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To understand how SIV infection in a small founder population of cells at the portal of entry transitions in less than two weeks to systemic infection, with massive levels of [...], Although there has been great progress in treating human immunodeficienry virns 1 (HIV-1) infection (1), preventing transmission has thus far proven an elusive goal. Indeed, recent trials of a candidate vaccine and microbicide have been disappointing, both for want of efficacy and concerns about increased rates of transmission (2-4). Nonetheless, studies of vaginal transmission in the simian immunodeficienry virus (SIV)-rhesus macaque (Macacca mulatta) model point to opportunities at the earliest stages of infection in which a vaccine or microbicide might be protective, by limiting the expansion of infected founder populations at the portal of entrys (5-6). Here we show in this SIV-macaque model, that an outside-in endocervical mucosal signalling system, involving MIP-3 α (also known as CCL20), plasmarytoid dendritic cells and [CCR5.sup.+] cell-attracting chemokines produced by these cells, in combination with the innate immune and inflammatory responses to infection in both cervix and vagina, recrnits [CD4.sup.+] T cells to fuel this obligate expansion. We then show that glycerol monolaurate--a widely used antimicrobial compound (7) with inhibitory activity against the production of MIP-3α and other proinflammatory cytokines (8)--can inhibit mucosal signalling and the innate and inflammatory response to HIV-1 and SIV in vitro, and in vivo it can protect rhesus macaques from acute infection despite repeated intra-vaginal exposure to high doses of SIV. This new approach, plausibly linked to interfering with innate host responses that recruit the target cells necessary to establish systemic infection, opens a promising new avenue for the development of effective interventions to block HIV-1 mucosal transmission.

Author(s): Rebecca A Buonpane [1, 5]; Hywyn R O Churchill [1]; Beenu Moza [2]; Eric J Sundberg [2]; Marnie L Peterson [3]; Patrick M Schlievert [4]; David M Kranz (corresponding [...]

The ability of glycerol monolaurate (GML) to inhibit the effects of exotoxins on mammalian cells and prevent rabbit lethality from toxic shock syndrome (TSS) is explored. GML might be a useful compound in preventing the effects of Gram-positive exotoxins, potential agents of bioterrorism, on human cells without significant risk of toxicity.

A study is conducted to determine the amino acids within dodecapetide region (toxic shock syndrome toxin-I amino acids F119-D130) from Staphylococcus aureus that are required for interaction with vaginal epithelium. The results suggested that the toxic shock syndrome toxin-1 residue D130 might contribute to binding an epithelial receptor that facilitates it to penetrate the vaginal mucosa, include interleukin-8, and cause toxic shock syndrome

The impact of the presence of various [alpha] and [beta] chains of hemoglobin on the production of Staphylococcus aureus exotoxins is discussed. The findings reveal that these hemoglobin chains highly inhibit the production of Staphylococcus aureus strains.

Staphylococcus aureus (S. aureus) produces many different exotoxins including the gamma-toxins, HlgAB and HlgCB. Gamma-toxins form pores in both leukocyte and erythrocyte membranes, resulting in cell lysis. The genes encoding gamma-toxins are present in most strains of S. aureus, and are commonly expressed in clinical isolates recovered from menstrual Toxic Shock Syndrome (mTSS) patients. This study set out to investigate the cytotoxic and proinflammatory effects of gamma-toxins on vaginal epithelial surfaces. We found that both HlgAB and HlgCB were cytotoxic to cultured human vaginal epithelial cells (HVECs) and induced cytokine production at sub-cytotoxic doses. Cytokine production induced by gamma-toxin treatment of HVECs was found to involve epidermal growth factor receptor (EGFR) signaling and mediated by shedding of EGFR ligands from the cell surface. The gamma-toxin subunits displayed differential binding to HVECs (HlgA 93%, HlgB 97% and HlgC 28%) with both components (HlgAB or HlgCB) required for maximum detectable binding and significant stimulation of cytokine production. In studies using full thickness ex vivo porcine vaginal mucosa, HlgAB or HlgCB stimulated a dose-dependent cytokine response, which was reduced significantly by inhibition of EGFR signaling. The effects of gamma-toxins on porcine vaginal tissue and cultured HVECs were validated using ex vivo human ectocervical tissue. Collectively, these studies have identified the EGFR-signaling pathway as a key component in gamma-toxin-induced proinflammatory changes at epithelial surfaces and highlight a potential therapeutic target to diminish toxigenic effects of S. aureus infections. [ABSTRACT FROM AUTHOR]