Abstract:Gram-negative bacterium-released outer-membrane vesicles (OMVs) and Gram-positive bacterium-released membrane vesicles (MVs) share significant similarities with mammalian cell-derived MVs (eg, microvesicles and exosomes) in terms of structure and their biological activities. Recent studies have revealed that bacterial OMVs/MVs could (1) interact with immune cells to regulate inflammatory responses, (2) transport virulence factors (eg, enzymes, DNA and small RNAs) to host cells and result in cell injury, (3) en… Show more
“…Therefore, this classic concept In this sense, it has to be noted that some works have recently shown in E. coli but also in other more niche-specific species, such as some periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia), the association between their released OMVs and the activation of NOD1 and/or NOD2 in the host, which strongly suggests that the presence of PGN fragments within the cited vesicles potentially contributes to the inflammatory response in the infected tissues (152)(153)(154). In fact, in recent years OMVs have been recognized to be effective virulence factor delivery systems, and hence, the presence of certain PGN fragments within OMVs could contribute to this role (155)(156)(157). Moreover, to conclude and as additional evidence that Gram-negative PGN biology interacts with pathogenesis (in this case, with a close relation to OMVs), some studies have directly related PGN dynamics to the modulation of OMV production levels, which would have obvious consequences for virulence (158,159).…”
Section: Interaction Of Peptidoglycan With the Host Release Of Peptidmentioning
The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and relevant antibiotics, urges research to find new therapeutic weapons to combat the infections caused by these microorganisms. An essential previous step in the development of these therapeutic solutions is to identify their potential targets in the biology of the pathogen. This is precisely what we sought to do in this review specifically regarding the barely exploited field analyzing the interplay among the biology of the peptidoglycan and related processes, such as β-lactamase regulation and virulence. Hence, here we gather, analyze, and integrate the knowledge derived from published works that provide information on the topic, starting with those dealing with the historically neglected essential role of the Gram-negative peptidoglycan in virulence, including structural, biogenesis, remodeling, and recycling aspects, in addition to proinflammatory and other interactions with the host. We also review the complex link between intrinsic β-lactamase production and peptidoglycan metabolism, as well as the biological costs potentially associated with the expression of horizontally acquired β-lactamases. Finally, we analyze the existing evidence from multiple perspectives to provide useful clues for identifying targets enabling the future development of therapeutic options attacking the peptidoglycan-virulence interconnection as a key weak point of the Gram-negative pathogens to be used, if not to kill the bacteria, to mitigate their capacity to produce severe infections.
“…Therefore, this classic concept In this sense, it has to be noted that some works have recently shown in E. coli but also in other more niche-specific species, such as some periodontal pathogens (Aggregatibacter actinomycetemcomitans, Porphyromonas gingivalis, Treponema denticola, and Tannerella forsythia), the association between their released OMVs and the activation of NOD1 and/or NOD2 in the host, which strongly suggests that the presence of PGN fragments within the cited vesicles potentially contributes to the inflammatory response in the infected tissues (152)(153)(154). In fact, in recent years OMVs have been recognized to be effective virulence factor delivery systems, and hence, the presence of certain PGN fragments within OMVs could contribute to this role (155)(156)(157). Moreover, to conclude and as additional evidence that Gram-negative PGN biology interacts with pathogenesis (in this case, with a close relation to OMVs), some studies have directly related PGN dynamics to the modulation of OMV production levels, which would have obvious consequences for virulence (158,159).…”
Section: Interaction Of Peptidoglycan With the Host Release Of Peptidmentioning
The clinical and epidemiological threat of the growing antimicrobial resistance in Gram-negative pathogens, particularly for β-lactams, the most frequently used and relevant antibiotics, urges research to find new therapeutic weapons to combat the infections caused by these microorganisms. An essential previous step in the development of these therapeutic solutions is to identify their potential targets in the biology of the pathogen. This is precisely what we sought to do in this review specifically regarding the barely exploited field analyzing the interplay among the biology of the peptidoglycan and related processes, such as β-lactamase regulation and virulence. Hence, here we gather, analyze, and integrate the knowledge derived from published works that provide information on the topic, starting with those dealing with the historically neglected essential role of the Gram-negative peptidoglycan in virulence, including structural, biogenesis, remodeling, and recycling aspects, in addition to proinflammatory and other interactions with the host. We also review the complex link between intrinsic β-lactamase production and peptidoglycan metabolism, as well as the biological costs potentially associated with the expression of horizontally acquired β-lactamases. Finally, we analyze the existing evidence from multiple perspectives to provide useful clues for identifying targets enabling the future development of therapeutic options attacking the peptidoglycan-virulence interconnection as a key weak point of the Gram-negative pathogens to be used, if not to kill the bacteria, to mitigate their capacity to produce severe infections.
