Group A Streptococcus induces less p65 nuclear translocation and non-classical nuclear factor kappa B activation in macrophages, which possibly leads to a weaker inflammatory response

Wu, Shu-Hui; Ma, Cuiqing; Xue, Guanhua; Zhang, Ling; Miao, Qingfeng; Li, Miao; Li, Wenjian; Song, Xiaotian; Wang, Xiurong; Liu, Jianguo; Wei, Lin

doi:10.1016/j.ijid.2016.01.018

Cited by 7 publications

(6 citation statements)

References 38 publications

(29 reference statements)

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“…It is also noteworthy that the M12 and M55 serotypes are associated with post-streptococcal glomerulonephritis (Ferrieri et al, 1970;Dillon, 1979), an important sequelae of S. pyogenes infection, but not with invasive disease. The activation of NF-kB and MAPK in macrophages/monocytes by S. pyogenes (Wu et al, 2016) leads to the production of pro-inflammatory cytokines like TNFa in a MyD88-dependent fashion (Gratz et al, 2008). Similar to our finding that SIC-containing bacterial growth medium triggered activation of both the NF-kB and p38 MAPK pathways, growth medium of other Gram-positive bacteria, like S. aureus, triggered the release of antimicrobial peptides via the same pathways (Zhu et al, 2013).…”

Section: Discussionsupporting

confidence: 81%

“…However, M1 might not be a direct TLR agonist, but rather operating through interactions with other secreted streptococcal products (Valderrama et al, 2017), triggering the subsequent cytokine release. Similar to CD14, the expression of TLR2 can be induced by bacterial products and whole bacteria, like S. pyogenes (Wu et al, 2016). However, the primary interaction of the bacterial product can be with CD14 followed by the involvement of a TLR (Van Amersfoort and Kuiper, 2007).…”

Section: Discussionmentioning

confidence: 99%

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Streptococcal protein SIC activates monocytes and induces inflammation

et al. 2021

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Summary Streptococcus pyogenes is a major bacterial pathogen in the human population and isolates of the clinically important M1 serotype secrete protein Streptococcal inhibitor of complement (SIC) known to interfere with human innate immunity. Here we find that SIC from M1 bacteria interacts with TLR2 and CD14 on monocytes leading to the activation of the NF-κB and p38 MAPK pathways and the release of several pro-inflammatory cytokines (e.g. TNFα and INFγ). In human plasma, SIC binds clusterin and histidine-rich glycoprotein, and whole plasma, and these two purified plasma proteins enhanced the activation of monocytes by SIC. Isolates of the M55 serotype secrete an SIC homolog, but this protein did not activate monocytes. M1 isolates are common in cases of invasive S. pyogenes infections characterized by massive inflammation, and the results of this study indicate that the pro-inflammatory property of SIC contributes to the pathology of these severe clinical conditions.

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Section: Discussionsupporting

confidence: 81%

Section: Discussionmentioning

confidence: 99%

Streptococcal protein SIC activates monocytes and induces inflammation

et al. 2021

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“…A recent study on community-acquired pneumonia showed higher PCT concentrations associated with typical bacteria than with atypical bacteria [ 25 ]. One experimental study described several differences in intracellular signaling after TLR activation between Group A Streptococci, Staphylococcus aureus and E. coli , and speculated that this results in a lower inflammatory response in Streptococci [ 26 ]. Another in-vitro study compared cytokine production induced in cord blood cells by heat-killed Group B Streptococci, E. coli and Staphylococcus epidermidis , and found quite different response patterns with higher cytokine levels for E. coli and Streptococci [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

Influence of pathogen and focus of infection on procalcitonin values in sepsis patients with bacteremia or candidemia

