Pathways of host cell exit by intracellular pathogens

Flieger, Antje; Frischknecht, Friedrich; Häcker, Georg; Hornef, Mathias W.; Pradel, Gabriele

doi:10.15698/mic2018.12.659

Cited by 62 publications

(76 citation statements)

References 233 publications

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“…Intracellular pathogens may induce killing as a strategy to exit from the host cell. Induction of programmed cell death, such as apoptosis, necroptosis or pyroptosis, or the damaging of host cell-derived membranes such as endosomal, vacuolar and plasma membrane have been demonstrated as mechanisms [reviewed in 23]. Reports on the molecular mechanisms underlying S. aureus induced host cell killing are rather inconsistent, which likely arises from the diversity of virulence factors within S. aureus .…”

Section: Introductionmentioning

confidence: 99%

IntracellularStaphylococcus aureusemploys the cysteine protease staphopain A to induce host cell death in epithelial cells

Stelzner

Hertlein

Sroka

et al. 2020

Preprint

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Staphylococcus aureus is a major human pathogen, which can invade and survive in non-professional and professional phagocytes. Intracellularity is thought to contribute to pathogenicity and persistence of the bacterium. Upon internalization by epithelial cells, cytotoxic S. aureus strains can escape from the phagosome, replicate in the cytosol and induce host cell death. Here, we identified a staphylococcal cysteine protease to induce cell death by intracellular S. aureus after translocation into the host cell cytoplasm. We demonstrated that loss of staphopain A function leads to delayed onset of host cell death and prolonged intracellular replication of S. aureus in epithelial cells. Overexpression of staphopain A in a non-cytotoxic strain facilitated intracellular killing of the host cell even in the absence of detectable intracellular replication. Moreover, staphopain A contributed to efficient colonization of the lung in a mouse pneumonia model. Our study suggests that staphopain A is utilized by S. aureus to mediate escape from the host cell and thus contributes to tissue destruction and dissemination of infection. Author Summary Staphylococcus aureus is a well-known antibiotic-resistant pathogen that emerges in hospital and community settings and can cause a variety of diseases ranging from skin abscesses to lung inflammation and blood poisoning. The bacterium asymptomatically colonizes the upper respiratory tract and skin of about one third of the human population and takes advantage of opportune conditions, like immunodeficiency or breached barriers, to cause infection. Although S. aureus is not regarded as a professional intracellular bacterium, it can be internalized by human cells and subsequently exit the host cells by induction of cell death, which is considered to cause tissue destruction and spread of infection. The bacterial virulence factors and underlying molecular mechanisms involved in the intracellular lifestyle of S. aureus remain largely unknown. We identified a bacterial cysteine protease to contribute to host cell death mediated by intracellular S. aureus. Staphopain A induced killing of the host cell after translocation of the pathogen into the cell cytosol, while bacterial proliferation was not required. Further, the protease enhanced survival of the pathogen during lung infection. These findings reveal a novel, intracellular role for the bacterial protease staphopain A.

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Section: Introductionmentioning

confidence: 99%

IntracellularStaphylococcus aureusemploys the cysteine protease staphopain A to induce host cell death in epithelial cells

Stelzner

Hertlein

Sroka

et al. 2020

Preprint

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“…Although in ammation is mainly a defensive response to pathogens with harmful consequences, its downstream effects, such as the metabolic changes or in ux of immune cells, may actually promote the growth of pathogens and the spread of tissues. The de ection of the immune response directed by microbes through speci c signals may further reduce the antibacterial effect and enhance the bene ts of pathogens [(Flieger et al 2018)]. In the pathogen infection, Though the main role of the Tregs is to inhibit damage to tissues and also limit severe in ammation caused by the infection, the accumulation of Tregs also does the opposite, which weaken protecting immune response to pathogens and enhance pathogen persistence [(Stephen-Victor et al 2017a)].…”

Section: Discussionmentioning

confidence: 99%

Aspergillus fumigatus change Gasdermin-D-dependent pyrolysis of the lung through regulating TRL2-dependent Regulatory T cells differentiation