“…OMVs are generated by blebbing outwards from the OM, during which process they include soluble components inside and adherent material, on the external surface [109] . EVs produced by gram-positive bacteria are structurally similar to OMVs, with sizes ranging from 10 to 400 nm [107] . They carry bacterial components including nucleic acid, proteins, lipids, enzymes and toxins.…”
Section: Evs Mediated Cross Talk Communication Between Bacteria and Hmentioning
Development of drug resistance represents the major cause of cancer therapy failure, determines disease progression and results in poor prognosis for cancer patients. Different mechanisms are responsible for drug resistance. Intrinsic genetic modifications of cancer cells induce the alteration of expression of gene controlling specific pathways that regulate drug resistance: drug transport and metabolism; alteration of drug targets; DNA damage repair; and deregulation of apoptosis, autophagy, and pro-survival signaling. On the other hand, a complex signaling network among the entire cell component characterizes tumor microenvironment and regulates the pathways involved in the development of drug resistance. Gut microbiota represents a new player in the regulation of a patient's response to cancer therapies, including chemotherapy and immunotherapy. In particular, commensal bacteria can regulate the efficacy of immune checkpoint inhibitor therapy by modulating the activation of immune responses to cancer. Commensal bacteria can also regulate the efficacy of chemotherapeutic drugs, such as oxaliplatin, gemcitabine, and cyclophosphamide. Recently, it has been shown that such bacteria can produce extracellular vesicles (EVs) that can mediate intercellular communication with human host cells. Indeed, bacterial EVs carry RNA molecules with gene expression regulatory ability that can be delivered to recipient cells of the host and potentially regulate the expression of genes involved in controlling the resistance to cancer therapy. On the other hand, host cells can also deliver human EVs to commensal bacteria and similarly, regulate gene expression. EVmediated intercellular communication between commensal bacteria and host cells may thus represent a novel research area into potential mechanisms regulating the efficacy of cancer therapy.
“…These specific proteins contained in exosomes can reveal which mother cells they are from. For example, exosomes derived from intestinal epithelial cells contain various metabolic enzymes [16]; exosomes derived from T cells have T cell surface receptor proteins; and the ones from dendritic cells contain a large number of proteins associated with antigen-presenting cells, such as MHC class I molecules, MHC class II molecules, and costimulatory molecules CD80 and CD86 [17]. These proteins can be used as markers to provide a basis for early diagnosis of disease, such as tumors.…”
Exosomes are extracellular vesicles with a diameter of 30–100 nm, which are released into the extracellular space by fusion of multivesicular and plasma membranes. These vesicles actually play a distinct role in cell communication, although they were considered as membrane debris in the past. The endosomal sorting complex required for transport (ESCRT)-dependent and ESCRT-independent mechanisms are currently considered to be involved in the sorting of exosomes, and the release of exosomes is related to the members of Rab protein family and SNARE family. In recent years, the therapeutic potential of exosomes has become apparent. For example, via the direct transplantation of exosomes, the ischemic area after stroke is reduced, and the neurological function is improved significantly. Furthermore, they can be used as effective drug delivery vehicles due to their unique characteristics such as low immunogenicity and nanometer size. In conclusion, exosomes provide a cell-free treatment for ischemic stroke.
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