<i>Bacteroides fragilis</i>-Derived Lipopolysaccharide Produces Cell Activation and Lethal Toxicity via Toll-Like Receptor 4

Mancuso, Giuseppe; Midiri, Angelina; Biondo, Carmelo; Beninati, Concetta; Gambuzza, Maria Elsa; Macrì, D.; Bellantoni, Antonella; Weintraub, Andrej; Espevik, Terje; Teti, Giuseppe

doi:10.1128/iai.73.9.5620-5627.2005

Cited by 74 publications

(62 citation statements)

References 49 publications

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“…Resident or thioglycolate-elicited mouse macrophages were obtained, as described (35), and incubated with live bacteria at different multiplicities of infection for 2 h. Subsequently, the plates were washed with warm medium and cells were further cultured for various times in the presence of gentamicin (100 g/ml) before harvesting cells and/or supernatants. In control experiments, cells were cultured continuously in the presence of E. coli LPS.…”

Section: Culture and Stimulation Of Peritoneal Macrophagesmentioning

confidence: 99%

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

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223

214

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It is known that host cells can produce type I IFNs (IFN-αβ) after exposure to conserved bacterial products, but the functional consequences of such responses on the outcome of bacterial infections are incompletely understood. We show in this study that IFN-αβ signaling is crucial for host defenses against different bacteria, including group B streptococci (GBS), pneumococci, and Escherichia coli. In response to GBS challenge, most mice lacking either the IFN-αβR or IFN-β died from unrestrained bacteremia, whereas all wild-type controls survived. The effect of IFN-αβR deficiency was marked, with mortality surpassing that seen in IFN-γR-deficient mice. Animals lacking both IFN-αβR and IFN-γR displayed additive lethality, suggesting that the two IFN types have complementary and nonredundant roles in host defenses. Increased production of IFN-αβ was detected in macrophages after exposure to GBS. Moreover, in the absence of IFN-αβ signaling, a marked reduction in macrophage production of IFN-γ, NO, and TNF-α was observed after stimulation with live bacteria or with purified LPS. Collectively, our data document a novel, fundamental function of IFN-αβ in boosting macrophage responses and host resistance against bacterial pathogens. These data may be useful to devise alternative strategies to treat bacterial infections.

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Section: Culture and Stimulation Of Peritoneal Macrophagesmentioning

confidence: 99%

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Mancuso

Midiri

Biondo

et al. 2007

The Journal of Immunology

Self Cite

223

214

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“…HEK 293-CD14/TLR4/MD2 and HEK 293 control cells were grown as described previously [36]. For stimulation experiments, cells were plated in 24-well tissue culture plates (5 Â 10 5 cells/ mL) and incubated for 5 h with different concentrations of stimuli.…”

Section: Detection Of Endotoxin Contaminationmentioning

confidence: 99%

Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

et al. 2011

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Although type I interferons (IFN-a/b) have been traditionally associated with antiviral responses, their importance in host defense against bacterial pathogens is being increasingly appreciated. Little is known, however, about the occurrence and functional role of IFN-a/b production in response to pathogenic yeasts. Here, we found that conventional DCs, but not macrophages nor plasmacytoid DCs, mounted IFN-b responses after in vitro stimulation with Candida spp. or Saccharomyces cerevisiae. These responses absolutely required MyD88, a Toll-like receptor (TLR) adaptor molecule, and were partially dependent on TLR9 and TLR7. Moreover, Candida DNA, as well as RNA, could recapitulate the IFN-b response. After intravenous challenge with Candida albicans, most mice lacking the IFN-a/b receptor died from their inability to control fungal growth, whereas all WT controls survived. These data suggest that recognition of yeast nucleic acids by TLR7 and TLR9 triggers a host-protective IFN-a/b response.Key words: Candida albicans . Cytokines . DCs . Fungal infections . Macrophages Supporting Information available online IntroductionCandida albicans (C. albicans) is, among fungi, the most common pathogen of humans. Although they are normally harmless commensals of the intestinal and urinary tract, C. albicans and other Candida species can cause recurrent mucosal infections in otherwise healthy subjects and life-threatening conditions in hospitalized or immunocompromised patients [1]. In recent years, C. albicans has become the fourth most common cause of bloodstream infections, with an incidence of between 1 and 24 cases per 100 000 and a mortality rate of 30-50% [2]. Since the host immune status is the major factor that determines the transition of C. albicans from commensalism to pathogenicity, elucidating the mechanisms underlying immune response initiation, particularly those underlying recognition of fungal components, is crucial to developing new and more effective strategies to combat these infections. In fact, despite the availability of new classes of antifungal drugs, current available therapies are only partially effective and are associated with significant side effects.Antimicrobial responses are initiated by the activation of germ-line-encoded receptors (pattern-recognition receptors, PRRs) expressed by cells of the innate immune system, mainly by macrophages and DCs, which monitor potential portals of pathogen entry. Each PRR binds directly or indirectly to one or more evolutionary conserved microbial molecules (pathogenassociated molecular patterns, PAMPs) and triggers intracellular signal transduction cascades culminating in distinctive transcriptional and nontranscriptional responses. By this mechanism, PRRs link microbial recognition with the selective activation of specific arms of the innate immune system [3].Ã These authors have contributed equally to this study. Eur. J. Immunol. 2011. 41: 1969-1979 DOI 10.1002 Immunity to infection 1969Considerable progress has been recently made in the identification ...

