Abstract
Staphylococcus aureus is a pathogen of great importance to clinical and veterinary medicine. Recently, there has been a growing interest in S. aureus extracellular vesicles (EVs) in the pathogenesis of this bacterium. Released by living cells into the extracellular milieu, EVs are membranous structures carrying macromolecules such as proteins, nucleic acids, and metabolites. These structures play several physiological roles and are, among others, considered a mechanism of intercellular communication within S. aureus populations but also in trans kingdom interactions. S. aureus EVs were shown to transport important bacterial survival and virulence factors, such as β-lactamases, toxins, and proteins associated with bacterial adherence to host cells, and to trigger the production of cytokines and promote tissue inflammation. In this chapter, we will review the main studies regarding S. aureus EVs, including their composition and roles in host-pathogen interactions, and the possible applications of EVs for vaccines and therapy development against staphylococcal infections.
Keywords
- EV
- membrane vesicles
- composition
- bacterial survival
- cargo delivery
- immunomodulation
- host-pathogen interactions
- immunization
- vaccine
- therapy
1. Introduction
1.1 EVs characteristics
The release of extracellular vesicles (EVs) is a long-known phenomenon widely reported, mainly in eukaryotes [1, 2, 3, 4]. Archaea and Bacteria also release EVs, making their occurrence an evolutionally conserved feature among all three kingdoms [5]. They can be referred as membrane vesicles, microvesicles, ectosomes, exosomes, apoptotic bodies, outer membrane vesicles (OMVs), and others, depending on their origin and characteristics [5, 6]. The study of these particles is of great interest, as they are considered a mechanism of cell-free intercellular communication and
1.2 History of bacterial EVs
The first study regarding bacterial EVs dates back to 1966, when lipid-like structures purified from culture supernatants of
1.3 S. aureus and its derived EVs
One emerging field of great interest is the involvement of EVs in the infections caused by
2. Biogenesis of bacterial EVs
Several models have been proposed to elucidate how bacteria release EVs. Since the study of Gram-negative bacteria OMVs dates to the ‘60s, this phenomenon is better established and documented. Several hypotheses are proposed to explain EVs production, which include one or a combination of many processes [43]. It has been proposed that the accumulation of molecules in the periplasm space alters turgor pressure, promoting OMV release [44, 45]. In another model, alterations in lipid structure and topology could lead to modifications in the membrane curvature, resulting in vesicle bubbling from the outer membrane [46]. On the contrary, EVs biogenesis is still poorly understood in Gram-positive bacteria [47] due to the recent discovery of EV release by these microorganisms [11]. Notably, efforts have been made to better understand how EVs can get through the thick PGN layer present in the Gram-positive bacteria’s cell wall structure.
In
In addition to the importance of PSMs and lipoproteins in staphylococcal EV biogenesis, it was demonstrated that penicillin-binding proteins (PBPs) and autolysins also influence
3. S. aureus vesicle cargo composition
3.1 S. aureus vesicle protein cargo
Different molecules may be incorporated into EVs during their biogenesis: nucleic acids, proteins, lipids, and metabolites [5, 8, 60, 61]. Most studies on
Strain | No. of proteins | Function | Ref. |
---|---|---|---|
01ST93 | Non-cytotoxic to host cells (Hep-2) | [31] | |
03ST17 | 143 | Non-cytotoxic to host cells (Hep-2, HaCaT) | [31, 38] |
Cytotoxic to host cells (HaCaT) | [62] | ||
Immunomodulation | [38, 62] | ||
Mast cell recruitment and exacerbation of skin inflammation | |||
06ST1048 | Cytotoxic to host cells (Hep-2) | [29, 31] | |
143 | Delivery of Spa protein through EVs (Hep-2) | [29] | |
