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Schematic representation of host-pathogen EVs interaction and the distinct classes of RNA molecules in bacterial and fungal vesicles.
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The extracellular vesicle (EVs) traffic has been highlighted as a very important pathway of cellular communication. EVs are produced by prokaryotes and eukaryotes organisms and can carry molecules to help maintain homeostasis, responding to general disbalance, infections, and allowing rapid modulation of the immune system. In the context of infecti...
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Malaria parasites are unicellular eukaryotic pathogens that develop through a complex lifecycle involving two hosts, an anopheline mosquito and a vertebrate host. Throughout this lifecycle, the parasite encounters widely differing conditions and survives in distinct ways, from an intracellular lifestyle in the vertebrate host to exclusively extrace...
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... Hence, it is crucial to understand the regulatory effects of secreted sncR-NAs on host cells during bacterial infection. Researchers have increasingly identified the presence of sncRNAs, which regulate host biological activities, in the outer membrane vesicles (OMVs) secreted by Gram-negative bacteria (Han et al. 2019;Liu et al. 2021;Munhoz da Rocha et al. 2020;Stanton 2021). Therefore, this review aims to describe the intracellular and extracellular regulatory functions of bacterial sncRNAs and further explores the molecular mechanisms of pathogen-host regulation by OMV-encapsulated bacterial sncRNAs. ...
Small noncoding RNAs (sncRNAs) play important regulatory roles in bacterial physiological processes and host-pathogen interactions. Meanwhile, bacterial outer membrane vesicles (OMVs), as naturally secreted outer membrane structures, play a vital role in the interaction between bacteria and their living environment, including the host environment. However, most current studies focus on the biological functions of sncRNAs in bacteria or hosts, while neglecting the roles and regulatory mechanisms of the OMVs that encapsulate these sncRNAs. Therefore, this review aims to summarize the intracellular regulatory roles of bacterial sncRNAs in promoting pathogen survival by regulating virulence, modulating bacterial drug resistance, and regulating iron metabolism, and their extracellular regulatory function for influencing host immunity through host-pathogen interactions. Additionally, we introduce the key role played by OMVs, which serve as important cargoes in bacterial sncRNA–host interactions. We propose emerging pathways of sncRNA action to further discuss the mode of host-pathogen interactions, highlighting that the inhibition of sncRNA delivery by OMVs may prevent the occurrence of infection to some extent. Hence, this review lays the foundation for future prophylactic treatments against bacterial infections and strategies for addressing bacterial drug resistance.
Key points
•sncRNAs have intracellular and extracellular regulatory functions in bacterial physiological processes and host-pathogen interactions.
•OMVs are potential mediators between bacterial sncRNAs and host cells.
•OMVs encapsulating sncRNAs have more potential biological functions.
... In most cases, RNAs (mRNAs, tRNA halves, miRNAs, siRNAs…) have been identified as the active 'message-bearing' molecules within EVs (Valadi et al. 2007). EV RNAs have also been shown to play major roles in host-pathogen interactions (Munhoz Da Rocha et al. 2020). ...
Extracellular vesicles (EVs) are now recognized as key players in the biology of numerous organisms, including pathogenic fungi. However, studying EVs in these organisms remains challenging. The recent implementation of new protocols to purify EVs in the pathogenic yeast Cryptococcus neoformans has resulted in a more detailed description of their structure and protein composition. Although a few publications describing RNA molecules associated with EVs have already been published, we reasoned that these new protocols would be beneficial for gaining a deeper understanding of the EV transcriptome. We thus purified EVs and confirmed that some RNAs were associated with these EV extracts. Iodixanol gradient analyses also revealed that these RNAs co-sedimented with EVs. We then sequenced these RNAs in parallel with RNAs extracted from the very cells producing these EVs using different types of sequencing libraries. Our data confirm the presence of siRNAs and tRFs associated with EVs, some of which are enriched. We also identified some snoRNAs, which in Cryptococcus are mostly borne by coding gene or lncRNA introns.
... Their activity may contribute to processes related to the physiology of fungi as well as the pathogenesis of infections they cause [20,42,43]. Molecules transported in vesicles may be more resistant to unfavorable environmental conditions and degradation [44] and act at a greater distance from pathogen cells settled in a particular host niche [4,6]. The involvement of C. albicans EVs in the formation and remodeling of the biofilm matrix, immunomodulatory properties, Figure 7. HPLC profiles of NAT26 peptide incubated with EVs produced by biofilms of C. albicans strain 3147 (green line) or strain SC5314 (blue line). ...