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“…Structurally, these forms are very similar to one another and to the B. fragilis LPS, previously determined to be of low toxicity (20). However, they differ from the S. Minnesota LPS and MPLA forms at key areas known to influence TLR4 activation, mainly in the length and number of acyl chains (Fig.…”

Section: Discussionmentioning

confidence: 76%

“…Like MPLA, LPS obtained from these bacterial species is less toxic than E. coli LPS (17,19). The published Bacteroides fragilis LPS structure has been shown to be at least 1,000-fold less toxic than E. coli LPS in vivo after D-galactosamine priming (20). The striking differences in toxicity in response to the various Gram-negative species LPS forms has led Munford to propose that the structural features of LPS act as guides enabling the host Toll-like receptor 4 (TLR4)/ MD2 receptor system to distinguish the low-toxicity commensal Gram-negative bacteria from the more highly pathogenic members of the family Enterobacteriaceae (21).…”

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confidence: 99%

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Adjuvant Activity of Naturally Occurring Monophosphoryl Lipopolysaccharide Preparations from Mucosa-Associated Bacteria

Chilton

Hadel

et al. 2013

Infect Immun

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c Natural heterogeneity in the structure of the lipid A portion of lipopolysaccharide (LPS) produces differential effects on the innate immune response. Gram-negative bacterial species produce LPS structures that differ from the classic endotoxic LPS structures. These differences include hypoacylation and hypophosphorylation of the diglucosamine backbone, both differences known to decrease LPS toxicity. The effect of decreased toxicity on the adjuvant properties of many of these LPS structures has not been fully explored. Here we demonstrate that two naturally produced forms of monophosphorylated LPS, from the mucosa-associated bacteria Bacteroides thetaiotaomicron and Prevotella intermedia, function as immunological adjuvants for antigen-specific immune responses. Each form of mucosal LPS increased vaccination-initiated antigen-specific antibody titers in both quantity and quality when given simultaneously with vaccine antigen preparations. Interestingly, adjuvant effects on initial T cell clonal expansion were selective for CD4 T cells. No significant increase in CD8 T cell expansion was detected. MyD88/Tolllike receptor 4 (TLR4) and TRIF/TLR4 signaling pathways showed equally decreased signaling with the LPS forms studied here as with endotoxic LPS or detoxified monophosphorylated lipid A (MPLA). Natural monophosphorylated LPS from mucosa-associated bacteria functions as a weak but effective adjuvant for specific immune responses, with preferential effects on antibody and CD4 T cell responses over CD8 T cell responses.

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Bacteroides fragilis-Derived Lipopolysaccharide Produces Cell Activation and Lethal Toxicity via Toll-Like Receptor 4

Cited by 74 publications

References 49 publications

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Type I IFN Signaling Is Crucial for Host Resistance against Different Species of Pathogenic Bacteria

Recognition of yeast nucleic acids triggers a host‐protective type I interferon response

Adjuvant Activity of Naturally Occurring Monophosphoryl Lipopolysaccharide Preparations from Mucosa-Associated Bacteria

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