Abstract
Sexually transmitted infections (STIs) unequivocally represent a major public health concern in both industrialized and developing countries. Previous efforts to develop vaccines for systemic immunization against a large number of STIs in humans have been unsuccessful. There is currently a drive to develop mucosal vaccines and adjuvants for delivery through the genital tract to confer protective immunity against STIs. Identification of molecular signatures that can be used as biomarkers for adjuvant potency can inform rational development of potent mucosal adjuvants. Here, we used systems biology to study global gene expression and signature molecules and pathways in the mouse vagina after treatment with two classes of experimental adjuvants. The Toll-like receptor 9 agonist CpG ODN and the invariant natural killer T cell agonist alpha-galactosylceramide, which we previously identified as equally potent vaginal adjuvants, were selected for this study. Our integrated analysis of genome-wide transcriptome data determined which signature pathways, processes and networks are shared by or otherwise exclusive to these 2 classes of experimental vaginal adjuvants in the mouse vagina. To our knowledge, this is the first integrated genome-wide transcriptome analysis of the effects of immunomodulatory adjuvants on the female genital tract of a mammal. These results could inform rational development of effective mucosal adjuvants for vaccination against STIs.
Highlights
The vast majority of human pathogens invade the body and/or establish infections in the mucosal tissues, only a handful of mucosal vaccines are currently licensed for human use
We have previously shown that the Toll-like receptor 9 (TLR9) agonist CpG ODN and the invariant natural killer T (NKT) cell agonist a-galactosylceramide can function as potent vaginal adjuvants when administered together with herpes simplex virus type 2 (HSV-2) glycoprotein D, giving rise to comparable protective immunity against genital HSV-2 infection and disease in mice [7,8]
This study strived to pinpoint signature molecules, pathways, and processes involved in innate immune responses in the mouse vagina following local administration of experimental mucosal adjuvants
Summary
The vast majority of human pathogens invade the body and/or establish infections in the mucosal tissues, only a handful of mucosal vaccines are currently licensed for human use. Previous attempts to develop vaccines for systemic immunization against other sexually transmitted pathogens in humans have failed [1,2] This failure has prompted a great interest in developing vaccines and immunomodulators for delivery via mucosal routes, including the female genital tract, to confer protective mucosal immunity to sexually transmitted pathogens. While sexually transmitted pathogens generate pathogen-specific immune responses, local administration of non-replicating antigens into the vagina engenders little to no protective mucosal immune response [3,4]. To overcome this hurdle, immunologic adjuvants with the ability to mount mucosal immune responses with co-administered vaccine antigens to confer immunity in the female genital tract are desirable. Rational design of effective and safe mucosal adjuvants for human use requires a thorough understanding of the mode of action of promising candidate adjuvants in addition to identification of biomarkers that predict their potency
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