8325–4 | Induction of the MAPK pathway (THP-1 and MLE-12) | [63] | |
Cytotoxicity to host cells (HeLa) | [64] | ||
Hemolytic activity | [63, 64] | ||
8325-4Δ | Low cytotoxic to host cells (HeLa) | [64] | |
Weaker induction of MAPK pathway (THP-1 and MLE-12) | [63] | ||
ATCC 14458 | 90 | ND | [11] |
Cytotoxic to host cells (HaCaT) | [30] | ||
Immunomodulation | |||
Immunomodulation | [37] | ||
Immunomodulation | [35] | ||
Induce skin inflammation in mice | [30, 37] | ||
Promote lung inflammation in mice | [35] | ||
Protective against lung infections | [42] | ||
Transfer of resistance to β-lactams | [32] | ||
ATCC 25923 | Cytotoxic to host cells (HaCaT) | [65] | |
Immunomodulation | |||
Prevention of biofilm formation by other bacteria | [66] | ||
ATCC 6538 | Non-cytotoxic to host cells (HDMECs) | [36] | |
Induce recruitment of monocytes (THP-1) | |||
Immunomodulation | |||
BWMR22 | Exogenous EVs from vancomycin treated culture promote | [67] | |
CI1449 | Exogenous EVs confer bacterial resistance to whole blood killing | [68] | |
JE2 | 180 | Cytotoxic to host cells (human leukocytes, THP-1 cells, human macrophages MΦ) | [40, 57] |
Immunomodulation | |||
JE2 Δ | Decreased cytotoxicity and immunomodulation (THP-1 cells) | [57] | |
JE2-Δ | 212 | Non-cytotoxic to host cells (human leukocytes, A549, HL60, and rabbit erythrocytes) | [40] |
Non-protective against lethal sepsis | |||
JE2Δ | Non-cytotoxic to host cells (human leukocytes, A549, HL60, and rabbit erythrocytes) | [40] | |
Protective against lethal sepsis | |||
JE2Δ | 198 | Decreased cytotoxicity to host cells (human macrophages) | [57] |
Defective in the induction of IL-1β, IL-18, and IL-6, and caspase-1 activation | |||
M060 | 153 | Cytotoxic to host cells (Hep-2, COS-7 and HaCaT) | [31, 65] |
153 | Immunomodulation | [65] | |
MSSA476 | LB1: 131 BHI2: 617 | Exogenous EVs promotes bacterial survival | [69] |
MW2 | 168 | ND | [34] |
N305* | 222 | Non-cytotoxic to host cells (PS and MAC-T) | [33] |
Immunomodulation | |||
Induction of neutrophil recruitment | |||
ND | [34] | ||
Newman | Immunomodulation | [70] | |
O11* | 164 | ND | [34] |
O46* | 171 | ND | [34] |
RF122* | 160 | ND | [34] |
RN4220 | 92 | ND | [41] |
RN4220 Δagr | 119 | Engineered EVs protect mice against viral infections | [41] |
ST692 | 3: 137 4: 156 | Transfer of resistance to β-lactams | [71] |
USA300 | Immunomodulation | [56] | |
Protective against systemic and skin infections | [69] |
As shown in Table 1,
In this regard, a recent study characterized and compared the proteome of EVs derived from several
3.2 Selective protein cargo sorting into EVs
Since EVs bud out of the cytoplasmic membrane, it is natural that their composition mainly reflects the physiological state of the producing cells, as it has been shown by several studies characterizing the EV cargo [73, 74]. However, several studies showed strong evidence that protein cargo sorting is a selective regulated process in both Gram-negative and Gram-positive bacteria [8, 34, 75, 76]. As mentioned before, OMV biogenesis involves the capture of components associated with the periplasm and the OM. Interestingly, OMVs derived from
Several studies demonstrated that
3.3 S. aureus vesicle cargo: other components
As mentioned earlier, data regarding the characterization of the other components of staphylococcal EVs apart from proteins are scarce. Although some studies demonstrated that lipids, carbohydrates, or nucleic acids are also associated with
4. S. aureus -EVs functions
First considered “trash bags” to remove unwanted molecules from cells, nowadays, it is well-established that EVs play essential roles for bacterial fitness. Several described biological functions of OMVs and EVs include offensive and defensive mechanisms, such as quorum sensing, competition, delivery of toxins, resistance to antibiotics, horizontal DNA transfer, and transfer of regulatory RNAs (sRNAs), which can hijack the host immune response altering host-pathogen interactions.
