Increased Resistance to Taenia crassiceps Murine Cysticercosis in Qa-2 Transgenic Mice

We previously reported important differences in resistance to Taenia crassiceps murine cysticercosis between BALB/c substrains. It was suggested that resistance might correlate with expression of the nonclassic class I major histocompatibility complex (MHC) Qa-2 antigen; BALB/cAnN is Qa-2 negative and highly susceptible to T. crassiceps, whereas BALB/cJ expresses Qa-2 and is highly resistant. In this study, we investigated the role of Qa-2 in mediating resistance to cysticercosis by linkage analysis and infection of Qa-2 transgenic mice. In BALB/cAnN × (C57BL/6J × BALB/cAnN)F₁ and BALB/cAnN × (BALB/cJ × BALB/cAnN)F₁ backcrosses, the expression of Qa-2 antigen correlated with resistance to cysticercosis. Significantly fewer parasites were recovered from infected Qa-2 transgenic male and female mice than from nontransgenic mice of similar genetic background. These results clearly demonstrate that the Qa-2 MHC antigen is involved in resistance to T. crassiceps cysticercosis.

Taenia solium cysticercosis is a parasitic disease that seriously affects human health (24) and causes important economic losses in pig farming of developing countries (1) where conditions that favor parasite transmission persist. The essential role of pigs as an obligatory intermediate host in the parasite life cycle offers the opportunity to interfere with transmission by inducing acquired immunity through vaccination (10, 13, 18), by decreasing susceptibility through genetic manipulation (14), or both. Systematic exploration of the role of genetic factors in cysticercosis and the identification of protective immunogens are hampered by the high costs and slow data retrieval involved in studies with pigs. However, another cestode, Taenia crassiceps, that naturally infects rodents (3) is highly suitable for experimentation. It shows extensive antigenic cross-reactivity and cross-protective immunity with T. solium (7, 21); the antigenic similarity is such that T. crassiceps antigens can be used for immunodiagnosis of human cysticercosis (9). Furthermore, T. crassiceps and T. solium both have a typical two-host taeniid life cycle and morphologically and structurally related larval stages. Since T. crassiceps can reproduce asexually, experimental infection is readily attained by injecting the cysticerci in the peritoneal cavity of the mouse (3). Thus, T. crassiceps murine cysticercosis has been shown to be a useful experimental model of metacestode infection in the study of genetic factors involved in host resistance (2, 20) and underlying immunological mechanisms (19, 23, 25).Initial findings showed that genes linked to H-2 affect T. crassiceps growth in mice (20). Thus, significant differences in the extent of the parasitosis were found between mice carrying the H-2^d (BALB/cAnN and DBA/2) haplotype, which were the most susceptible, and mice with H-2^b (BALB/B, C57BL/6J, and C57BL/10J) or H-2^k (BALB/K, C3H/HeJ, and C3H/FeJ) haplotype, which were comparatively resistant. Further studies (2) showed low susceptibility of congenic and recombinant B10 mice, regardless of H-2 haplotype, indicating that genes in C57BL background confer resistance to the parasitosis such that they override the effect of H-2. The effect of genes outside H-2 on the control of parasite growth was also revealed by the differential susceptibility of three H-2^d BALB/c substrains, of which BALB/cAnN was highly susceptible, whereas BALB/cJ was highly resistant and BALB/cByJ displayed and intermediate degree of susceptibility (2). BALB/cAnN and BALB/cJ, which are genetically quite similar strains, differ in several phenotypes, including the expression of the Qa-2 antigen (11, 16). This antigen is a nonclassical class I major histocompatibility complex (MHC) molecule encoded by four genes (Q6 to Q9) located telomeric to the H-2D loci (11, 22). BALB/cJ (Qa-2^low), a Qa-2 expressor substrain, has only active Q6 and Q7 genes because Q8 and Q9 have fused, resulting in an inactive Q8/Q9^d gene (11, 15). In BALB/cAnN (Qa-2^null), an additional deletion of genomic DNA has occurred between the Q6 and Q7 genes, leading to their inactivation and accounting for the Qa-2 null expression (11). We proposed previously that differences in susceptibility to T. crassiceps observed between BALB/cJ and BALB/cAnN might be related to Qa-2 antigen expression (2). Here we describe that results of genetic linkage studies are entirely consistent with this hypothesis. Furthermore, a role of Qa-2 in mediating resistance to T. crassiceps was directly established by the diminution of parasite loads in infected Qa-2 transgenic mice.