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Published on: December 8, 2023
Myxobacteria-Derived Outer Membrane Vesicles: Potential Applicability Against Intracellular Infections
Adriely Goes1,2, Philipp Lapuhs1,2, Thomas Kuhn1,2
1Helmholtz Centre for Infection Research (HZI), Biogenic Nanotherapeutics Group (BION), Helmholtz Institute for Pharmaceutical Research Saarland (HIPS), Campus E8.1, 66123 Saarbrücken, Germany.
Abstract:
In 2019, it was estimated that 2.5 million people die from lower tract respiratory infections annually. One of the main causes of these infections is Staphylococcus aureus, a bacterium that can invade and survive within mammalian cells. S. aureus intracellular infections are difficult to treat because several classes of antibiotics are unable to permeate through the cell wall and reach the pathogen. This condition increases the need for new therapeutic avenues, able to deliver antibiotics efficiently. In this work, we obtained outer membrane vesicles (OMVs) derived from the myxobacteria Cystobacter velatus strain Cbv34 and Cystobacter ferrugineus strain Cbfe23, that are naturally antimicrobial, to target intracellular infections, and investigated how they can affect the viability of epithelial and macrophage cell lines. We evaluated by cytometric bead array whether they induce the expression of proinflammatory cytokines in blood immune cells. Using confocal laser scanning microscopy and flow cytometry, we also investigated their interaction and uptake into mammalian cells. Finally, we studied the effect of OMVs on planktonic and intracellular S. aureus. We found that while Cbv34 OMVs were not cytotoxic to cells at any concentration tested, Cbfe23 OMVs affected the viability of macrophages, leading to a 50% decrease at a concentration of 125,000 OMVs/cell. We observed only little to moderate stimulation of release of TNF-alpha, IL-8, IL-6 and IL-1beta by both OMVs. Cbfe23 OMVs have better interaction with the cells than Cbv34 OMVs, being taken up faster by them, but both seem to remain mostly on the cell surface after 24 h of incubation. This, however, did not impair their bacteriostatic activity against intracellular S. aureus. In this study, we provide an important basis for implementing OMVs in the treatment of intracellular infections.
Insights
Outer membrane vesicles (OMVs) from myxobacteria show potential for treating intracellular infections, including those caused by Staphylococcus aureus. These OMVs exhibit bacteriostatic activity against intracellular bacteria without significant toxicity to most cells.
Area of Science:
- Microbiology
- Cell Biology
- Drug Delivery
Background:
- Lower respiratory tract infections cause millions of deaths annually, with Staphylococcus aureus (S. aureus) being a major pathogen.
- Intracellular S. aureus infections are challenging to treat due to limited antibiotic penetration into host cells.
- Novel therapeutic strategies are needed to effectively deliver antimicrobials to intracellular pathogens.
Purpose of the Study:
- To investigate the potential of naturally antimicrobial outer membrane vesicles (OMVs) from Cystobacter velatus and Cystobacter ferrugineus as a delivery system for targeting intracellular infections.
- To evaluate the cytotoxic effects, immune cell interactions, and antimicrobial activity of these OMVs against S. aureus.
Main Methods:
- Production and characterization of OMVs from C. velatus (Cbv34) and C. ferrugineus (Cbfe23).
- Assessment of OMV cytotoxicity on epithelial and macrophage cell lines using flow cytometry.
- Evaluation of pro-inflammatory cytokine release (TNF-alpha, IL-8, IL-6, IL-1beta) via cytometric bead array.
- Microscopy and flow cytometry to study OMV-host cell interaction and uptake.
- Testing OMV efficacy against planktonic and intracellular S. aureus.
Main Results:
- Cbv34 OMVs showed no cytotoxicity, while Cbfe23 OMVs reduced macrophage viability by 50% at 125,000 OMVs/cell.
- Both OMV types induced minimal to moderate pro-inflammatory cytokine release.
- Cbfe23 OMVs demonstrated enhanced interaction and faster uptake into cells compared to Cbv34 OMVs.
- Despite limited intracellular accumulation after 24h, both OMVs effectively inhibited intracellular S. aureus growth (bacteriostatic activity).
Conclusions:
- Myxobacterial OMVs are promising candidates for developing new therapies against intracellular bacterial infections.
- Further research can optimize OMV formulations for improved delivery and efficacy in treating challenging S. aureus infections.
- OMVs offer a potential platform for delivering antimicrobials to combat intracellular pathogens, addressing a critical unmet medical need.
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