Genetic control of acquired resistance to Heligmosomoides polygyrus: overcoming genetically determined weak responder status by strategic immunization with ivermectin-abbreviated infections.

The induction of acquired resistance to H. polygyrus, following treatment of mice by a 6 day immunizing infection abbreviated with the anthelmintic drug ivermectin (6d I-AI), was investigated. Four worms were sufficient to elicit > 80% protection against challenge and immunizing infections > 50 worms generated > 95% protection in female NIH mice. A few worms were recovered during the second week from immunized challenged mice but these were rapidly expelled from the gut lumen. Treatment with hydrocortisone from day 10 postinfection, permitted worm burdens to accumulate over the following 2 weeks. The 6d I-AI protocol enabled females of strains previously designated as weak responders to develop potent acquired resistance to challenge (CBA mice showed > 90% protection), although weak responder strain male mice were not significantly protected. Delaying treatment with ivermectin by as little as 24 h resulted in poorer expression of acquired resistance. A positive correlation between the increasing interval from infection to treatment with ivermectin and worm burdens after challenge, and the negative correlation with IgGI antibody responses after challenge indicated that the immunodepressive activities of 7 day and older worms down-regulated local intestinal immune responses. Mice characterized by weak responder phenotype were significantly more sensitive to downregulation than mouse strains showing strong responder phenotype. In consequence, optimal timing of treatment with anthelmintics during exposure to the immunizing infection, intending to minimize exposure to the immunodepressive stages of the parasite, is sufficient to overcome reported genetic constraints on the development of resistance in this system.