Immunoregulatory effects of <i>Lactococcus lactis‐</i>derived extracellular vesicles in allergic asthma

Lee, Dong-Hyun; Park, Han Ki; Lee, Heera; Sohn, Hyeukjun; Sim, Soyoon; Park, Hyeon Ju; Shin, Yoo Seob; Kim, Eui Chong; Choi, Youngwoo; Park, Hae‐Sim

doi:10.1002/clt2.12138

Cited by 18 publications

(7 citation statements)

References 54 publications

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“…In vivo, we have shown that intranasal treatment with vesicles reduces the number of eosinophils in the lungs compared to allergic controls. A similar effect was observed with intranasal application of recombinant flagellin (63,64). A recent study suggests that the binding of flagellin to surface receptors on eosinophils such as TLR5 may prevent eosinophil sensitisation (65).…”

Section: Discussionsupporting

confidence: 58%

Extracellular vesicles of the probiotic E. coli O83 activate innate immunity and prevent allergy in mice

Schabussova

Schmid

Razim

et al. 2023

Preprint

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Background:E. coli O83 (Colinfant Newborn) is a Gram-negative (G-) probiotic bacterium used in the clinic. When administered orally, it reduces allergic sensitisation but not allergic asthma. Intranasal administration may be more effective as it reaches the lungs directly. G- bacteria release outer membrane vesicles (OMVs) to communicate with the environment. Here we investigate whether intranasally administered E. coli O83 OMVs (EcO83-OMVs) can reduce allergy in mice. Methods: EcO83-OMVs were isolated by ultracentrifugation and characterised with respect to their number, morphology (shape and size), composition (proteins and lipopolysaccharide; LPS), recognition by innate receptors (using transfected HEK293 cells) and immunomodulatory potential (in naïve splenocytes and bone marrow-derived dendritic cells; BMDCs). Their allergy-preventive effect was investigated in a mouse model of allergic airway inflammation. Results: EcO83-OMVs are spherical nanoparticles with a size of about 110 nm. They contain LPS and protein cargo. We identified a total of 1120 proteins, 136 of which were enriched in OMVs compared to parent bacteria. Proteins from the flagellum dominated. OMVs activated the pattern recognition receptors TLR2/4/5 as well as NOD1 and NOD2. EcO83-OMVs were internalised by epithelial cells and induced the production of pro- and anti-inflammatory cytokines in splenocytes and BMDCs. Intranasal administration of EcO83-OMVs inhibited airway hyperresponsiveness, decreased airway eosinophilia, Th2 cytokine production and mucus secretion. Conclusion: We demonstrate for the first time that intranasally administered OMVs from probiotic G- bacteria have an anti-allergic effect. Our study highlights the advantages of OMVs as a safe platform for prophylactic treatment of allergy.

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Section: Discussionsupporting

confidence: 58%

Extracellular vesicles of the probiotic E. coli O83 activate innate immunity and prevent allergy in mice

Schabussova

Schmid

Razim

et al. 2023

Preprint

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“…Previously, asthmatic patients have been shown to be more significantly sensitized to bacterial EVs from Enterobacter cloacae , Pseudomonas aeruginosa , and Staphylococcus aureus with higher levels of EV-specific IgG in their serum 20 . However, levels of IgG4 specific to Lactococcus lactis -derived EVs were significantly lower in patients with allergic asthma than in HCs 34 . Since IgG4 antibody is known as a soluble marker of repeated and long-term exposure to external molecules in a noninfectious setting 35 , EV-specific IgG4 levels could be analyzed as a serum biomarker for diagnosing asthma rather than for performing metagenomic analysis, which is time- and cost-consuming.…”

Section: Discussionmentioning

confidence: 79%

Micrococcus luteus-derived extracellular vesicles attenuate neutrophilic asthma by regulating miRNAs in airway epithelial cells

