Stimulation of Human Monocytes with the Gram-Positive Vaccine VectorStreptococcus gordonii

Abstract

Streptococcus gordonii is a bacterial vaccine vector which has previously been shown to activate dendritic cells in vitro and to induce local and systemic immune responses in vivo. In the present study, human monocytes (THP-1 cell line and peripheral blood monocytes) were characterized following interaction with S. gordonii. Treatment of human monocytes with S. gordonii but not latex beads induced a clear up-regulation of CD83, CD40, CD80, and CD54 and the down-regulation of CD14. Furthermore, bacterial treatment stimulated an increased expression of Toll-like receptor 5 (TLR5), TLR6, and TLR7, production of the proinflammatory cytokines tumor necrosis factor alpha and interleukin 1 beta, and reduction of the phagocytic activity. This work shows that the immunostimulatory activity of S. gordonii is not restricted to induction of dendritic-cell maturation but also affects the differentiation process of human monocytes.Streptococcus gordonii is a nonpathogenic gram-positive commensal bacterium and component of the normal microbial flora of the human oral cavity (13) which was developed as a vaccine vector (20,24,26). A variety of antigens of different origins and sizes have been expressed on the surface of S. gordonii and were shown to be immunogenic by the systemic and mucosal routes (oral, nasal, vaginal, and intragastric) both in mice and in monkeys (6, 17-21, 23-25, 31). Using the model of adoptive transfer of transgenic T lymphocytes, we recently demonstrated that an antigen-specific primary activation of CD4 ϩ T cells is induced in the nasal mucosa-associated lymphoid tissue, draining lymph nodes, and spleen following intranasal immunization with recombinant S. gordonii (16). It has also been shown in a phase I clinical trial that S. gordonii is safe in humans when administered by the nasal/oral route and that it can be rapidly eradicated either spontaneously or with antibiotic treatment (14).The mechanisms involved in the immunostimulating activity of this vaccine vector need to be further investigated. We have previously demonstrated that S. gordonii is efficiently internalized by both murine and human dendritic cells (DCs), and it induces their maturation and activation as shown by phenotypic and functional changes (3,4,30). The model antigens expressed on the surfaces of recombinant bacteria are processed and presented by DCs not only in association with major histocompatibility complex (MHC) class II but also MHC class I molecules much more efficiently than the soluble antigen (30). Furthermore, human DCs were more efficient than B cells at presenting the heterologous antigen expressed on the surface of S. gordonii (4).Migrating DCs can originate from monocytes that continuously exit the bloodstream and enter body tissues, where they encounter differentiation (8,28,29,36). Monocytes are immature precursors with a double differentiation potential (27). It has been demonstrated that macrophages and monocyte-derived DCs can readily interconvert into one another until the late stages of their differentiatio...

Streptococcus gordonii promotes rapid differentiation of monocytes into dendritic cells through interaction with the sialic acid-binding adhesin

“…Maturation signals, including those originating from bacteria and cytokines, are the main factors determining whether monocytes differentiate into DCs or macrophages [26]. Recent studies indicate that oral streptococci can influence the differentiation of monocytes into DCs and the maturation of DCs [24,27]. The results of this study coincide with those findings.…”

Phagocytosis ofBorrelia burgdorferi, the Lyme Disease Spirochete, Potentiates Innate Immune Activation and Induces Apoptosis in Human Monocytes

“…2A). As surface expression of CD14 on monocytes has been reported to diminish following incubation with lipopolysaccharide and whole bacteria (28,73,77), we considered the possibility that the ostensible decrease in monocyte numbers was due to down-regulation of this surface marker. While we did, in fact, detect mean fluorescence intensity decreases of approximately 20 and 40% in monocytes incubated with live organisms at MOIs of 10 and 100, respectively (data not shown), these modest changes did not impede our ability to identify monocytes within the PBMCs, even at the highest MOI employed (Fig.…”

Role of surface proteins SspA and SspB of Streptococcus gordonii in innate immunity

“…The bacterium has garnered interest as a potential live oral vaccine delivery vector due to its commensal nature and its ease in genetic manipulation (Lee, 2003;Oggioni et al, 1999). Although S. gordonii is a commensal bacterium, it is readily recognized by professional antigen-presenting cells, such as monocytes and dendritic cells (DCs), inducing both the production of cytokines and the upregulation of surface proteins indicative of cellular maturation (Chan et al, 2007;Ciabattini et al, 2006;Corinti et al, 1999). The activation of antigen-presenting cells by extracellular bacteria is thought to occur predominantly through Toll-like receptor (TLR) recognition of pathogenassociated molecular patterns (PAMPs) that are expressed by the bacteria (Kawai & Akira, 2005).…”