... Their activity may contribute to processes related to the physiology of fungi as well as the pathogenesis of infections they cause [20,42,43]. Molecules transported in vesicles may be more resistant to unfavorable environmental conditions and degradation [44] and act at a greater distance from pathogen cells settled in a particular host niche [4,6]. The involvement of C. albicans EVs in the formation and remodeling of the biofilm matrix, immunomodulatory properties, and resistance to the antifungal drug fluconazole have been repeatedly demonstrated [20][21][22]45,46]. ...
It has been repeatedly reported that the cells of organisms in all kingdoms of life produce nanometer-sized lipid membrane-enveloped extracellular vesicles (EVs), transporting and protecting various substances of cellular origin. While the composition of EVs produced by human pathogenic fungi has been studied in recent decades, another important challenge is the analysis of their functionality. Thus far, fungal EVs have been shown to play significant roles in intercellular communication, biofilm production, and modulation of host immune cell responses. In this study, we verified the involvement of biofilm-derived EVs produced by two different strains of Candida albicans—C. albicans SC5314 and 3147 (ATCC 10231)—in various aspects of biofilm function by examining its thickness, stability, metabolic activity, and cell viability in the presence of EVs and the antifungal drug caspofungin. Furthermore, the proteolytic activity against the kininogen-derived antimicrobial peptide NAT26 was confirmed by HPLC analysis for C. albicans EVs that are known to carry, among others, particular members of the secreted aspartic proteinases (Saps) family. In conclusion, EVs derived from C. albicans biofilms were shown to be involved in biofilm tolerance to caspofungin, biofilm detachment, and fungal proteolytic activity.
... Many studies have shown that fungal-derived EVs contain nucleic acids, including RNA (ribonucleic acid) and DNA (deoxyribonucleic acid), which have many different functions. A variety of RNA molecules are present in fungal EVs, including ncRNA, mRNA, snoRNA, snRNA, tRNA, microRNA, miRNA, and asRNA (De Toledo et al., 2019;Munhoz da Rocha et al., 2020). Less extensive research has been conducted on their DNA content, which remains to be explored in depth. ...
Fungi are eukaryotic microorganisms found in nature, which can invade the human body and cause tissue damage, inflammatory reactions, organ dysfunctions, and diseases. These diseases can severely damage the patient’s body systems and functions, leading to a range of clinical symptoms that can be life-threatening. As the incidence of invasive fungal infections has progressively increased in the recent years, a wealth of evidence has confirmed the “double-edged sword” role of fungal extracellular vesicles (EVs) in intercellular communication and pathogen-host interactions. Fungal EVs act as mediators of cellular communication, affecting fungal-host cell interactions, delivering virulence factors, and promoting infection. Fungal EVs can also have an induced protective effect, affecting fungal growth and stimulating adaptive immune responses. By integrating recent studies, we discuss the role of EVs in fungi, providing strong theoretical support for the early prevention and treatment of invasive fungal infections. Finally, we highlight the feasibility of using fungal EVs as drug carriers and in vaccine development.
... The content of EVs is diverse, and include RNAi, antigenic and major histocompatibility complex molecules, among other cargos. EVs play an important role in short or long distance communication between cells and tissues, and contribute to diverse biological processes such as regulation of cell viability and modulation of immune responses (Abels & Breakefield, 2016;Chidester et al., 2020;EL Andaloussi et al., 2013;Munhoz da Rocha et al., 2020;Engin, 2021). ...
Host-Pathogen interactions involve finely regulated mechanisms contributing to the establishment of infection (Méthot and Alizon, 2014). Upon contact, signaling cascades are induced in both the microorganism and the host with different objectives: i) the invading microorganism aims to enter the host, establish itselfand cause damage, ii) the host aims to prevent pathogen’s entry and persistence. Thus, both protagonists expose their attack and defense strategies. In the aforementioned events, participation of the actin cytoskeleton and the endomembrane system is essential in both the host and the pathogen.
Multiple microorganisms manipulate the host cytoskeleton by remodeling actin filaments and microtubules to facilitate invasion or to escape host defenses (Morrissette and Sibley, 2002; Wen et al., 2020; Dutta et al., 2022). The actin cytoskeleton of parasites also participates in host cell entry (invasion), cell migration (motility), transport of molecules between organelles (vesicular transport), and phagocytosis (acquisition of nutrients), all these cellular processes being crucial for the virulence of the infectious agent (Kumar et al., 2014; Mansuri et al., 2014; Manich et al., 2018; Bañuelos et al., 2022).
