Critical Role of the Complement System in Group B Streptococcus -Induced Tumor Necrosis Factor Alpha Release

Autor: Rochelle M. Jean-Jacques, Richard B. Sisson, Ofer Levy, Jennifer L. Christianson, Anne Nicholson-Weller, Paul J. Godowski, Michael R. Wessels, Kol A. Zarember, Hilde-Kari Guttormsen, Michael C. Carroll, Colette Cywes
Rok vydání: 2003
Předmět:
Zdroj: Infection and Immunity. 71:6344-6353
ISSN: 1098-5522
0019-9567
DOI: 10.1128/iai.71.11.6344-6353.2003
Popis: Group B Streptococcus (Streptococcus agalactiae, or GBS) is a major cause of neonatal sepsis and meningitis leading to significant morbidity and mortality (39). GBS also infects pregnant and parturient women and is a growing cause of infections in nonpregnant adults with underlying chronic illness (18). Both acquired and innate immunity are important to host defense against GBS. The role of antibody in facilitating opsonophagocytosis is well described (28). In addition, the complement system contributes to opsonophagocytosis of GBS in both the presence and the absence of specific antibodies (5, 50). However, the role of complement activation with respect to GBS-induced cytokine release has not been defined. Innate immune responses of newborns to GBS infection are also believed to include receptor-mediated recognition of this pathogen by host leukocytes, resulting in the release of inflammatory mediators, including tumor necrosis factor alpha (TNF-α), into the systemic circulation (30). Several lines of evidence suggest that GBS-induced TNF-α release is relevant to the pathophysiology of neonatal sepsis. Isolates of GBS that cause sepsis in human newborns have a relatively high inflammatory potential as reflected by enhanced induction of cytokines, including TNF-α, in vitro (6). Moreover, human newborns infected with GBS have been shown to release TNF-α into the systemic circulation (51). In a rat model of GBS infection, TNF-α release was greater in newborn than in adult rats, the extent of TNF-α release correlated with mortality, and an antibody to TNF-α was protective against early death (43). Despite the growing appreciation of the importance of GBS-induced TNF-α release to the pathophysiology of infection, the mechanisms by which this agent of neonatal bacteremia induces TNF-α release in whole blood have not yet been defined. Human plasma and serum greatly potentiate the inflammatory activity of gram-negative bacteria via lipopolysaccharide (LPS)-binding protein-mediated delivery of LPS to the monocyte LPS receptor complex (CD14/MD2/TLR4) (45). Less is known of the mechanisms by which soluble host components might amplify responses to gram-positive bacteria. Studies of monocytes in culture have demonstrated that heat-labile factors in serum potentiate the ability of gram-positive bacteria to induce cytokine release (15, 24). Addition of fibronectin (34) or LPS-binding protein (32) to cell culture media can modestly enhance GBS-induced TNF-α release from monocytes. However, the extent to which either of these factors may account for the enhancing effect of human serum and whether these mechanisms are operative in whole blood are unknown. GBS is thought to induce TNF-α synthesis via engagement of leukocyte innate immune receptors and subsequent intracellular signaling, resulting in activation of the transcription factors NF-κB and activator protein 1 (48). Several innate immune receptors are candidates for host cell recognition of GBS, but the literature in support of a role for one or another innate immune receptor has been conflicting. In addition, to our knowledge, none of these studies have addressed the potential role of plasma or serum in modulating GBS-induced inflammatory responses. CD14 is a glycosylphosphatidylinositol-linked surface receptor expressed abundantly on monocytes that has affinity for certain microbial surface components, including LPS, peptidoglycan, and lipoteichoic acids (37, 45). CD14 functions as a coreceptor with other pattern recognition receptors such as Toll-like receptors (TLRs) for a number of microbial products. Some studies of GBS activation of monocytes in vitro suggested a role for CD14 in triggering the release of TNF-α in response to whole GBS particles (32) or GBS-derived cell wall components (16), whereas others have suggested that CD14 is not required for cell activation by gram-positive bacteria, including GBS (7, 14). The TLRs are another family of receptors that may be involved in responses to GBS (1, 25, 33). Although TLR2 is involved in the detection of gram-positive bacterial cell wall components (e.g., lipoteichoic acid and peptidoglycan) (40) as well as whole gram-positive bacteria such as Listeria monocytogenes (20) and Staphylococcus aureus (46), it does not appear to be involved in activation of monocytes by whole heat-killed GBS (20). However, GBS apparently elaborates a heat-labile soluble factor capable of activating monocytes in a TLR2- and CD14-dependent fashion (23). Thus, TLR2 may participate in host recognition of GBS in vivo. Among the receptors proposed to contribute to inflammatory signaling by GBS are the leukocyte β-integrins. β-Integrins are heterodimeric surface receptors that bind microbe- and host-derived ligands and contribute to both phagocytosis of microbial particles and microbe-induced leukocyte signaling (17). The C-terminal lectin domain of CR3 can bind directly to microbial surface constituents including LPS, mycobacterial polysaccharides, and fungal β-glucan (52). Another mechanism by which integrin receptors can bind microbial particles occurs when microbes are opsonized by complement, in particular the opsonic fragment C3bi, and subsequently bind to the A (or I) domain of CD11b/CD18 (CR3). In addition to CR3, monocytes also express CR4 (CD11c/CD18), an integrin receptor that binds many of the same ligands as CR3 does. Overall, little is known of the potential role of CR4 in bacterial activation of host cells. Several studies have suggested a role for CD11b/CD18 in mediating cytokine induction in cultured cells in response to heat-killed GBS in vitro (15, 16, 32). However, more recent studies have suggested that TLRs (and CD14) may be central to GBS-induced activation and that CR3, although important for phagocytosis of GBS, does not contribute to GBS-induced cytokine release (22, 23). Among studies that support a role for CR3 in GBS-induced cytokine release, some employing serum-free conditions demonstrate lectin-like interactions between GBS and CR3 (2) that can trigger cytokine release (3). Such studies raise the possibility that host-derived soluble extracellular components do not play a role in the activation of monocytes by GBS. To our knowledge, however, none of these studies have directly addressed the potential role of plasma or serum in modulating GBS-induced TNF-α release. The immature immune system of newborns manifests impaired production and priming of neutrophils, relatively lower complement activity, decreased production of antibodies, and a high percentage of naive T lymphocytes (38). Studies comparing the relative capacities of adult and newborn peripheral blood mononuclear cells (PBMCs) or adherent monocytes to mount cytokine responses to microbes or their surface components have yielded conflicting results (7, 51). As GBS is an important cause of neonatal bacteremia (39) and because TNF-α released upon bloodstream infection with GBS appears to play a significant role in clinical outcomes of GBS infection (6, 43, 51), we sought to define host determinants of TNF-α induction in newborn and adult whole blood and from blood-derived monocytes. We have found that both newborn and adult plasma or serum dramatically enhance GBS-induced TNF-α release from human monocytes. Studies employing human serum depleted of specific complement components and mice deficient in complement component C3 demonstrated the critical role of the alternative complement pathway in such potentiation. Experiments employing neutralizing monoclonal antibodies (MAbs) and mice deficient in complement receptor CR3 demonstrated the importance of CR3 and CR4. These studies provide evidence that the alternative complement pathway accounts for the ability of plasma and serum to markedly enhance the inflammatory activity of GBS via deposition of complement fragments and subsequent activation of monocytes via CR3 and CR4.
Databáze: OpenAIRE
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