Role of Inflammatory Mediators in Resistance and Susceptibility to Pneumococcal Infection

Kerr, A.; Irvine, June; Search, Jennifer J.; Gingles, Neill A.; Kadioglu, Aras; Andrew, Peter W.; McPheat, William L.; Booth, Charles G.; Mitchell, Tim

doi:10.1128/iai.70.3.1547-1557.2002

Cited by 102 publications

(114 citation statements)

References 55 publications

(40 reference statements)

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“…This would parallel the observations made regarding the role of cytokines such as TNF-␣ in the host response to infections caused by another Gram-positive pathogen, Streptococcus pneumoniae (45,46). Clearly, overproduction of TNF-␣ and other inflammatory mediators contributes to the pathogenesis of septic shock and multiorgan failure during overwhelming pneumococcal infection.…”

Section: Discussionsupporting

confidence: 51%

Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Wang

Meng

Kuhlman

et al. 2007

The Journal of Immunology

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MAPK phosphatase (MKP)-1 is an archetypal member of the dual specificity protein phosphatase family that dephosphorylates MAPK. We have previously demonstrated that MKP-1 acts as a negative regulator of p38 and JNK in immortalized macrophages after stimulation with peptidoglycan isolated from Gram-positive bacteria. To define the physiological function of MKP-1 during Gram-positive bacterial infection, we studied the innate immune responses to Gram-positive bacteria using Mkp-1 knockout (KO) mice. We found that Mkp-1−/− macrophages exhibited prolonged activation of p38 and JNK, but not of ERK, following exposure to either peptidoglycan or lipoteichoic acid. Compared with wild-type (WT) macrophages, Mkp-1−/− macrophages produced more proinflammatory cytokines such as TNF-α and IL-6. Moreover, after challenge with peptidoglycan, lipoteichoic acid, live or heat-killed Staphylococcus aureus bacteria, Mkp-1 KO mice also mounted a more robust production of cytokines and chemokines, including TNF-α, IL-6, IL-10, and MIP-1α, than did WT mice. Accordingly, Mkp-1 KO mice also exhibited greater NO production, more robust neutrophil infiltration, and more severe organ damage than did WT mice. Surprisingly, WT and Mkp-1 KO mice exhibited no significant difference in either bacterial load or survival rates when infected with live S. aureus. However, in response to challenge with heat-killed S. aureus, Mkp-1 KO mice exhibited a substantially higher mortality rate compared with WT mice. Our studies indicate that MKP-1 plays a critical role in the inflammatory response to Gram-positive bacterial infection. MKP-1 serves to limit the inflammatory reaction by inactivating JNK and p38, thus preventing multiorgan failure caused by exaggerated inflammatory responses.

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Section: Discussionsupporting

confidence: 51%

Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Wang

Meng

Kuhlman

et al. 2007

The Journal of Immunology

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“…A previous study reported that after intranasal pneumococcal infection, TNF-␣ receptor KO mice exhibit elevated bacteremia and progress more rapidly to a fatal outcome (12). Although studies showed that TNF-␣ may be dispensable in pulmonary responses, it appears to be a necessary beneficial regulator of systemic organ protection in pneumococcal disease (15).…”

Section: Discussionmentioning

confidence: 99%

“…Although studies showed that TNF-␣ may be dispensable in pulmonary responses, it appears to be a necessary beneficial regulator of systemic organ protection in pneumococcal disease (15). The role of TNF-␣ may be a double-edged sword, since TNF-␣ is important in the early stages of infection but its levels need to be controlled later to avoid an exacerbated inflammatory response (12).…”

Section: Discussionmentioning

confidence: 99%

“…In mice, the development of disease and the host response to the pneumococcal challenge have been studied with different strains of wild-type (WT) and knockout (KO) animals (13,14,18,25,27), but all of these studies were performed with nonimmunized mice only and reported that resolution of infection in the naïve host is mediated primarily through phagocytosis and intracellular killing by neutrophils and macrophages, which are recruited to the site of infection in response to proinflammatory cytokine and interleukin release by T lymphocytes. In accordance with this, it has been suggested that gamma interferon (IFN-␥) and tumor necrosis factor alpha (TNF-␣) produced by NK and T cells have a crucial involvement not only in the natural host defense but also in acquired resistance against S. pneumoniae (12,24). Furthermore, events which mediate the early innate release of pro-and antiinflammatory cytokines in response to this pathogen may have a profound influence on the quality and intensity of the subsequent adaptive immune response.…”

mentioning

confidence: 91%

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Optimized Immune Response Elicited by a DNA Vaccine Expressing Pneumococcal Surface Protein A Is Characterized by a Balanced Immunoglobulin G1 (IgG1)/IgG2a Ratio and Proinflammatory Cytokine Production