4.1 S. aureus -EVs in cell toxicity
Studies demonstrated that
4.2 S. aureus -EVs in antibiotic resistance and biofilm formation
Besides delivering toxins to host cells,
4.3 S. aureus -EVs in immunomodulation
Various studies also demonstrated the role of
Wang et al. demonstrated that EVs derived from the S. aureus JE2 strain could activate TLR2 signaling of NLRP3 inflammasomes in human macrophages through K+ efflux and apoptosis-associated speck-like protein (ASC) recruitment [57]. ASC is a key adaptor complex required for caspase-1 activation, which leads to the release of the mature forms of IL-1β and IL-18 cytokines. They also investigated whether EVs derived from a mutant for the
A recent study conducted by Rodriguez et al. demonstrated that nucleic acid associated with
As described above, most studies regarding
5. S. aureus -EVs delivery to host cells
5.1 S. aureus -EVs integrity and cell toxicity
Secretion of molecules and virulence factors is an essential component of
Other studies confirmed this role of EVs. For instance, disrupted EVs produced by
5.2 S. aureus -EVs internalization into host cells
As important as the transport of cargo by EVs is how they transfer their cargo to recipient cells. They can act extracellularly through ligand-receptor interactions or intracellularly after their internalization into target cells and cargo release [79]. In the latter case, EVs’ internalization may occur through several pathways, which all subsequently lead to an intracellular release of their cargo. These pathways include membrane fusion, phagocytosis, macropinocytosis, and lipid-raft-, caveolin- or clathrin-mediated endocytosis [80].
Studies showed that
6. S. aureus -EVs environmental modulation
6.1 Impact of growth conditions in S. aureus -EV release
Besides intrinsic bacterial factors, several external factors were also shown to modify EV production. In
6.2 Impact of growth conditions in S. aureus -EV cargo composition
Culture conditions also alter EV content since bacteria modulate gene expression and protein secretion to cope with environmental changes. Indeed, comparative proteomic analysis revealed that 131 and 617 proteins were identified in EVs derived from
Additionally, EV content can also be impacted by a combination of several factors. For instance, Andreoni et al. evidenced that EVs produced by lysogenic strains had a significantly higher amount of DNA than those of the cured strains when a DNA-damaging SOS antibiotic was used, while the DNA content was unchanged in EVs purified from cultures treated with β-lactam [68]. This can be explained by the prophage-induced cell lysis caused by SOS-response triggering components, leading to an increase of DNA inside EVs, which does not occur with β-lactams since they target bacterial cell wall biosynthesis. These findings evidence that both intrinsic and external factors impact EV release and content, but much research is necessary to better elucidate EV biogenesis and cargo selection in
7. S. aureus -EVs and host cells specificity
7.1 S. aureus -EVs strain specificity
Cytotoxicity and immunomodulation of EVs towards host cells vary according to the
7.2 Host cell lines specificity
On the other hand, the cell lines used
8. Applications of bacterial EVs
8.1 Use of EVs as a vaccine platform
As reviewed above, EVs interact with host cells leading to cytotoxicity, immunomodulation, tissue disruption, and other effects that mimic those caused by living bacteria during infection. These characteristics make EVs interesting vectors for delivering antigens and other components, some of which may have adjuvant properties. These features make EVs good candidates for vaccine development. Several studies have shown that EVs can induce adaptive immunity and confer protection against infections caused by both Gram-negative and Gram-positive pathogenic bacteria [83, 84, 85]. For instance, mice immunized with 1 μg of
8.2 Use of EVs against S. aureus infections
Regarding
In another study, Askarian et al. demonstrated that intraperitoneal vaccination with USA300-derived EVs promoted a high production of antibodies, in addition to the protection of mice against subcutaneous and systemic
8.3 Use S. aureus -EVs against other infections
Interestingly, Yuan et al. used EVs derived from the
9. Conclusions
As addressed here, EVs transport various types of biomolecules that have been reportedly associated with bacterial survival and host-pathogen interactions.
Acknowledgments
This work was conducted in the frame of BactInflam International Associated Laboratory between INRAE (France) and UFMG (Brazil). This work was part of the CARAVEL project financed by the MICA division from INRAE. BSRL was supported by the International Cooperation Program CAPES/COFECUB at the Federal University of Minas Gerais, funded by CAPES – the Brazilian Federal Agency for the Support and Evaluation of Graduate Education of the Brazilian Ministry of Education (number 88887.179897/2018-00).
Conflict of interest
The authors declare no conflict of interest.
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