FSL-1, a bacterial-derived toll-like receptor 2/6 agonist, enhances resistance to experimental HSV-2 infection.
BACKGROUND
Herpes simplex virus type 2 (HSV-2) is a leading cause of genital ulceration that can predispose individuals to an increased risk of acquiring other sexually transmitted infections. There are no approved HSV-2 vaccines and current suppressive therapies require daily compound administration that does not prevent all recurrences. A promising experimental strategy is the use of toll-like receptor (TLR) agonists to induce an innate immune response that provides resistance to HSV-2 infection. Previous studies showed that anti-herpetic activity varied based on origin of the agonists and activation of different TLR indicating that activity likely occurs through elaboration of a specific innate immune response. To test the hypothesis, we evaluated the ability of a bacterial-derived TLR2/6 agonist (FSL-1) to increase resistance to experimental genital HSV-2 infection.


METHODS
Vaginal application of FSL-1 at selected doses and times was evaluated to identify potential increased resistance to genital HSV-2 infection in the mouse model. The FSL-1 induced cytokine profile was quantified using kinetically collected vaginal lavages. Additionally, cytokine elaboration and organ weights were evaluated after single or multiple FSL-1 doses to establish a preliminary safety profile. Human vaginal EC cultures were used to confirm the mouse model outcomes.


RESULTS
The results showed that vaginally-applied FSL-1 created an environment resistant to a 25-fold higher HSV-2 challenge dose. Mechanistically, vaginal FSL-1 application led to transient elaboration of cytokines linked to anti-herpetic innate immune responses. No gross local or peripheral immunotoxicity was observed even after multiple dosing. FSL-1 also created an anti-herpetic environment in cultures of human vaginal epithelial cells (EC).


CONCLUSIONS
The results showed, for the first time, that the bacterial-derived TLR2/6 agonist FSL-1 induced significant resistance to HSV-2 infection when applied in mice or human vaginal EC cultures. Cytokine evaluation illustrated that anti-herpetic activity correlated with induction of a specific profile. The identified anti-herpetic profile provides an invaluable resource for the future design of novel compounds to reduce genital HSV-2 transmission and improves understanding of the complex innate immune response to potential pathogens elicited by the vaginal mucosa.
Rose
William A
WA
Department of Microbiology and Immunology, University of Texas Medical Branch, Galveston, TX, USA. warose@utmb.edu
McGowin
Chris L
CL
Pyles
Richard B
RB
D000282:Administration, Intravaginal; D000818:Animals; D001426:Bacterial Proteins / Q000276:immunology*; D002478:Cells, Cultured; D016207:Cytokines / Q000276:immunology; D004075:Diglycerides / Q000008:administration & dosage* / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D006558:Herpes Genitalis / Q000276:immunology / Q000517:prevention & control*; D018258:Herpesvirus 2, Human / Q000276:immunology*; D006801:Humans; D007113:Immunity, Innate; D051379:Mice; D009842:Oligopeptides / Q000008:administration & dosage* / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000819:agonists* / Q000276:immunology; D051216:Toll-Like Receptor 6 / Q000819:agonists* / Q000276:immunology; D014779:Virus Replication
D001426:Bacterial Proteins; D016207:Cytokines; D004075:Diglycerides; C460864:FSL-1 lipoprotein, synthetic; D009842:Oligopeptides; D051195:Toll-Like Receptor 2; D051216:Toll-Like Receptor 6