Genetic Loci Involved in Antibody Response to Mycobacterium avium ssp. paratuberculosis in Cattle

Mycobacterium avium subspecies paratuberculosis (MAP) causes paratuberculosis or Johne’s disease in cattle, a chronic granulomatous gastroenteritis [1,2]. Johne’s disease occurs worldwide and is primarily a disease of ruminants, including cattle, sheep, goats, and farmed deer. However, the disease has a wide host range and has been reported to occur in non-ruminants species, such as wild rabbits [3] and their predators, foxes and stoats [4], and in primates such as mandrills and macaques [5,6]. MAP is responsible for huge economic losses, particularly in dairy cattle herds [7]. Moreover, several studies have suggested a link between MAP and Crohn’s disease in man [8–10]. However, the evidence for a link between Johne’s and Crohn’s diseases remains controversial and the causal role of MAP has not been proven [11–13].In cattle, the disease starts with the slow development of intestinal lesions in infected animals, a proportion of these animals become clinically ill after two to six years [14]. Clinical signs of infection include progressive weight loss, intractable diarrhoea, decreased milk production and ultimately death [15]. However, in cattle, Johne’s disease is not treatable and vaccine efficacy it is still controversial. The prevalence of MAP in farmed animals in Europe is approximately 20% [16]. The main route of transmission of MAP is the faecal-oral route [17]; however, it can also be transmitted in the semen of bulls, in milk to the newborn calf, and in utero across the placenta [2]. In addition it has also been suggested that MAP can exist within the tissues of animals for years without causing clinical disease [18,19]. Although the mechanisms that affect the balance between acquired resistance and progression to clinical disease are unknown, they may involve maturation of the immune system in terms of the various T-cell subsets and the specific tissue distribution of immune cells. In the early stages of the infection, MAP infects macrophages in lymphoid tissue in the ileum, where it inhibits phagosome maturation and induces the recruitment of inflammatory cells, resulting in granulomatous enteritis. Cattle typically become infected with MAP as calves; however, clinical signs of infection do not usually appear before two years of age, and are most commonly seen after the second or third lactation. Infected cattle may spread MAP to other animals in the herd through faecal contamination of the environment, prior to the appearance of clinical signs [20]. Current Johne’s diagnostic tests have low sensitivity for detecting the infection in pre-clinical animals (0.45–0.5) [21], thus testing for MAP may not identify all infected animals. The sub-clinical stage of MAP infection is characterized by loss of pro-inflammatory Th1 response and an increased antibody-mediated Th2 response, however, the mechanism by which MAP interacts with the bovine immune system and suppresses Th1 response remains unclear [22]. Susceptibility to MAP infection has been found to be heritable [23–26] with heritability estimates ranging from 0.06 to 0.102, depending the definition of infection, the statistical model used and the population studied. Several studies have addressed the identification of genetic loci associated with MAP susceptibility by testing candidate genes, by genome-wide linkage or association studies. Polymorphisms in functional candidate genes, SLC11A1 [27], TLR1, 2 and 4, [28] and CARD15 [29] have been associated with susceptibility with MAP infection in cattle. CARD15 has also been associated with increased the risk of Crohn’s disease in humans [30,31]. Genome wide linkage analysis provided evidence for a QTL for MAP susceptibility on Bos taurus chromosome 20 [32] and recently, a genome wide association study using a high density single nucleotide polymorphism (SNP) panel (the Illumina BovineSNP50 BeadChip) identified regions on chromosomes 3 and 9 that are highly significantly associated with the presence of MAP in tissue and faeces [33]. However, neither of these publications present evidence for strong functional candidate genes associated with Johne’s disease in these chromosomal regions. The current study presents evidence for loci associated with MAP susceptibility that were identified using a high density SNP panel (the Illumina BovineSNP50BeadChip whole genome SNP assay) in a case-control study with a sample size of about 900 Holstein cattle using the presence of antibody against the bacterium as the definition of susceptibility.