the identi cation of single-nucleotide polymorphisms (SNPs) associated with PTB susceptibility and tolerance using whole-genome sequence (WGS) (Canive et al, 2021a 15 ; Canive et al, 2021b 16 ; Canive et al, 2022a 17 , Alonso-Hearn et al, 2022 14 ).…”

“…The identi cation and selection of animals naturally less susceptible to MAP infection or with increased resistance to PTB is important for disease control and breeding purposes (Alonso-Hearn et al, 2022 14 ). Genome-wide association studies (GWAS) have allowed the identi cation of single-nucleotide polymorphisms (SNPs) associated with PTB susceptibility and tolerance using whole-genome sequence (WGS) (Canive et al, 2021a 15 ; Canive et al, 2021b 16 ; Canive et al, 2022a 17 , Alonso-Hearn et al, 2022 14 ). However, interpreting the biological mechanisms behind these SNPs remains a challenge.…”

The Upregulation of Cathepsin G Is Associated with Resistance to Bovine Paratuberculosis

“…Several studies have demonstrated that host genetics governs variations in susceptibility to MAP infection, and therefore selective breeding could decrease the susceptibility to MAP infection [ 13 ]. In recent years, genome-wide association studies (GWAS) have identified single nucleotide polymorphisms (SNPs) associated with susceptibility to MAP infection [ 14 , 15 , 16 , 17 ].…”