Wei¹,

Xing²,

Ke³

et al. 2020

Preprint

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Aspergillus fumigatus, as opportunistic fungi, lead to infection in the lungs and even systemic infection. The A. fumigatus interacts with the body through a series of complex and dynamic processes. After the fungi have invaded the host, it has a series of adaptive mechanisms which it applies to evade being detected by a host immune system also ways to retaliate against the immune responses. Regulatory T cells (Tregs) in enhancing immune tolerance and immune escape by inhibiting the body's immune response are concerned. It could increase the sensitivity of bacterial infections. When A. fumigatus enters the host, it stimulates Toll-like receptor 2 (TLR2) and triggers the signal transduction pathway. However, how Tregs affects susceptibility to A. fumigatus and TLR2 changes Tregs in A. fumigatus infection is unclear. We examined whether A. fumigatus induces Tregs proliferation in vivo, molecular mechanisms underlying A. fumigatus-stimulated TLR2 activation and the contribution of Tregs activation to susceptibility to A. fumigatus. We observed that Tregs to CD4+T cells ratio increased in samples from patients infected with Aspergillus fumigatus. After conducting tests in mice, it was revealed that when mice were infected with A. fumigatus, there was an enhancement in the Tregs to CD4+T cells ratio and Foxp3 expression levels which happen in the lungs also up-regulate. Inhibited Tregs by using CD25 neutralizing antibodies, and we found that the number of fungal burdens in the lung was decreased when these CD25 neutralizing antibodies are used. In our research, A. fumigatus infection can indeed stimulate TLR2 expression to increase, and for the lungs, damages and fungal burden caused by TLR2−/−mice were reduced. Then it also found that in TLR2−/-mice, pyrolysis-related proteins (GSDMD, IL-1α, and IL-1β) changed. It was concluded that for TLR2 knockout animals, the Treg cells quantities are significantly linked to vulnerability to be infected with A. fumigatus. The infection triggered the proliferation and differentiation of CD4+CD25+Foxp3+ Tregs through the activation of TLR2 pathway. It is a potential mechanism to evade host defense in A. fumigatus infection of the lung. And this effect can regulate GSDMD-dependent pyrolysis, and may involve TRL2 signals partially.

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“…The host cytoskeleton is an obvious target to affect vomocytosis, given its clear role both in maintaining normal cellular structure and in driving the expulsion of several pathogenic bacteria (Flieger, Frischknecht, Hacker, Hornef, & Pradel, 2018). Addition of cytochalasin D, which inhibits actin polymerisation within host macrophages, enhances vomocytosis of C. neoformans (Alvarez & Casadevall, 2006).…”

Section: What Is the Mechanism Of Vomocytosis?mentioning

confidence: 99%

“…The process of vomocytosis requires that internal vesicles release their cargo onto the extracellular milieu. Interestingly, the group showed that the absence of annexin A2, both in vitro and in vivo, results in an enlarged cryptococcal capsule; suggesting that there might be a "sweet spot" in capsule size whereby too small (acapsular strains) or too large a capsule both abrogate vomocytosis.The host cytoskeleton is an obvious target to affect vomocytosis, given its clear role both in maintaining normal cellular structure and in driving the expulsion of several pathogenic bacteria(Flieger, Frischknecht, Hacker, Hornef, & Pradel, 2018). In 2016,Stukes et al showed that annexin A2, a membrane-binding protein involved in bringing membranes together and promoting fusion during several cellular processes including exocytosis of secretory vesicles, affects the occurrence of vomocytosis(Stukes et al, 2016).…”

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confidence: 99%

Vomocytosis: What we know so far

Seoane

May

2019

Cellular Microbiology

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Vomocytosis, or nonlytic exocytosis, has been reported for Cryptococcus neoformans since 2006. Since then, the repertoire of vomocytosing pathogens and host cells has increased and so have the molecular components linked to vomocytosis occurrence. Nonetheless, the mechanism underlying this phenomenon, whether it is triggered by the host or the pathogen, and how it affects disease progression are still unresolved. This review contains a summary of the main findings regarding vomocytosis and the outstanding questions puzzling scientists to this day.

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Pathways of host cell exit by intracellular pathogens

Cited by 62 publications

References 233 publications

IntracellularStaphylococcus aureusemploys the cysteine protease staphopain A to induce host cell death in epithelial cells

IntracellularStaphylococcus aureusemploys the cysteine protease staphopain A to induce host cell death in epithelial cells

Aspergillus fumigatus change Gasdermin-D-dependent pyrolysis of the lung through regulating TRL2-dependent Regulatory T cells differentiation

Vomocytosis: What we know so far

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