Phagocyte extracellular traps formation contributes to host defense against Clostridium perfringens infection

Liu, Yang; Liang, Jing; Li, Jianwei; Lü, Xing; Li, Fen-Xin; Wang, Na; Wu, Yujing; Ma, Yuze; Zhang, Xing; Xue, Jian; Zhang, Xinyue; Lei, Z. H.; Wang, Xiao; Yu, Shui-Xing

doi:10.1016/j.cyto.2023.156276

Cited by 6 publications

(5 citation statements)

References 35 publications

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“…As similarly observed in TBNC (Fig. S9), this was likely ascribed to re-entering into the sporulation process of RJ-1 in vivo 43 and subsequent digestion by phagocytes that might result in the release of RNA from the spores intracellularly 44,45 . We also co-cultured human PDAC samples with RJ-1 for 24 hours and found a large-scale reduction of collagen and Col-I as well as the appearance of vegetative cells inside the tumor (Fig.…”

Section: Mainsupporting

confidence: 70%

Clostridium ablates tumors by degrading collagen mesh and inducing ferroptosis

Yang,

Meng,

Chen

et al. 2024

Preprint

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The supportive role of extracellular matrix in tumor growth and the drug resistance of tumor cells stand the major challenges in treating cancer. Here, we report the discovery of an oncolytic Clostridium strain, named RJ-1, which simultaneously expresses collagenases and produces iron-containing particles through intrabacterial mineralization. The secreted collagenases degrade pre-existing collagen mesh and show a collagen concentration-dependent degradation feature. Iron-containing particles released from RJ-1 by autolysis generate ferrous ions in the lysosomal acid environment following cell uptake and subsequently induce ferroptosis via the Fenton reaction. Due to selective germination in tumor sites, systemic administration of RJ-1 spores synchronously destructs dense tumor extracellular matrix and causes non-apoptotic tumor cell death. In collagen-dense tumor-bearing mice, a single intravenous injection achieves a favorable tolerance and rapid oncolysis of giant tumors with a size of ~1000 mm3. This work finds a dual collagenase-expressing and iron-concentrating bacterium, proposing an alternative strategy to combat tumors.

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Section: Mainsupporting

confidence: 70%

Clostridium ablates tumors by degrading collagen mesh and inducing ferroptosis

Yang,

Meng,

Chen

et al. 2024

Preprint

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“…This release was found to be less significant, in contrast to the notable release observed in non‐polarized macrophages 33 . It is worth noting that the polarization of macrophages is not a prerequisite for METs formation, as most research investigations have employed non‐polarized macrophages such as J774.A1, RAW264.7 macrophage cell lines, as well as murine peritoneal macrophages and bone marrow‐derived macrophages (BMDMs) 16,30,34 . Overall, further research is needed to fully elucidate the relationship between macrophage polarization and METs release, and to determine how different signals influence this process.…”

Section: Macrophage Extracellular Trapsmentioning

confidence: 99%

“…The release of METs can be triggered by various bacteria, including Gram‐positive bacteria such as Staphylococcus aureus , 16,35 Streptococcus agalactiae , 36 Bacillus licheniformis , 37 Bacillus subtilis , 37 and Clostridium perfringens , 34 whereas Gram‐negative bacteria include Escherichia coli , 27 Mannheimia haemolytica , 26 Haemophilus influenzae , 38 Porphyromonas gingivalis , 39 Salmonella enterica , 30 Histophilus somni , 40 Pseudomonas aeruginosa , 41 as well as other bacterial species like Mycobacterium tuberculosis , 29,42 Mycobacterium abscessus , 43 Mycobacterium massiliense , 44 Mycoplasma hyopneumoniae , 45 and Leptospira interrogans 46 …”

Section: Macrophage Extracellular Trapsmentioning

confidence: 99%

“…BMDMs and J774.A1 macrophages have been found to actively release DNA into the extracellular space, adorned with histone and MPO, and a significant increase in PAD4 expression in BMDMs in response to C. perfringens . This response is triggered by a variety of factors, including NADPH oxidase, extracellular signal‐regulated kinase (ERK) 1/2, MPO, histones, NE, P38 MAPK, and store‐operated calcium entry, while does not rely on lactate dehydrogenase activity 34 . Moreover, in vivo, studies have revealed that the use of DNase I to break down METs results in compromised defense against induced gas gangrene, resulting in elevated death rates, escalated tissue destruction, and enhanced bacterial proliferation 34 …”