In line, bacteria have developed attack nanomachineries, such as injectosomes and molecular nanosyringes. These structures are of protein nature and allow toxins or bacterial effectors to be injected into target cells, which facilitates entry or induces host cell destruction (Ruano-Gallego et al., 2015; Wagner et al., 2018).
Eukaryotic cells have a system of interconnected endomembranes that is highly conserved between species (Gurkan et al., 2007; Grissom et al., 2020). This system is involved in protein degradation, recycling and secretion, notably through the formation of extracellular vesicles (EVs). The content of EVs is diverse, and include RNAi, antigenic and major histocompatibility complex molecules, among other cargos. EVs play an important role in short or long distance communication between cells and tissues, and contribute to diverse biological processes such as regulation of cell viability and modulation of immune responses (Abels & Breakefield, 2016; Chidester et al., 2020; EL Andaloussi et al., 2013; Munhoz da Rocha et al., 2020; Engin, 2021).
Advances in microscopy techniques, biochemical, cellular and molecular biology, proteomics, bioinformatics, and other fields have enabled the generation of new knowledge to better understand the molecular strategies employed by microorganisms and the host in their ongoing battle for supremacy. This Research Topic presents recent findings describing how different parasites: Entamoeba histolytica, Echinococcus granulosus, and Bastocystis as well as the bacteria Salmonella enterica modulate host responses by various processes such as actin rearrangement and secretion of EVs to promote host cell entry or tissue invasion.
... Communication between cells appears to be a fundamental mechanism for all living beings [28]. During co-evolution, various rival cells could interfere with it while disrupting its steadiness, giving them competitive advantages [29]. ...
The self-assembling of nanosized materials is a promising field for research and development. Multiple approaches are applied to obtain inorganic, organic and composite nanomaterials with different functionality. In the present work, self-assembling nanocomplexes (NCs) were prepared on the basis of enzymes and polypeptides followed by the investigation of the influence of low-molecular weight biologically active compounds on the properties of the NCs. For that, the initially possible formation of catalytically active self-assembling NCs of four hydrolytic enzymes with nine effectors was screened via molecular modeling. It allowed the selection of two enzymes (hexahistidine-tagged organophosphorus hydrolase and penicillin acylase) and two compounds (emodin and naringenin) having biological activity. Further, such NCs based on surface-modified enzymes were characterized by a batch of physical and biochemical methods. At least three NCs containing emodin and enzyme (His6-OPH and/or penicillin acylase) have been shown to significantly improve the antibacterial activity of colistin and, to a lesser extent, polymyxin B towards both Gram-positive bacteria (Bacillus subtilis) and Gram-negative bacteria (Escherichia coli).
... EVs serve as mediators of infection and defenses during plant-fungal pathogen interactions ( Figure 2). Active extracellular vesicular transport, passive transport via trans-cell wall diffusion, binding and internalization through membrane-associated receptors, and other trans-membrane pores or channels are all possible sRNA trafficking mechanisms across the plant-fungal interface [5,111,117,[161][162][163][164][165]. A diverse collection of plant sRNAs, including miRNAs and siRNAs, are selectively loaded into the EVs of plant cells [85,163]. ...
Fungal plant pathogens use proteinaceous effectors as well as newly identified secondary metabolites (SMs) and small non-coding RNA (sRNA) effectors to manipulate the host plant's defense system via diverse plant cell compartments, distinct organelles, and many host genes. However , most molecular studies of plant-fungal interactions have focused on secreted effector proteins without exploring the possibly equivalent functions performed by fungal (SMs) and sRNAs, which are collectively known as "non-proteinaceous effectors". Fungal SMs have been shown to be generated throughout the plant colonization process, particularly in the early biotrophic stages of infection. The fungal repertoire of non-proteinaceous effectors has been broadened by the discovery of fungal sRNAs that specifically target plant genes involved in resistance and defense responses. Many RNAs, particularly sRNAs involved in gene silencing, have been shown to transmit bidirectionally between fungal pathogens and their hosts. However, there are no clear functional approaches to study the role of these SM and sRNA effectors. Undoubtedly, fungal SM and sRNA effectors are now a treasured land to seek. Therefore, understanding the role of fungal SM and sRNA effectors may provide insights into the infection process and identification of the interacting host genes that are targeted by these effectors. This review discusses the role of fungal SMs and sRNAs during plant-fungal interactions. It will also focus on the translocation of sRNA effectors across kingdoms, the application of cross-kingdom RNA interference in managing plant diseases and the tools that can be used to predict and study these non-proteinaceous effectors.