et al. 2018

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BackgroundThis study aimed to evaluate the accuracy of procalcitonin (PCT) serum concentrations to diagnose Gram-negative bacteremia and the association of PCT serum concentrations with more specific pathogens and the focus of infection.MethodsSecondary analysis of the prospectively collected patient-level dataset from a cluster randomized quality improvement trial was performed. The trial included sepsis patients with organ dysfunction treated in the participating intensive care units from 2011 to 2015. Test performance for the prediction of Gram-negative bacteremia was assessed by receiver operating curve analysis. Independent effects of specific pathogen groups and foci of infection on PCT concentrations were assessed by linear logistic regression models.ResultsBlood cultures (BC) and PCT concentrations had been taken in 4858 of 6561 documented patients. PCT was significantly higher in Gram-negative bacteremia compared to Gram-positive bacteremia or candidemia (p < 0.001). The area under the curve was 0.72 (95% confidence interval 0.71–0.74) for the prediction of Gram-negative bacteremia compared to all other blood culture results including negative blood cultures. The optimized cutoff value was 10 ng/ml (sensitivity 69%, specificity 35%). PCT differed significantly between specific groups of pathogens (p < 0.001) with highest concentrations in Escherichia coli, Streptococcus species and other Enterobacteriaceae. PCT was highest in urogenital followed by abdominal infection and lowest in respiratory infection (p < 0.001). In a linear regression model, Streptococci, E. coli and other Enterobacteriaceae detected from BC were associated with three times higher PCT values. Urogenital or abdominal foci of infection were associated with twofold increased PCT values independent of the pathogen.ConclusionsSerum PCT concentrations are higher in patients with Gram-negative bacteremia than in patients with Gram-positive bacteremia or candidemia. However, the discriminatory power of this difference is too low to guide therapeutic decisions. Variations in PCT serum concentrations are not determined solely by Gram-negative or Gram-positive bacteria but are also affected by distinct groups of pathogens and different foci of infection.Trial registrationClinicalTrials.gov, NCT01187134. Registered on 23 August 2010.Electronic supplementary materialThe online version of this article (10.1186/s13054-018-2050-9) contains supplementary material, which is available to authorized users.

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“…Surprisingly, results showed that compared with E. coli , GAS induced a lower expression level of inflammatory cytokines within 7 h of stimulation, and slight inflammation in the lung (Figure 2A ). Accordingly, our previous results showed that the level of NF-κB activation induced by GAS was much lower than that by Staphylococcus aureus , but was similar to that induced by E. coli (Wu et al, 2016 ). It was not clear as to why the levels of inflammatory mediators induced by GAS were much lower than those induced by E. coli .…”

Section: Discussionmentioning

confidence: 72%

M Protein of Group a Streptococcus Plays an Essential Role in Inducing High Expression of A20 in Macrophages Resulting in the Downregulation of Inflammatory Response in Lung Tissue

Gao

et al. 2018

Front. Cell. Infect. Microbiol.

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Group A streptococcus (GAS), a common pathogen, is able to escape host immune attack and thus survive for longer periods of time. One of the mechanisms used by GAS is the upregulated expression of immunosuppressive molecules, which leads to a reduction in the production of inflammatory cytokines in immune cells. In the present study, we found that macrophages produced lower levels of proinflammatory cytokines (IL-1β, TNF-α, IL-6) when challenged with GAS than they did when challenged with Escherichia coli (E. coli). Simultaneously, in a mouse model of lung infection, GAS appeared to induce a weaker inflammatory response compared to E. coli. Our data also indicated that the expression of the A20 transcriptional regulator was higher in GAS-infected macrophages than that in macrophages infected with E. coli, and that high expression of A20 correlated with a reduction in the production of TRAF6. SiRNA targeting of A20 led to the increased production of TRAF6, IL-1β, TNF-α, and IL-6, suggesting that A20 inhibits synthesis of these key proinflammatory cytokines. We also investigated the pathway underlying A20 production and found that the synthesis of A20 depends on My88, and to a lower extent on TNFR1. Finally, we showed a significant reduction in the expression of A20 in macrophages stimulated by M protein-mutant GAS, however, a speB-GAS mutant, which is unable to degrade M protein, induced a greater level of A20 production than wild type GAS. Collectively, our data suggested that M protein of GAS was responsible for inducing A20 expression in macrophages, which in turn down-regulates the inflammatory cytokine response in order to facilitate GAS in evading immune surveillance and thus prolong survival in the host.

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Group A Streptococcus induces less p65 nuclear translocation and non-classical nuclear factor kappa B activation in macrophages, which possibly leads to a weaker inflammatory response

Abstract: Compared to S. aureus and E. coli infection, GAS induced a weaker nuclear translocation and distinct combination of NF-κB subunits in macrophages, which probably leads to a weak inflammatory response.

Cited by 7 publications

References 38 publications

Streptococcal protein SIC activates monocytes and induces inflammation

Streptococcal protein SIC activates monocytes and induces inflammation

Influence of pathogen and focus of infection on procalcitonin values in sepsis patients with bacteremia or candidemia

M Protein of Group a Streptococcus Plays an Essential Role in Inducing High Expression of A20 in Macrophages Resulting in the Downregulation of Inflammatory Response in Lung Tissue

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