Role of the bovine immune system and genome in resistance to gastrointestinal nematodes

Gastrointestinal nematode infections of cattle remain a constraint on the e fficient raising of cattle on pasture throughout the world. Most of the com mon genera of parasites found in cattle stimulate an effective level of pro tective immunity in most animals within the herd after the animals have bee n on pasture for several months. In contrast, cattle remain susceptible to infection by Ostertagia for many months, and immunity that actually reduces the development of newly acquired larvae is usually not evident until the animals are more than 2 years old. This prolonged susceptibility to reinfec tion is a major reason that this parasite remains the most economically imp ortant GI nematode in temperate regions of the world. Although, animals rem ain susceptible to reinfection for a prolonged period of time, there are a number of manifestations of the immune response that result in an enhanced level of herd immunity. These include a delay in the development time of th e parasites, an increase in the number of larvae that undergo an inhibition in development, morphological changes in the worms, stunting of newly acqu ired worms, and most importantly a reduction in the number of eggs produced by the female worms. The overall result of these manifestations of immunit y is a reduction in parasite transmission within the cattle herd. The immune mechanisms responsible for these different types of functional i mmunity remain to be defined. In general, CI nematode infections in mammals elicit very strong Th2-like responses characterized by high levels of Inte rleukin 4 (IL4), high levels of IgG1 and IgE antibodies, and large numbers of mast cells. In cattle, the most extensively studied GI nematode, in rega rds to host immune responses, is Ostertagia ostertagi. In Ostertagia infect ions, antigens are presented to the host in the draining lymph nodes very s oon after infection, and within the first 3-4 days of infection these cells have left the nodes, entered the peripheral circulation, and have homed to tissues immediately surrounding the parasite where they become established . The immune response seen in the abomasum is in many ways are similar to t hat seen other mammalian hosts, with high levels of expression of IL4 in th e draining lymph nodes and in lymphocytes isolated from the mucosa. But unl ike a number of other systems, lymphocyte populations taken from Ostertagia infected cattle seem to be up-regulated for a number of other cytokines, m ost notably Interferon-(IFN-(), implying that in Ostertagia infections, the immune response elicit is not simply a stereotypic Th2 response. In additi on, effector cell populations in the tissues surrounding the parasites, are not typical, inferring the Ostertagia has evolved means to suppress or eva de protective immune mechanisms. Studies have also demonstrated that the number of nematode eggs/gram (EPG) in feces of pastured cattle is strongly influenced by host genetics and tha t the heritability of this trait is approxiamately 0.30. In addition, EPG v alues are not < < normally > > distributed and a small percentage of a herd is responsible for the majority of parasite transmission. This suggests th at genetic management of a small percentage of the herd can considerably re duce overall parasite transmission. A selective breeding program has been i nitiated to identify the host genes controlling resistance/susceptibility t o the parasites. The best indicator of the number of Cooperia infecting a h ost is the EPG value, while Ostertagia is best measured by serum pepsinogen levels, weight gain, and measures of anemia. Other phenotypic measures are either not significantly associated with parasite numbers or are very weak ly correlated. In addition, calves can be separated into three types: (1) Type I which nev er demonstrates high EPG values. (2) Type II which shows rises in EPC value s through the first 2 months on pasture which then fall and remain at level s associated with Type I calves, and (3) Type III calves which maintain hig h EPG levels. The approximate percentage of these calves is 25:50:25 respec tively. Because these cattle are segregating for traits involved in resista nce and susceptibility to GI nematodes, this resource population is being u sed to effectively detect the genomic locations of these Economic Trait Loc i (ETL). For relational analysis between phenotype and genome location, ove r 80,000 genotypes have been generated by PCR amplification, and marker gen otypes have been scored to produce inheritance data. The marker allele inhe ritance data is currently being statistically analyzed to detect patterns o f co-segregation between allele haplotype and EPG phenotypes. Statistical p ower of this genome-wide scan has been strengthened by including genotypic data from the historic pedigree. In our herd, paternal half-sib families ra nge from 5-13 progeny/sire, and extensive marker genotypes are available fr om ancestors of the population most of which are paternally descended from a single founding sire. Once ETL have been identified the next will be to refine ETL map resolution in attempt to discover the genes underlying disease phenotypes. Accurate i dentification of genes controlling resistance will offer the producer sever al alternatives for disease control. For a non-organic producer, the small percentage of susceptible animals can be targeted for drug administration. This approach would reduce both the cost of anthelmintics used and the odds for selection of drug resistant mutants, because the selective agent (drug ) would not be applied over the entire parasite population. A second treatm ent option would be based on correcting a heritable immunologic condition. In this case, susceptible animals could be the targets for immunotherapy in volving vaccines of immunomodulation. A final option would be genetic selec tion to remove susceptible animals from the herd. Producers with a high deg ree of risk for parasite-induced production losses, such as organic produce rs of producers in geographic areas with environmental conditions favorable to high rates of transmission would benefit the most from this strategy. I n contrast, producers at low risk could take a more conservative approach a nd select against susceptibility when other factors were equal. Published b y Elsevier Science B.V.