... Pathogens can use EVs to communicate, which facilitates the persistence of infection, impacts pathogen motility, and determines tissue tropism (Cipriano and Hajduk, 2018). In the intracellular milieu, pathogens can alter the homeostasis of host cells, inducing the differential expression of RNAs and proteins (Rodrigues et al., 2015;Munhoz da Rocha et al., 2020). EVs originating from infected cells can modulate the immune response and also affect host membrane properties (Cipriano and Hajduk, 2018). ...
... Vesicles as extracellularly secreted and biologically active structures might participate in the communication between fungi and human cells inducing the immune system response (Herkert et al., 2019;Munhoz da Rocha et al., 2020). For EVs released by C. albicans planktonic cells, a few studies were presented previously showing the ambiguous character of the triggered response (Vargas et al., 2015;Vargas et al., 2020;Zamith-Miranda et al., 2021). ...
Currently, non-albicans Candida species, including C. tropicalis, C. glabrata, and C. parapsilosis, are becoming an increasing epidemiological threat, predominantly due to the distinct collection of virulence mechanisms, as well as emerging resistance to antifungal drugs typically used in the treatment of candidiasis. They can produce biofilms that release extracellular vesicles (EVs), which are nanometric spherical structures surrounded by a lipid bilayer, transporting diversified biologically active cargo, that may be involved in intercellular communication, biofilm matrix production, and interaction with the host. In this work, we characterize the size and protein composition of these structures for three species of non-albicans Candida fungi forming biofilm, indicating considerable heterogeneity of the investigated population of fungal EVs. Examination of the influence of EVs on cytokine production by the human monocytic cell line THP-1 differentiated into macrophage-like cells revealed that the tested vesicles have a stimulating effect on the secretion of tumor necrosis factor α and interleukin 8, while they reduce the production of interleukin 10. This may indicate the proinflammatory nature of the effect of EVs produced by these species on the host immune cells. Moreover, it has been indicated that vesicles may be involved in C. tropicalis biofilm resistance to fluconazole and caspofungin. This reveals the important role of EVs not only in the physiology of C. tropicalis, C. glabrata, and C. parapsilosis fungi but also in the pathogenesis of infections associated with the production of fungal biofilm.
... Even though DNA and RNA were found in EVs from L. reuteri BBC3 and L. casei BL23 (Domínguez Rubio et al., 2017;Hu et al., 2021), the characterization of nucleic acids from probiotics remains to be studied. Small RNA contained in EVs from probiotics might possibly regulate gene expression in host cells, as it is the case for EVs from pathogenic bacteria, and this interaction could have implications in preventing and treating infections (Lee, 2019;Munhoz da Rocha et al., 2020). Extracellular vesicles from probiotics have shown to contain phage nucleic acids (Domínguez Rubio et al., 2017;Champagne-Jorgensen et al., 2021b;Gu et al., 2021) and phage proteins (Domínguez Rubio et al., 2017;Gu et al., 2021). ...
Probiotics have been shown to be effective against infectious diseases in clinical trials, with either intestinal or extraintestinal health benefits. Even though probiotic effects are strain-specific, some “widespread effects” include: pathogen inhibition, enhancement of barrier integrity and regulation of immune responses. The mechanisms involved in the health benefits of probiotics are not completely understood, but these effects can be mediated, at least in part, by probiotic-derived extracellular vesicles (EVs). However, to date, there are no clinical trials examining probiotic-derived EVs health benefits against infectious diseases. There is still a long way to go to bridge the gap between basic research and clinical practice. This review attempts to summarize the current knowledge about EVs released by probiotic bacteria to understand their possible role in the prevention and/or treatment of infectious diseases. A better understanding of the mechanisms whereby EVs package their cargo and the process involved in communication with host cells (inter-kingdom communication), would allow further advances in this field. In addition, we comment on the potential use and missing knowledge of EVs as therapeutic agents (postbiotics) against infectious diseases. Future research on probiotic-derived EVs is needed to open new avenues for the encapsulation of bioactives inside EVs from GRAS (Generally Regarded as Safe) bacteria. This could be a scientific novelty with applications in functional foods and pharmaceutical industries.