Ferreira

Darrieux

Oliveira

et al. 2008

Clin Vaccine Immunol

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We have previously shown that DNA immunization with PspA (pneumococcal surface protein A) DNA is able to elicit protection comparable to that elicited by immunization with PspA protein (with alum as adjuvant), even though the antibody levels elicited by DNA immunization are lower than those elicited by immunization with the protein. This work aims at characterizing the ability of sera to bind to the pneumococcal surface and to mediate complement deposition, using BALB/c wild-type and interleukin-4 knockout mice. We observed that higher anti-PspA levels correlated with intense antibody binding to the pneumococcal surface, while elevated complement deposition was observed with sera that presented balanced immunoglobulin G1 (IgG1)/IgG2a ratios, such as those from DNA-immunized mice. Furthermore, we demonstrated that gamma interferon and tumor necrosis factor alpha were strongly induced after intraperitoneal pneumococcal challenge only in mice immunized with the DNA vaccine. We therefore postulate that although both DNA and recombinant protein immunizations are able to protect mice against intraperitoneal pneumococcal challenge, an optimized response would be achieved by using a DNA vaccine and other strategies capable of inducing balanced Th1/Th2 responses.

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“…Whether human mast cells interact with the pneumococcus is unknown. However, we previously showed more mast cells in the airways of mice that successfully cleared pneumococci from their lungs following intranasal infection compared with those that did not (32).…”

mentioning

confidence: 90%

Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin

Cruse

Fernandes

Salort

et al. 2010

The Journal of Immunology

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Mast cells are emerging as contributors to innate immunity. Mouse mast cells have a pivotal role in protection against bacterial infection, and human cord blood-derived mast cells reduce bacterial viability in culture. The objectives of this study were to determine whether human lung mast cells (HLMCs) might be protective against pneumococcal lung infection through direct antimicrobial activity. Tissue-derived HLMCs and the human mast cell lines HMC-1 and LAD2 were cocultured with wild-type and mutant pneumococci, and viability and functional assays were performed. Mast cells were also stimulated with purified pneumolysin. HLMCs killed wild-type serotype-2 (D39) pneumococci in coculture but had no effect on an isogenic pneumolysin-deficient (PLN-A) pneumococcus. D39 wild-type, but not PLN-A pneumococci, induced the release of leukotriene C4 from human mast cells in a dose-dependent manner, which was not accompanied by histamine release. Stimulation of mast cells with sublytic concentrations of purified pneumolysin replicated this effect. Furthermore, pneumolysin induced the release of the cathelicidin LL-37 from HLMCs, purified LL-37 reduced pneumococcal viability, and neutralizing Ab to LL-37 attenuated mast cell-dependent pneumococcal killing. In addition, at high concentrations, all pneumococcal strains tested reduced HLMC viability through a combination of pneumolysin and H2O2-dependent mechanisms. HLMCs exhibit direct antimicrobial activity to pneumococci through their activation by pneumolysin. This antimicrobial activity is mediated, in part, by the release of LL-37 from HLMCs. This suggests that mast cells provide an early warning system and potentially limit pneumococcal dissemination early in the course of invasive pulmonary pneumococcal disease.

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Role of Inflammatory Mediators in Resistance and Susceptibility to Pneumococcal Infection

Cited by 102 publications

References 55 publications

Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Knockout of Mkp-1 Enhances the Host Inflammatory Responses to Gram-Positive Bacteria

Optimized Immune Response Elicited by a DNA Vaccine Expressing Pneumococcal Surface Protein A Is Characterized by a Balanced Immunoglobulin G1 (IgG1)/IgG2a Ratio and Proinflammatory Cytokine Production

Human Lung Mast Cells Mediate Pneumococcal Cell Death in Response to Activation by Pneumolysin

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