Mechanisms of apoptosis inhibition in Chlamydia pneumoniae-infected neutrophils

Sarkar, Arup; Möller, Sonja; Bhattacharyya, Asima; Behnen, Martina; Rupp, Jan; Zandbergen, Ger van; Solbach, Werner; Laskay, Tamás

doi:10.1016/j.ijmm.2015.04.006

Cited by 33 publications

(22 citation statements)

References 44 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This is consistent with our finding showing that SopB-dependent Akt activitation does not directly affect the ability of Salmonella to replicate but rather delays host cell death [15,40–43]. This may be a more widespread strategy since the PI3K-Akt signaling cascade is also targeted by other bacterial pathogens, including Chlamydia trachomatis , Chlamydia pneumonia , Coxiella burnettii and Mycobacterium tuberculosis , to delay or prevent apoptosis in infected cells [44–47]. …”

Section: Discussionsupporting

confidence: 90%

A second wave of Salmonella T3SS1 activity prolongs the lifespan of infected epithelial cells

et al. 2017

View full text Add to dashboard Cite

Type III secretion system 1 (T3SS1) is used by the enteropathogen Salmonella enterica serovar Typhimurium to establish infection in the gut. Effector proteins translocated by this system across the plasma membrane facilitate invasion of intestinal epithelial cells. One such effector, the inositol phosphatase SopB, contributes to invasion and mediates activation of the pro-survival kinase Akt. Following internalization, some bacteria escape from the Salmonella-containing vacuole into the cytosol and there is evidence suggesting that T3SS1 is expressed in this subpopulation. Here, we investigated the post-invasion role of T3SS1, using SopB as a model effector. In cultured epithelial cells, SopB-dependent Akt phosphorylation was observed at two distinct stages of infection: during and immediately after invasion, and later during peak cytosolic replication. Single cell analysis revealed that cytosolic Salmonella deliver SopB via T3SS1. Although intracellular replication was unaffected in a SopB deletion mutant, cells infected with ΔsopB demonstrated a lack of Akt phosphorylation, earlier time to death, and increased lysis. When SopB expression was induced specifically in cytosolic Salmonella, these effects were restored to levels observed in WT infected cells, indicating that the second wave of SopB protects this infected population against cell death via Akt activation. Thus, T3SS1 has two, temporally distinct roles during epithelial cell colonization. Additionally, we found that delivery of SopB by cytosolic bacteria was translocon-independent, in contrast to canonical effector translocation across eukaryotic membranes, which requires formation of a translocon pore. This mechanism was also observed for another T3SS1 effector, SipA. These findings reveal the functional and mechanistic adaptability of a T3SS that can be harnessed in different microenvironments.

show abstract

Section: Discussionsupporting

confidence: 90%

A second wave of Salmonella T3SS1 activity prolongs the lifespan of infected epithelial cells

et al. 2017

View full text Add to dashboard Cite

show abstract

“…8A). A variety of pathogens that modulate neutrophil apoptosis induce secretion of CXCL8 as their preferred mechanism of neutrophil apoptosis inhibition [55,56,[67][68][69]. Our data showing that F. novicida-infected neutrophils secrete CXCL8 are significant, as they indicate a distinct mechanism used by F. novicida to delay neutrophil apoptosis that is not shared with F. tularensis [17].…”

Section: Discussionmentioning

confidence: 82%

“…Identification and characterization of the bacterial factors that mediate neutrophil apoptosis inhibition during Francisella infection are a focus of current research in our laboratory. During infection with C. pneumoniae, LPS is responsible for inducing CXCL8 secretion, but the corresponding mechanism used by A. phagocytophilum is unknown [55,56,69]. F. tularensis LPS does not influence PMN apoptosis [17].…”

