Exosomes and Other Extracellular Vesicles: The New Communicators in Parasite Infections
2015; Elsevier BV; Volume: 31; Issue: 10 Linguagem: Inglês
10.1016/j.pt.2015.06.009
ISSN1471-5007
AutoresGillian Coakley, Rick M. Maizels, Amy H. Buck,
Tópico(s)MXene and MAX Phase Materials
ResumoEVs are secreted by most or all organisms and are emerging as a ubiquitous and functionally diverse type of host–pathogen interaction. EVs contain a diverse suite of molecules including proteins, lipids, and nucleic acids, some of which are known to have immunomodulatory properties. Parasite-derived EVs can communicate information and transfer genetic material to host cells or other parasites. Host-derived EVs can play a key role in host defense and are candidates for generating a vaccine against pathogenic infection. Extracellular vesicles (EVs) have emerged as a ubiquitous mechanism for transferring information between cells and organisms across all three kingdoms of life. In addition to their roles in normal physiology, vesicles also transport molecules from pathogens to hosts and can spread antigens as well as infectious agents. Although initially described in the host–pathogen context for their functions in immune surveillance, vesicles enable multiple modes of communication by, and between, parasites. Here we review the literature demonstrating that EVs are secreted by intracellular and extracellular eukaryotic parasites, as well as their hosts, and detail the functional properties of these vesicles in maturation, pathogenicity and survival. We further describe the prospects for targeting or exploiting these complexes in therapeutic and vaccine strategies. Extracellular vesicles (EVs) have emerged as a ubiquitous mechanism for transferring information between cells and organisms across all three kingdoms of life. In addition to their roles in normal physiology, vesicles also transport molecules from pathogens to hosts and can spread antigens as well as infectious agents. Although initially described in the host–pathogen context for their functions in immune surveillance, vesicles enable multiple modes of communication by, and between, parasites. Here we review the literature demonstrating that EVs are secreted by intracellular and extracellular eukaryotic parasites, as well as their hosts, and detail the functional properties of these vesicles in maturation, pathogenicity and survival. We further describe the prospects for targeting or exploiting these complexes in therapeutic and vaccine strategies. More than 1 billion people worldwide are burdened by parasitic disease, including malaria [1Murray C.J. et al.Global, regional, and national incidence and mortality for HIV, tuberculosis, and malaria during 1990–2013: a systematic analysis for the Global Burden of Disease Study 2013.Lancet. 2014; 384: 1005-1070Abstract Full Text Full Text PDF PubMed Scopus (690) Google Scholar] and neglected tropical diseases such as leishmaniasis, Chagas disease and helminthiases (http://whqlibdoc.who.int/hq/2012/WHO_HTM_NTD_2012.1_eng.pdf), with most prevailing in developing regions such as eastern Asia, sub-Saharan Africa, and the Americas [2Lustigman S. et al.A research agenda for helminth diseases of humans: the problem of helminthiases.PLoS Negl. Trop. Dis. 2012; 6: e1582Crossref PubMed Scopus (229) Google Scholar]. The prospects for drug resistance are alarming, with an increasing incidence in livestock that highlights a potential threat to the human population through zoonotic transmission as well as having strong economic and social implications [3Prichard R.K. et al.A research agenda for helminth diseases of humans: intervention for control and elimination.PLoS Negl. Trop. Dis. 2012; 6: e1549Crossref PubMed Scopus (153) Google Scholar]. There is a clear need for more efficacious therapies, which require an improved understanding of how these parasites adapt to, and manipulate, their host environment. Most parasites at some stage in their life cycle rely on the ability to communicate with one another and with their hosts, but the mechanisms underpinning this communication are still coming to light. Research in this area has largely focused on the soluble proteins secreted by parasites, many of which down-modulate the host immune response (reviewed in [4McSorley H.J. et al.Immunomodulation by helminth parasites: defining mechanisms and mediators.Int. J. Parasitol. 