MicroRNAs Constitute a Negative Feedback Loop in<i>Streptococcus pneumoniae</i>–Induced Macrophage Activation

Griss, Kathrin; Bertrams, Wilhelm; Sittka-Stark, A; Seidel, Kerstin; Stielow, Christina; Hippenstiel, Stefan; Suttorp, Norbert; Eberhardt, Martin; Wilhelm, Jochen; Vera, Julio; Schmeck, Bernd

doi:10.1093/infdis/jiw109

Cited by 22 publications

(19 citation statements)

References 48 publications

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“…S. pneumoniae D39serotype 2 and a multi-resistant clinical isolate serotype 19A (AMR, resistant against Penicillin 8 µg/ml, Cefotaxim 4µg/ml, Erythromycin 256 µg/ml, Clindamycin 256 µg/ml, Tetracycline 32 µg/ml) were cultured as described before [14]. They were grown on sheep blood agar plates for 10 h and then transferred to Todd Hewitt Yeast (THY) medium (Carl Roth GmbH, Karlsruhe) at a density of 4 × 10 7 bacteria/ml (Ultraspec 10 Cell Densitometer, Amersham Biosciences).…”

Section: S Pneumoniae Culture and Growth Kineticsmentioning

confidence: 99%

Antibacterial activity of a Tribolium castaneum defensin in an in vitro infection model of Streptococcus pneumoniae

et al. 2019

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Streptococcus pneumoniae (S. pneumoniae) is the most common bacterial cause of communityacquired pneumonia. Increasing rates of antibiotic-resistant S. pneumoniae strains impair therapy and necessitate alternative treatment options. In this study, we analysed insect-derived antimicrobial peptides (AMPs) for antibacterial effects on S. pneumoniae in a human in vitro infection model. AMP effects on bacterial growth were examined by colony forming unit (CFU)-assays, and growth curve measurements. Furthermore, cytotoxicity to primary human macrophages was detected by measuring lactate-dehydrogenase release to the supernatant. One AMP (Defensin 1) was tested in a model of primary human monocyte-derived macrophages infected with S. pneumoniae strain D39 and a multi-resistant clinical isolate. Inflammatory reactions were characterised by qPCR and multiplex-ELISA. In total, the antibacterial effects of 23 AMPs were characterized. Only Tribolium castaneum Defensin 1 showed significant antibacterial effects against S. pneumoniae strain D39 and a multiresistant clinical isolate. During in vitro infection of primary human macrophages with S. pneumoniae D39, Defensin 1 displayed strong antibacterial effects, and consequently reduced bacteria-induced cytokine expression and release. In summary, Tribolium castaneum Defensin 1 showed profound antibacterial effectivity against Streptococcus pneumoniae D39 and a multi-resistant clinical isolate without unwanted cytotoxic or inflammatory side effects on human blood-derived macrophages.

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Section: S Pneumoniae Culture and Growth Kineticsmentioning

confidence: 99%

Antibacterial activity of a Tribolium castaneum defensin in an in vitro infection model of Streptococcus pneumoniae

et al. 2019

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“…Stimulation of the human monocytic cell line THP1 by a TLR ligand, LPS, induces miR-146a/b expression in an NF-κB-dependent fashion, and this induction inhibits innate immune responses (49). In addition, pneumococcal infection of human macrophages induces expression of several microRNAs, including miR-146a, in a TLR-2-dependent manner, which prevents excessive inflammation (50). We performed microRNA array analysis using neutrophil like-differentiated HL60 cells, S. pneumoniae strains and rPfbA (Supplementary Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Human macrophages challenged with S. pneumoniae induce a negative feedback loop, preventing excessive inflammation via miR-146a and potentially other miRNAs on the TLR2-MyD88 axis (50). On the other hand, pneumococcal endopeptidase O enhances macrophage phagocytosis in a TLR2- and miR-155-dependent manner (58).…”

Section: Discussionmentioning

confidence: 99%

Streptococcus pneumoniae evades host cell phagocytosis and limits host mortality through its cell wall anchoring protein PfbA

