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Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus.

ABSTRACT: Group B streptococcus (GBS), the most frequent single isolate in neonatal sepsis and meningitis, potently activates inflammatory macrophage genes via myeloid differentiation antigen 88 (MyD88). However, events parallel to and downstream of MyD88 that instruct the macrophage response are incompletely understood. In this study, we found that only MyD88, not the Toll-like receptor (TLR) adapter proteins MAL/TIRAP, TRIF, and TRAM, essentially mediates the cytokine (tumor necrosis factor [TNF] and interleukin-6) and chemokine (RANTES) responses to whole GBS organisms, although MAL, TRIF, and TRAM have been shown to mediate the responses to substructures in other gram-positive and gram-negative bacteria. GBS-induced, MyD88-dependent phosphorylation of the mitogen-activated protein kinase p38 activated the transcription factor AP-1 and early growth response factor 1 (Egr-1) but not NF-kappaB. Furthermore, phosphorylation of Ets-like molecule 1 (Elk-1) was mediated by p38. However, in contrast to Egr-1 and AP-1, Elk-1 was dispensable for transcriptional activation of TNF by GBS organisms. Studies of macrophages from Elk-1-deficient mice revealed that Elk-1 was furthermore nonessential for the TNF responses to purified TLR2 and TLR4 agonists, which was in notable contrast to what was revealed in studies employing in vitro expression systems. In conclusion, MyD88, p38, and Egr-1, but not Elk-1, essentially mediate the inflammatory cytokine response to GBS organisms.

SUBMITTER: Kenzel S

PROVIDER: S-EPMC2687355 | biostudies-literature | 2009 Jun

REPOSITORIES: biostudies-literature

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Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus.

Kenzel Sybille S Santos-Sierra Sandra S Deshmukh Sachin D SD Moeller Inga I Ergin Bilge B Fitzgerald Katherine A KA Lien Egil E Akira Shizuo S Golenbock Douglas T DT Henneke Philipp P

Infection and immunity 20090330 6

Group B streptococcus (GBS), the most frequent single isolate in neonatal sepsis and meningitis, potently activates inflammatory macrophage genes via myeloid differentiation antigen 88 (MyD88). However, events parallel to and downstream of MyD88 that instruct the macrophage response are incompletely understood. In this study, we found that only MyD88, not the Toll-like receptor (TLR) adapter proteins MAL/TIRAP, TRIF, and TRAM, essentially mediates the cytokine (tumor necrosis factor [TNF] and in ...[more]

PMID: 19332535

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Project description:The M1T1 clone of group A Streptococcus (GAS) is associated with severe invasive infections, including necrotizing fasciitis and septicemia. During invasive M1T1 GAS disease, mutations in the covRS regulatory system led to upregulation of an ADP-ribosyltransferase, SpyA. Surprisingly, a GAS ?spyA mutant was resistant to killing by macrophages and caused higher mortality with impaired bacterial clearance in a mouse intravenous challenge model. GAS expression of SpyA triggered macrophage cell death in association with caspase-1-dependent interleukin 1? (IL-1?) production, and differences between wild-type (WT) and ?spyA GAS macrophage survival levels were lost in cells lacking caspase-1, NOD-like receptor protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), or pro-IL-1?. Similar in vitro findings were identified in macrophage studies performed with pseudomonal exotoxin A, another ADP-ribosylating toxin. Thus, SpyA triggers caspase-1-dependent inflammatory cell death in macrophages, revealing a toxin-triggered IL-1?-dependent innate immune response pathway critical in defense against invasive bacterial infection.Group A Streptococcus (GAS) is a leading human pathogen capable of producing invasive infections even in healthy individuals. GAS bacteria produce a toxin called SpyA that modifies host proteins through a process called ADP ribosylation. We describe how macrophages, frontline defenders of the host innate immune system, respond to SpyA by undergoing a specialized form of cell death in which they are activated to release the proinflammatory cytokine molecule interleukin 1? (IL-1?). Release of IL-1? activates host immune cell clearance of GAS, as we demonstrated in tissue culture models of macrophage bacterial killing and in vivo mouse infectious-challenge experiments. Similar macrophage responses to a related toxin of Pseudomonas bacteria were also shown. Thus, macrophages recognize certain bacterial toxins to activate a protective immune response in the host.

Project description:Group B Streptococcus (GBS), also known as Streptococcus agalactiae, is a common member of the microbial flora in healthy individuals. However, problems may arise when GBS-colonized mothers become pregnant. GBS may be transferred from a colonized mother to her newborn or developing fetus, which may result in complications such as miscarriage, pre-term birth, meningitis, pneumonia, or sepsis. Macrophages play an especially important role in the fetal and newborn response to GBS due to the limited development of the adaptive immune system early in life. The goal of this study was to expand what is currently known about how GBS manipulates macrophage cell signaling to evade the immune system and cause disease. To this end, we investigated whether the PI3K-Akt pathway was involved in several key aspects of the macrophage response to GBS. We explored whether certain GBS strains, such as sequence type (ST)-17 strains, rely on this pathway for the more rapid macrophage uptake they induce compared to other GBS strains. Our findings suggest that this pathway is, indeed, important for macrophage uptake of GBS. Consistent with these findings, we used immunofluorescence microscopy to demonstrate that more virulent strains of GBS induce more actin projections in macrophages than less virulent strains. Additionally, we explored whether PI3K-Akt signaling impacted the ability of GBS to survive within macrophages after phagocytosis and whether this pathway influenced the survival rate of macrophages themselves following GBS infection. The PI3K-Akt pathway was found to promote the survival of both macrophages and intracellular GBS following infection. We also observed that inhibition of the PI3K-Akt pathway significantly reduced GBS-mediated activation of NFκB, which is a key regulator of cell survival and inflammatory responses. Overall, these insights into strain-dependent GBS-mediated manipulation of the PI3K-Akt pathway and its downstream targets in infected macrophages may provide new insights for the development of diagnostic and therapeutic tools to combat severe GBS disease.

Dataset Information

Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus.

Publications

Role of p38 and early growth response factor 1 in the macrophage response to group B streptococcus.

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