Increased Resistance Against Acute Polymicrobial Sepsis in Mice Challenged with Immunostimulatory CpG Oligodeoxynucleotides Is Related to an Enhanced Innate Effector Cell Response

Weighardt, Heike; Feterowski, Carolin; Veit, Martin; Rump, Martina; Wagner, Hermann; Holzmann, Bernhard

doi:10.4049/jimmunol.165.8.4537

Cited by 121 publications

(108 citation statements)

References 59 publications

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“…6 demonstrate that levels of the activating cytokines, TNF-␣ and IFN-␥, are reduced within the alveolar space following P. aeruginosa infection as well. IFN-␥ has been reported to be important in mediating microbicidal activity (27)(28)(29), and diminished production of this protein is associated with defective killing of intracellular bacteria by both AMs and PMNs (30 -32). Our data suggest that impaired phagocytic function after BMT may be secondary to deficient production of IFN-␥ as well as TNF-␣, although the cellular source that is defective in this capacity (e.g., T cells, NK cells, or AMs) remains to be determined.…”

Section: Discussionmentioning

confidence: 99%

Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation

Ojielo

Cooke²,

Mancuso

et al. 2003

The Journal of Immunology

128

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Bone marrow transplantation (BMT) is an important therapeutic option for a variety of malignant and nonmalignant disorders. Unfortunately, BMT recipients are at increased risk of infection, and in particular, pulmonary complications occur frequently. Although the risk of infection is greatest during the neutropenic period immediately following transplant, patients are still vulnerable to pulmonary infections even after neutrophil engraftment. We evaluated the risk of infection in this postengraftment period by using a well-established mouse BMT model. Seven days after syngeneic BMT, B6D2F1 mice are no longer neutropenic, and by 3 wk, they demonstrate complete reconstitution of the peripheral blood. However, these mice remain more susceptible throughout 8 wk to infection after intratracheal administration of Pseudomonas aeruginosa; increased mortality in the P. aeruginosa-infected BMT mice correlates with increased bacterial burden in the lungs as well as increased systemic dissemination. This heightened susceptibility to infection was not secondary to a defect in inflammatory cell recruitment to the lung. The inability to clear P. aeruginosa in the lung correlated with reduced phagocytosis of the bacteria by alveolar macrophages (AMs), but not neutrophils, decreased production of TNF-α by AMs, and decreased levels of TNF-α and IFN-γ in the bronchoalveolar lavage fluid following infection. Expression of the β2 integrins CD11a and CD11c was reduced on AMs from BMT mice compared with wild-type mice. Thus, despite restoration of peripheral blood count, phagocytic defects in the AMs of BMT mice persist and may contribute to the increased risk of infection seen in the postengraftment period.

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Section: Discussionmentioning

confidence: 99%

Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation

Ojielo

Cooke²,

Mancuso

et al. 2003

The Journal of Immunology

128

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“…TLRs have also been shown to be expressed on human peripheral blood PMNs (61) and to mediate antimicrobial responses (59,62). PMNs can exert antifungal activity by both oxidative and nonoxidative mechanisms (63).…”

Section: Discussionmentioning

confidence: 99%

“…As TLR9 stimulation by CpG enhances innate effector (59) and Th1 responses in experimental models of infection (60), including aspergillosis (25), one would reasonably expect decreased resistance to fungi. We found that TLR9-deficient mice were incapable of mounting an Ag-specific Th1 response, yet they were highly resistant to both mucosal candidiasis and reinfection.…”

