TLR2-Mediated Cell Stimulation in Bacterial Vaginosis

Abstract

Bacterial vaginosis (BV) is associated with preterm labor, pelvic inflammatory disease and increased HIV acquisition, although the pathways that mediate these pathological effects have not been elucidated. To determine the presence of toll-like receptor (TLR)-ligands and their specificity in BV, genital tract fluids were collected from women with and without BV by cervicovaginal lavage (CVL). The CVL samples were evaluated for their ability to stimulate secretion of proinflammatory cytokines and to activate NF κB and the HIV long terminal repeat (LTR), indicators of TLR activation, in human monocytic cells. Stimulation with BV CVLs induced higher levels of IL-8 and TNFα secretion, as well as higher levels of HIV LTR and NF κB activation, than CVLs from women with normal healthy bacterial flora. To identify which TLRs were important in BV, 293 cells expressing specific TLRs were exposed to CVL samples. BV CVLs induced higher IL-8 secretion by cells expressing TLR2 than CVLs from women without BV. Surprisingly, BV CVLs did not stimulate cells expressing TLR4/MD2, although these cells responded to purified LPS, a TLR4 ligand. BV CVLs, in cells expressing TLR2, also activated the HIV LTR. Thus, these studies show that soluble factor(s) present in the lower genital tract of women with BV activate cells via TLR2, identifying a pathway through which BV may mediate adverse effects.

Nuclear Receptor Signaling Inhibits HIV-1 Replication in Macrophages through Multipletrans-Repression Mechanisms

“…, it is not surprising that a number of TLR ligands activate HIV-1 expression in immune cells (3,11,34,36,114,145,161). In agreement with other reports (3,11,36,98,114,145,161), we show that signaling through TLR2 activates HIV-1 expression in macrophages and DCs ( Fig. 2 and 3).…”

Suppression of human immunodeficiency virus type 1 replication in macrophages by commensal bacteria preferentially stimulating Toll-like receptor 4

“…Others have reported that Prevotella species potentially stimulated persistent HIV-1 infection through TLR2 (Mares et al, 2008;Spear et al, 2007). These observations suggest that the integrity of the outer membrane of bacteria to stimulate TLR2 or TLR4 is critical in rendering macrophages susceptible or resistant to HIV-1 infection.…”

HIV Type 1 Infection Up-Regulates TLR2 and TLR4 Expression and Function in Vivo and in Vitro

“…Once infection had been established (after 18 h), TLR2 and TLR4 were up-regulated in monocytes, probably to maintain the proinflammatory cytokine profile, which can also promote viral replication after provirus formation by activating NF-jB signaling in HIV-1-infected cells, similar to TLRs. [10][11][12][13][14] At the same time, TLR2 expression was downregulated in mDCs, the most important antigen-presenting cells, suggesting a viral mechanism to evade the immune response. 19 Thus, TLR activation may promote HIV-1 infection due to the effect of downstream signaling effectors on viral replication.…”

“…Subsequently, NF-jB can activate the HIV-1 genome by binding to the viral long terminal repeats (LTRs) in the provirus, even in models of HIV-1 latency. [10][11][12][13][14][15] TLRs are expressed in HIV-1 reservoir cells such as CD4 + T cells, macrophages, and DCs. [16][17][18][19] Various reports indicated that HIV-derived RNA can activate pDCs via TLR7 and TLR8.…”