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Vaccines for the 21st Century: A Tool for Decisionmaking
with an enzyme that is specific to heparin sulfate. When this occurs, the chlamydia decreases or loses attachment and is no longer infectious. When exogenous heparin or heparin sulfate is added, the chlamydia regains its infectivity; indeed, the level of attachment increases by some 50 percent.
Researchers have been able to model this mechanism by coating polystyrene beads with either the natural ligand or heparin sulfate. The beads attach to and enter epithelial cells very efficiently in a manner similar to chlamydia. They also elicit the same pattern of tyrosine polyphospholated host-cell proteins upon uptake, suggesting that they are mimicking the chlamydia pathway. This mechanism may provide a way to target delivery of vaccines to the mucosal surfaces that chlamydia infect.
Understanding of these adhesion molecules also suggests the possibility of a second antimicrobial strategy, that of using analogues to compete with and block the binding activity of chlamydia. Researchers experimented with different forms of heparin and discovered that the N-desulfated, O-sulfated form of the molecule would inhibit binding to the eucaryotic host cells without binding to the chlamydia elementary bodies. This suggests that one could design compounds that would not bind to the organism (which would risk potentiating or rescuing infectivity) and would be potent competitors for the host-cell receptor for this ligand. Such a chlamydia inhibitor might be added to various spermicidal compounds.
Immunology. Epidemiological data, animal models, and early vaccine trials demonstrate serotype-specific immunity to the 15 known serotypes of C. trachomatis var. trachoma. Immunity is relatively short-lived, typically waning in 6 months to 1 year. It is commonly believed that immunity is related to serotype-specific antigens. Three molecules on the surface of chlamydia are candidates for these targets: (1) the lipopolysaccharide (LPS), (2) the major outer membrane protein (MOMP), and (3) the adhesion-and-invasion ligand (see above).
LPS is genospecific, not serospecific, and neutralization cannot be demonstrated, so it doesn’t fit this serovariant-specific model. MOMP, on the other hand, is known to carry serovariant-specific antigens, and antibodies to these molecules neutralize infectivity. Even in polyvalent sera there is a big difference between homologous and heterologous neutralization. Unfortunately, MOMP is the only major surface component that is well understood. There may be other antigens, and this area is worthy of continued investigation.
C. trachomatis has only one gene for MOMP, but the gene and the protein vary across strains. Variation in amino acid sequence occurs in each of four variable sequence (VS) regions called VS1 through VS4; changes are most frequent in VS4 and least frequent in VS3. CD4 T-cell determinants have also been mapped in this protein, including two major ones, one in a conserved region between VS1 and VS2, the other overlapping with VS3. Since there seem to be