Wednesday, January 15, 2025
1/15/2025
Abstract The serious concerns of the health-care community around the current state of worldwide N. gonorrhoeae infec- tions are well known and documented in the infectious diseases, microbiology and immunology communities and literature. The major manifestations of gonococcal (GC) infection worldwide are genital tract infections and conjunctivitis, the latter a major problem in infants born in low and middle income countries, diagnosed as oph- thalmia neonatorum. There is a global concern about effective treatments due to antimicrobial resistance and the threat of pan-resistant, untreatable GC infections is high. Thus, new approaches, strategies and tools are needed to address the consequences from this exceedingly successful human pathogen. At the top of this list are vaccines and immunotherapeutics to control GC infection and transmission. Yet, unlike its cousin, N. men- ingitides, where vaccine-preventable disease has been obtained by targeting the immunogenic, serologically variable capsular polysaccharides or, more recently, surface proteins for serogroup B, such vaccine targets have not been identified on N. gonorrhoeae cells. Indeed, there are no known correlates of human immunity mediating resistance to GC infection. Furthermore, reinfection with N. gonorrhoeae seems to occur sufficiently frequently to suggest that vaccine antigens are either serologically variable and differ markedly among strains, or, infection with GC simply does not engender sufficient protective immune responses. The goal of this research project is to develop and validate a murine model of N. gonorrhoeae conjunctivitis in both adult and neonatal mice to study virulence and immunity to this pathogen in a readily accessible laboratory animal model. A second goal will be to evaluate the prophylactic and therapeutic potential of antibody therapeu- tics to N. gonorrhoeae to substantiate the utility of the conjunctival infection model for such studies. These targets include the conserved bacterial surface polysaccharide poly-N-acetyl glucosamine (PNAG) that we have shown surrounds the outer surface of N. gonorrhoeae and serves as a target for bactericidal antibody, and the surface lipooligosaccharide (LOS) recognized by monoclonal antibody (MAb) 2C7. We propose to take advantage of our extensive experience with murine models of ocular infections to study N. gonorrhoeae conjunctivitis in adult and neonatal mice. We will determine the growth and dose parameters needed to establish infection in both of these murine settings, the latter as a model for ophthalmia neonatorum. We will evaluate pathogenesis of multiple N. gonorrhoeae strains, test active and passive immunotherapies for impacting bacterial burdens and conjunctival pathology, and determine some of the in vitro and in vivo immune effectors needed to impact these measures of infection and disease. Success would open up the potential to readily study additional vaccines and therapies, as well as virulence factors and host innate and acquired im- munity to N. gonorrhoeae in a clinically-relevant setting. Thus, an in vivo murine model for GC conjunctival infection would fill in the gaps currently limiting the study of virulence and immunity to N. gonorrhoeae infections.
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