Section: Mets In Bacteriamentioning

confidence: 99%

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Emerging insights into macrophage extracellular traps in bacterial infections

Baz,

Hao,

Lan

et al. 2024

The FASEB Journal

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Macrophages possess a diverse range of well‐defined capabilities and roles as phagocytes, encompassing the regulation of inflammation, facilitation of wound healing, maintenance of tissue homeostasis, and serving as a crucial element in the innate immune response against microbial pathogens. The emergence of extracellular traps is a novel strategy of defense that has been observed in several types of innate immune cells. In response to infection, macrophages are stimulated and produce macrophage extracellular traps (METs), which take the form of net‐like structures, filled with strands of DNA and adorned with histones and other cellular proteins. METs not only capture and eliminate microorganisms but also play a role in the development of certain diseases such as inflammation and autoimmune disorders. The primary objective of this study is to examine the latest advancements in METs for tackling bacterial infections. We also delve into the current knowledge and tactics utilized by bacteria to elude or endure the effects of METs. Through this investigation, we hope to shed light on the intricate interactions between bacteria and the host's immune system, particularly in the context of microbicidal effector mechanisms of METs. The continued exploration of METs and their impact on host defense against various pathogens opens up new avenues for understanding and potentially manipulating the immune system's response to infections.

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“…C. perfringens induces NETs formation in murine neutrophils, which requires the intracellular pore-forming Mixed lineage kinase-like protein that oligomerizes in the membrane ( Liu et al., 2023a ; Liu et al., 2023b ). However, neither the signaling pathway involved in NET induction nor the C. perfringens virulence factor responsible for the NET inducing activity have been identified.…”

Section: Introductionmentioning

confidence: 99%

Clostridium perfringens phospholipase C, an archetypal bacterial virulence factor, induces the formation of extracellular traps by human neutrophils

Badilla-Vargas,

Pereira,

Molina-Mora

et al. 2023

Front. Cell. Infect. Microbiol.

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Neutrophil extracellular traps (NETs) are networks of DNA and various microbicidal proteins released to kill invading microorganisms and prevent their dissemination. However, a NETs excess is detrimental to the host and involved in the pathogenesis of various inflammatory and immunothrombotic diseases. Clostridium perfringens is a widely distributed pathogen associated with several animal and human diseases, that produces many exotoxins, including the phospholipase C (CpPLC), the main virulence factor in gas gangrene. During this disease, CpPLC generates the formation of neutrophil/platelet aggregates within the vasculature, favoring an anaerobic environment for C. perfringens growth. This work demonstrates that CpPLC induces NETosis in human neutrophils. Antibodies against CpPLC completely abrogate the NETosis-inducing activity of recombinant CpPLC and C. perfringens secretome. CpPLC induces suicidal NETosis through a mechanism that requires calcium release from inositol trisphosphate receptor (IP3) sensitive stores, activation of protein kinase C (PKC), and the mitogen-activated protein kinase/extracellular signal-regulated kinase (MEK/ERK) pathways, as well as the production of reactive oxygen species (ROS) by the metabolism of arachidonic acid. Proteomic analysis of the C. perfringens secretome identified 40 proteins, including a DNAse and two 5´-nucleotidases homologous to virulence factors that could be relevant in evading NETs. We suggested that in gas gangrene this pathogen benefits from having access to the metabolic resources of the tissue injured by a dysregulated intravascular NETosis and then escapes and spreads to deeper tissues. Understanding the role of NETs in gas gangrene could help develop novel therapeutic strategies to reduce mortality, improve muscle regeneration, and prevent deleterious patient outcomes.

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Phagocyte extracellular traps formation contributes to host defense against Clostridium perfringens infection

Cited by 6 publications

References 35 publications

Clostridium ablates tumors by degrading collagen mesh and inducing ferroptosis

Clostridium ablates tumors by degrading collagen mesh and inducing ferroptosis

Emerging insights into macrophage extracellular traps in bacterial infections

Clostridium perfringens phospholipase C, an archetypal bacterial virulence factor, induces the formation of extracellular traps by human neutrophils

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