Yamaguchi

Hirose

Takemura

et al. 2019

Preprint

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20Streptococcus pneumoniae is a Gram-positive bacterium belonging to the oral 21 streptococcus species, mitis group. This pathogen is a leading cause of 22 community-acquired pneumonia, which often evades host immunity and causes 23 systemic diseases, such as sepsis and meningitis. Previously, we reported that PfbA is a 24 β-helical cell surface protein contributing to pneumococcal adhesion to and invasion of 25 human epithelial cells in addition to its survival in blood. In the present study, we 26 investigated the role of PfbA in pneumococcal pathogenesis. Phylogenetic analysis 27 indicated that the pfbA gene is specific to S. pneumoniae within the mitis group. Our in 28 vitro assays showed that PfbA inhibits neutrophil phagocytosis, leading to 29 pneumococcal survival. We found that PfbA activates NF-κB through TLR2, but not 30 TLR4. In addition, TLR2/4 inhibitor peptide treatment of neutrophils enhanced the 31 survival of the S. pneumoniae ∆pfbA strain as compared to a control peptide treatment, 32whereas the treatment did not affect survival of a wild-type strain. In a mouse 33 pneumonia model, the host mortality and level of TNF-α in bronchoalveolar lavage 34 fluid were comparable between wild-type and ∆pfbA-infected mice, while deletion of 35 4 pfbA increased the bacterial burden in bronchoalveolar lavage fluid. In a mouse sepsis 36 model, the ∆pfbA strain demonstrated significantly increased host mortality and TNF-α 37 levels in plasma, but showed reduced bacterial burden in lung and liver. These results 38 indicate that PfbA may contribute to the success of S. pneumoniae species by inhibiting 39 host cell phagocytosis, excess inflammation, and mortality. 40 41 Importance 42Streptococcus pneumoniae is often isolated from the nasopharynx of healthy 43 children, but the bacterium is also a leading cause of pneumonia, meningitis, and sepsis. 44In this study, we focused on the role of a cell wall anchoring protein, PfbA, in the 45 pathogenesis of S. pneumoniae-related disease. We found that PfbA is a 46 pneumococcus-specific anti-phagocytic factor that functions as a TLR2 ligand, 47indicating that PfbA may represent a pneumococcal-specific therapeutic target. 48However, a mouse pneumonia model revealed that PfbA deficiency reduced the 49 bacterial burden, but did not decrease host mortality. Furthermore, in a mouse sepsis 50 model, PfbA deficiency increased host mortality. These results suggest that S. 51 5 pneumoniae optimizes reproduction by regulating host mortality through PfbA; 52 therefore, PfbA inhibition would not be an effective strategy for combatting 53 pneumococcal infection. Our findings underscore the challenges involved in drug 54 development for a bacterium harboring both commensal and pathogenic states. 55 56

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“…One such pathway is the IL-23/IL-17 pathway shown to contribute to the host response to numerous pathogens [53,54] . Multiple miRNA target this pathway, including miR-146 and miR-155 [55][56][57] . These miRNA are therefore able to regulate the alveolar macrophage's response to multiple pathogens by influencing proteins central to multiple signaling pathways.…”

Section: Macrophagesmentioning

confidence: 99%

Role of MicroRNA in the Lung's Innate Immune Response

Cohen¹

2016

J Innate Immun

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The immune response to respiratory pathogens must be robust enough to defend the host yet properly constrained such that inflammation-induced tissue damage is avoided. MicroRNA (miRNA) are small noncoding RNA which posttranscriptionally influence gene expression. In this review, we discuss recent experimental evidence of the contribution of miRNA to the lung's response to bacterial and viral pathogens.

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MicroRNAs Constitute a Negative Feedback Loop inStreptococcus pneumoniae–Induced Macrophage Activation

Cited by 22 publications

References 48 publications

Antibacterial activity of a Tribolium castaneum defensin in an in vitro infection model of Streptococcus pneumoniae

Antibacterial activity of a Tribolium castaneum defensin in an in vitro infection model of Streptococcus pneumoniae

Streptococcus pneumoniae evades host cell phagocytosis and limits host mortality through its cell wall anchoring protein PfbA

Role of MicroRNA in the Lung's Innate Immune Response

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