Section: Discussionmentioning

confidence: 99%

Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan

Kinkead

Fayram

Allen

2017

Journal of Leukocyte Biology

View full text Add to dashboard Cite

is a Gram-negative bacterium that is closely related to the highly virulent facultative intracellular pathogen, Data published by us and others demonstrate that virulence correlates directly with its ability to impair constitutive apoptosis and extend human neutrophil lifespan. In contrast, is attenuated in humans, and the mechanisms that account for this are incompletely defined. Our published data demonstrate that binds natural IgG that is present in normal human serum, which in turn, elicits NADPH oxidase activation that does not occur in response to As it is established that phagocytosis and oxidant production markedly accelerate neutrophil death, we predicted that may influence the neutrophil lifespan in an opsonin-dependent manner. To test this hypothesis, we quantified bacterial uptake, phosphatidylserine (PS) externalization, and changes in nuclear morphology, as well as the kinetics of procaspase-3, -8, and -9 processing and activation. To our surprise, we discovered that not only failed to accelerate neutrophil death but also diminished and delayed apoptosis in a dose-dependent, but opsonin-independent, manner. In keeping with this, studies of conditioned media (CM) showed that neutrophil longevity could be uncoupled from phagocytosis and that stimulated neutrophil secretion of CXCL8. Taken together, the results of this study reveal shared and unique aspects of the mechanisms used by species to manipulate neutrophil lifespan and as such, advance understanding of cell death regulation during infection.

show abstract

“…In endothelial cells, luteolin blocks Ca 2+ influx upon pathogenic stimuli, protecting these cells from apoptosis [51], whereas Ca influx into adipocytes is enhanced by luteolin treatment, leading to mitochondria apoptotic mediator release [52]. The antiapoptotic and proapoptotic signaling affected by luteolin also extends to various other signaling cascades, interconnecting with also those linked to C. pneumoniae infection, such as phosphatidylinsitide-3-kinase (PI3K) pathway [53,54] and Bcl-2 family proteins [55,56]. Similar to luteolin, the C. pneumonia -related apoptosis modulation seems to be cell type dependent, as for instance, epithelial cells turn resistant to apoptotic signals upon C. pneumoniae infection [57], while endothelial cells are shifted towards increased apoptotic tendency upon the infection [58].…”

Section: Plant Phenolics As Antichlamydial Agentsmentioning

confidence: 99%

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

Hanski

Vuorela

2016

Microorganisms

View full text Add to dashboard Cite

Throughout its known history, the gram-negative bacterium Chlamydia pneumoniae has remained a challenging target for antibacterial chemotherapy and drug discovery. Owing to its well-known propensity for persistence and recent reports on antimicrobial resistence within closely related species, new approaches for targeting this ubiquitous human pathogen are urgently needed. In this review, we describe the strategies that have been successfully applied for the identification of nonconventional antichlamydial agents, including target-based and ligand-based virtual screening, ethnopharmacological approach and pharmacophore-based design of antimicrobial peptide-mimicking compounds. Among the antichlamydial agents identified via these strategies, most translational work has been carried out with plant phenolics. Thus, currently available data on their properties as antichlamydial agents are described, highlighting their potential mechanisms of action. In this context, the role of mitogen-activated protein kinase activation in the intracellular growth and survival of C. pneumoniae is discussed. Owing to the complex and often complementary pathways applied by C. pneumoniae in the different stages of its life cycle, multitargeted therapy approaches are expected to provide better tools for antichlamydial therapy than agents with a single molecular target.

show abstract

Mechanisms of apoptosis inhibition in Chlamydia pneumoniae-infected neutrophils

Cited by 33 publications

References 44 publications

A second wave of Salmonella T3SS1 activity prolongs the lifespan of infected epithelial cells

A second wave of Salmonella T3SS1 activity prolongs the lifespan of infected epithelial cells

Francisella novicida inhibits spontaneous apoptosis and extends human neutrophil lifespan

Lead Discovery Strategies for Identification of Chlamydia pneumoniae Inhibitors

Contact Info

Product

Resources

About