In Vivo Selection for Neisseria gonorrhoeae Opacity Protein Expression in the Absence of Human Carcinoembryonic Antigen Cell Adhesion Molecules

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Abstract
The neisserial opacity (Opa) proteins are phase-variable, antigenically distinct outer membrane proteins that mediate adherence to and invasion of human cells. We previously reported that Neisseria gonorrhoeae Opa protein expression appeared to be selected for or induced during experimental murine genital tract infection. Here we further defined the kinetics of recovery of Opa variants from the lower genital tracts of female mice and investigated the basis for this initial observation. We found that the recovery of different Opa phenotypes from mice appears cyclical. Three phases of infection were defined. Following intravaginal inoculation with primarily Opa − gonococci, the majority of isolates recovered were Opa + (early phase). A subsequent decline in the percentage of Opa + isolates occurred in a majority of mice (middle phase) and was followed by a reemergence of Opa + variants in mice that were infected for longer than 8 days (late phase). We showed the early phase was due to selection for preexisting Opa + variants in the inoculum by constructing a chloramphenicol-resistant (Cm r ) strain and following Cm r Opa + populations mixed with a higher percentage of Opa − variants of the wild-type (Cm s ) strain. Reciprocal experiments (Opa − Cm r gonococci spiked with Opa + Cm s bacteria) were consistent with selection of Opa + variants. Based on the absence in mice of human carcinoembryonic antigen cell adhesion molecules, the major class of Opa protein adherence receptors, we conclude the observed selection for Opa + variants early in infection is not likely due to a specific adherence advantage and may be due to Opa-mediated evasion of innate defenses.