Section: Discussionmentioning

confidence: 99%

The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo

Bellocchio

Montagnoli

Bozza

et al. 2004

The Journal of Immunology

465

491

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In vitro studies have indicated the importance of Toll-like receptor (TLR) signaling in response to the fungal pathogens Candida albicans and Aspergillus fumigatus. However, the functional consequences of the complex interplay between fungal morphogenesis and TLR signaling in vivo remain largely undefined. In this study we evaluate the impact of the IL-1R/TLR/myeloid differentiation primary response gene 88 (MyD88)-dependent signaling pathway on the innate and adaptive Th immunities to C. albicans and A. fumigatus in vivo. It was found that 1) the MyD88-dependent pathway is required for resistance to both fungi; 2) the involvement of the MyD88 adapter may occur through signaling by distinct members of the IL-1R/TLR superfamily, including IL-1R, TLR2, TLR4, and TLR9, with the proportional role of the individual receptors varying depending on fungal species, fungal morphotypes, and route of infection; 3) individual TLRs and IL-1R activate specialized antifungal effector functions on neutrophils, which correlates with susceptibility to infection; and 4) MyD88-dependent signaling on dendritic cells is crucial for priming antifungal Th1 responses. Thus, the finding that the innate and adaptive immunities to C. albicans and A. fumigatus require the coordinated action of distinct members of the IL-1R/TLR superfamily acting through MyD88 makes TLR manipulation amenable to the induction of host resistance to fungi.

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“…CpG ODN exert a variety of effects upon macrophages, resulting in the induction of bactericidal responses, such as ROI (Weighardt et al ., 2000) and RNI (Ghosh et al ., 2001) production. As the involvement of PLD activation has recently been shown in ATP-induced killing of intracellular mycobacteria (Fairbairn et al ., 2001) and we have shown that it is crucial in the control of Msm viability (Fig.…”

Section: Cpg Odn Induce Intracellular Mycobacterial Growth Control Thmentioning

confidence: 99%

“…Similarly, other bacterial products such as bacterial DNA, characterized by unmethylated CpG motifs, have been previously described to induce reactive oxygen intermediates (ROI) (Weighardt et al ., 2000) and nitric oxide (NO) (Ghosh et al ., 2001) production in murine macrophages and to increase antimicrobial activity against intrac-ellular pathogens such as Listeria monocytogenes (Krieg et al ., 1998), Leishmania maior (Walker et al ., 1999) and mycobacterial species (Hayashi et al ., 2001;Juffermans et al ., 2002).…”

Section: Introductionmentioning

confidence: 99%

Role of macrophage phospholipase D in natural and CpG-induced antimycobacterial activity

et al. 2003

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SummaryThe present study addresses the differential ability of macrophages to control intracellular growth of nonpathogenic Mycobacterium smegmatis (Msm) and pathogenic M. tuberculosis (MTB). Results reported herein show that 3 h post infection, intracellular Msm , but not MTB, was significantly killed by macrophages. As the role of human macrophage phospholipase D (PLD) in the activation of antimicrobial mechanisms has been documented, we hypothesised the role of such enzyme in antimycobacterial mechanisms. To this aim, macrophage PLD activity was analysed at different times after exposure with either pathogenic MTB or non-pathogenic Msm. Results showed that, starting from 15 min after mycobacterial exposure, MTB did not induce macrophage PLD activity, whereas the environmental non-pathogenic Msm stably increased it. The direct contribution of PLD in intracellular mycobacterial killing was also analysed by inhibiting enzymatic activity with ethanol or calphostin C. Results show that PLD inhibition significantly increases intracellular Msm replication. In order to see whether the innate PLD-mediated antimicrobial mechanisms against MTB are also induced after CpG ODN stimulation, the role of PLD has been analysed in the course of CpG-mediated intracellular MTB killing. CpG DNA increased PLD activity in both uninfected and MTB-infected macrophages, and the inhibition of PLD activity resulted in a significant reduction of CpG-induced MTB killing. Taken together, our data suggest a relationship between host PLD activation and the macrophage ability to control intracellular mycobacterial growth.

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Increased Resistance Against Acute Polymicrobial Sepsis in Mice Challenged with Immunostimulatory CpG Oligodeoxynucleotides Is Related to an Enhanced Innate Effector Cell Response

Cited by 121 publications

References 59 publications

Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation

Defective Phagocytosis and Clearance of Pseudomonas aeruginosa in the Lung Following Bone Marrow Transplantation

The Contribution of the Toll-Like/IL-1 Receptor Superfamily to Innate and Adaptive Immunity to Fungal Pathogens In Vivo

Role of macrophage phospholipase D in natural and CpG-induced antimycobacterial activity

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