et al. 2023

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Bacterial extracellular vesicles (EVs) have been shown to regulate various pulmonary diseases, but their functions in asthma remain uncertain. To demonstrate the clinical significance of Micrococcus luteus-derived EVs (MlEVs) in asthma, we enrolled 45 asthmatic patients (20 patients with neutrophilic asthma [NA], 25 patients with eosinophilic asthma [EA]) and 40 healthy controls (HCs). When the prevalence of IgG1 and IgG4 specific to MlEVs was evaluated in serum by ELISA, lower levels of MlEV-specific IgG4 (but not IgG1) were noted in asthmatic patients than in HCs. Among asthmatic patients, significantly lower levels of MIEV-specific IgG4 were noted in patients with NA than in those with EA. Moreover, there was a positive correlation between serum MlEV-specific IgG4 levels and FEV1 (%) values. In asthmatic C57BL/6 mice, MlEVs significantly attenuated neutrophilic airway inflammation by reducing the production of IL-1β and IL-17 in bronchoalveolar lavage fluid as well as the number of group 3 innate lymphoid cells (ILC3s) in lung tissues. To clarify the functional mechanism of MlEVs in NA, the effect of MlEVs on airway epithelial cells (AECs) and immune cells was investigated ex vivo. According to microarray analysis, MlEVs upregulated hsa-miR-4517 expression in AECs. Moreover, this miRNA could suppress IL-1β production by monocytes, resulting in the inhibition of ILC3 activation and neutrophil recruitment. These findings suggest that MlEVs could be a novel therapeutic agent for managing unresolved NA by regulating miRNA expression in AECs.

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“…Using metagenomic analysis, increased levels of the bEVs of Klebsiella spp and decreased levels of bEVs from Lactobacillus , Sphingomona s, Akkermansia , and Micrococcus spp were found in the serum of patients with asthma [ 75 , 76 ]. Lactococcus lactis bEVs modulate T helper (Th)1/Th2 balance by stimulating dendritic cells in a mouse model of S. aureus -induced atopic dermatitis [ 77 ]. Lactobacillus plantarum EVs demonstrated protection against S. aureus -induced atopic dermatitis [ 78 ].…”

Section: Microbiome Revelations Spur Interest In Bugs-as-drugs For Ca...mentioning

confidence: 99%

Harnessing Bacterial Extracellular Vesicle Immune Effects for Cancer Therapy

Karaman,

Pathak,

Bayik

et al. 2024

PAI

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There are a growing number of studies linking the composition of the human microbiome to disease states and treatment responses, especially in the context of cancer. This has raised significant interest in developing microbes and microbial products as cancer immunotherapeutics that mimic or recapitulate the beneficial effects of host-microbe interactions. Bacterial extracellular vesicles (bEVs) are nano-sized, membrane-bound particles secreted by essentially all bacteria species and contain a diverse bioactive cargo of the producing cell. They have a fundamental role in facilitating interactions among cells of the same species, different microbial species, and even with multicellular host organisms in the context of colonization (microbiome) and infection. The interaction of bEVs with the immune system has been studied extensively in the context of infection and suggests that bEV effects depend largely on the producing species. They thus provide functional diversity, while also being nonreplicative, having inherent cell-targeting qualities, and potentially overcoming natural barriers. These characteristics make them highly appealing for development as cancer immunotherapeutics. Both natively secreted and engineered bEVs are now being investigated for their application as immunotherapeutics, vaccines, drug delivery vehicles, and combinations of the above, with promising early results. This suggests that both the intrinsic immunomodulatory properties of bEVs and their ability to be modified could be harnessed for the development of next-generation microbe-inspired therapies. Nonetheless, there remain major outstanding questions regarding how the observed preclinical effectiveness will translate from murine models to primates, and humans in particular. Moreover, research into the pharmacology, toxicology, and mass manufacturing of this potential novel therapeutic platform is still at early stages. In this review, we highlight the breadth of bEV interactions with host cells, focusing on immunologic effects as the main mechanism of action of bEVs currently in preclinical development. We review the literature on ongoing efforts to develop natively secreted and engineered bEVs from a variety of bacterial species for cancer therapy and finally discuss efforts to overcome outstanding challenges that remain for clinical translation.

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Immunoregulatory effects of Lactococcus lactis‐derived extracellular vesicles in allergic asthma

Cited by 18 publications

References 54 publications

Extracellular vesicles of the probiotic E. coli O83 activate innate immunity and prevent allergy in mice

Extracellular vesicles of the probiotic E. coli O83 activate innate immunity and prevent allergy in mice

Micrococcus luteus-derived extracellular vesicles attenuate neutrophilic asthma by regulating miRNAs in airway epithelial cells

Harnessing Bacterial Extracellular Vesicle Immune Effects for Cancer Therapy

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