Abstract
Human cytomegalovirus (HCMV) can be acquired sexually and is shed from the genital tract. Cross-sectional studies in women show that changes in genital tract microbial flora affect HCMV infection and/or shedding. Since genital microbial flora may affect HCMV infection or replication by stimulating cells through Toll-like receptors (TLR), we assessed the effects of defined TLR-ligands on HCMV replication in foreskin fibroblasts and ectocervical tissue. Poly I:C (a TLR3-ligand) and lipopolysaccharide (LPS, a TLR4-ligand) inhibited HCMV and induced secretion of IL-8 and Interferon-beta (IFNβ) in both foreskin fibroblasts and ectocervical tissue. The anti-HCMV effect was reversed by antibody to IFNβ. CpG (TLR9 ligand) and lipoteichoic acid (LTA, TLR2 ligand) also inhibited HCMV infection in ectocervical tissue and this anti-HCMV effect was also reversed by anti-IFNβ antibody. In contrast, LTA and CpG did not inhibit HCMV infection in foreskin fibroblasts. This study shows that TLR ligands induce an HCMV-antiviral effect that is mediated by IFNβ suggesting that changes in genital tract flora may affect HCMV infection or shedding by stimulating TLR. This study also contrasts the utility of two models that can be used for assessing the interaction of microbial flora with HCMV in the genital tract. Clear differences in the response to different TLR ligands suggests the explant model more closely reflects in vivo responses to genital infections.
Highlights
The seroprevalence of human cytomegalovirus (HCMV) in the United States general population is approximately 60% and is even higher in certain socioeconomic groups [1]
TLR3 and TLR4 ligands but not TLR2 or TLR9 ligands induce IL-8 secretion in foreskin fibroblasts Initial experiments were performed to determine if ligands for TLR2 (LTA), TLR3 (PolyI:C), TLR4 (LPS), or TLR9 (CpG 2395, a type C oligonucleotide) stimulate human foreskin fibroblasts (HFF) by measuring IL-8 secretion since IL-8 is secreted by a wide variety of cell types in response to stimulation by Toll-like receptors (TLR) ligands [21]
lipoteichoic acid (LTA) did not induce significant levels of IL-8 in ectocervical tissue, conditioned medium from LTA-treated ectocervical tissues inhibited HCMV infection by 56% and this was reversed by anti-IFNβ. These results demonstrate that IFNβ contributes to the anti-HCMV effect of TLR2, TLR3, TLR4, and TLR9 ligands in ectocervical tissues
Summary
The seroprevalence of human cytomegalovirus (HCMV) in the United States general population is approximately 60% and is even higher in certain socioeconomic groups [1]. HCMV causes severe disease when immunity is suppressed such as in organ transplant recipients or during the later stages of HIV-1 infection [2]. HCMV infection can be transmitted by bodily fluids of infected individuals, including saliva, blood, semen and cervical/vaginal secretions [3]. Infection of infants can occur from exposure to genital fluids during birth and this route of infection can lead to mild to severe neurological sequelae. Several studies suggest that alterations of genital tract flora in women can affect either initial infection by HCMV or virus replication/shedding. HCMV DNA was detected more frequently in vaginal washings from women with bacterial vaginosis (BV) than in women with normal genital tract flora [4]. BV is an alteration of the female genital tract flora consisting of an increase in both (page number not for citation purposes)
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