The Haemophilus influenzae type b capsule has long been recognized as an important virulence determinant. Capsule expression, however, is genetically unstable, and capsule-deficient mutants arise at frequencies of 0.1 to 0.5%. I have found that this instability is due to the presence of an 18-kb duplication of genes involved in type b capsule expression, and that loss of capsule expression occurs following rec-dependent recombination between the 2 copies of the 18-kb repeat. This seemingly paradoxical instability has led me to question the role that capsule expression plays in the long-term host/parasite relationship. The shift from b+ to b- has been observed in the nose of an infant rat, and b-mutants have been isolated from the nasopharynx of infants with systemic type b disease. Using an infant rat model, I will continue to examine the relationship between capsule expression, the ability to colonize, the ability to invade, and the long-term host/parasite equilibrium. It is also possible that the duplication has evolved as a mechanism for further amplification of this region (via unequal crossing over between the 2 copies at a replicating fork); the importance of increased capsule expression to pathogenesis is a subject that I intend to investigate. Although the presence of a capsule appears to be important for survival of the organism in the blood stream, it is still not clear whether other capsule types (particularly the structurally very similar type a capsule), if placed in the appropriate genetic background, might not be as virulent as the type b strains. Differences in LPS structure also appear to be important, but the relative importance of the specific capsule type, LPS structure and other potential virulence determinants has not yet been completely defined. By molecular cloning I will isolate and map the genes involved in type b capsule expression. This should allow me to construct the isogenic strains necessary to address the issue of why type b strains are more virulent than the other capsule types.
| Corn, P G; Anders, J; Takala, A K et al. (1993) Genes involved in Haemophilus influenzae type b capsule expression are frequently amplified. J Infect Dis 167:356-64 |
| Hoiseth, S K; Corn, P G; Anders, J (1992) Amplification status of capsule genes in Haemophilus influenzae type b clinical isolates. J Infect Dis 165 Suppl 1:S114 |
| Noel, G J; Hoiseth, S K; Edelson, P J (1992) Type b capsule inhibits ingestion of Haemophilus influenzae by murine macrophages: studies with isogenic encapsulated and unencapsulated strains. J Infect Dis 166:178-82 |
| Lagos, R; Avendano, A; Horwitz, I et al. (1991) Molecular epidemiology of Haemophilus influenzae within families in Santiago, Chile. J Infect Dis 164:1149-53 |