2013; 43: 301-310Crossref PubMed Scopus (214) Google Scholar, 5Stanisic D.I. et al.Escaping the immune system: how the malaria parasite makes vaccine development a challenge.Trends Parasitol. 2013; 29: 612-622Abstract Full Text Full Text PDF PubMed Scopus (43) Google Scholar]). For example, in the case of helminths, the egg stage of Schistosoma mansoni secretes an omega-1 glycoprotein, demonstrated in several studies to promote type 2 helper (Th2) skewing of dendritic cells (DCs) and T cells during infection [6Hussaarts L. et al.Rapamycin and omega-1: mTOR-dependent and -independent Th2 skewing by human dendritic cells.Immunol. Cell Biol. 2013; 91: 486-489Crossref PubMed Scopus (28) Google Scholar, 7Steinfelder S. et al.The major component in schistosome eggs responsible for conditioning dendritic cells for Th2 polarization is a T2 ribonuclease (omega-1).J. Exp. Med. 2009; 206: 1681-1690Crossref PubMed Scopus (239) Google Scholar]. The immunomodulatory lipoprotein antigen B is secreted by Echinococcus granulosus and facilitates Th2 polarization and limits migration of neutrophils to the site of infection [8Siracusano A. et al.Molecular cross-talk in host–parasite relationships: the intriguing immunomodulatory role of Echinococcus antigen B in cystic echinococcosis.Int. J. Parasitol. 2008; 38: 1371-1376Crossref PubMed Scopus (56) Google Scholar]. The ES-62 protein from Acanthocheilonema viteae has potent anti-inflammatory properties on mast cells [9Pineda M.A. et al.ES-62, a therapeutic anti-inflammatory agent evolved by the filarial nematode Acanthocheilonema viteae.Mol. Biochem. Parasitol. 2014; 194: 1-8Crossref PubMed Scopus (60) Google Scholar]. Protozoan parasites similarly secrete a range of immunomodulatory molecules; for example, Trypanosoma cruzi mucins have been associated with suppression of active T cell immune responses by inducing arrest in the cell cycle [10Nunes M.P. et al.Inhibitory effects of Trypanosoma cruzi sialoglycoproteins on CD4+ T cells are associated with increased susceptibility to infection.PLoS ONE. 2013; 8: e77568Crossref PubMed Scopus (17) Google Scholar]. Secreted parasite proteins have also been proposed to be involved in metabolic adaptation to the host environment [11Pan W. et al.Transcriptome profiles of the protoscoleces of Echinococcus granulosus reveal that excretory–secretory products are essential to metabolic adaptation.PLoS Negl. Trop. Dis. 2014; 8: e3392Crossref PubMed Scopus (21) Google Scholar] and tissue invasion, where proteases play a major role [12McKerrow J.H. et al.Proteases in parasitic diseases.Annu. Rev. Pathol. 2006; 1: 497-536Crossref PubMed Scopus (319) Google Scholar]. In the past 5 years, EVs have been revealed as another component of parasite secretion products that provide a previously unrecognized mechanism to package and protect a set of parasite cargo for uptake and integration into other cells. EVs are known to play a role in communication and genetic exchange between microbes [13Deatherage B.L. Cookson B.T. Membrane vesicle release in bacteria, eukaryotes, and archaea: a conserved yet underappreciated aspect of microbial life.Infect. Immun. 2012; 80: 1948-1957Crossref PubMed Scopus (468) Google Scholar]. The functional niches in which EVs operate in eukaryotic parasites and other pathogens are still emerging and are summarized in Table 1.Table 1Proposed Functions of Pathogen or Host-Derived Exosomes during InfectionaDetails in each column (from left to right) describe: the parasite species, the life stage and/or cellular origin of the EV, the proposed beneficiary (host or parasite), the proposed target and functional outcome, the mechanistic data in support of this function, and the primary literature reference.PathogenEV originHost or parasite?EV targetFunctional responseEffector mechanismRefsProtozoaLeishmania amazonensisMacrophages exposed to promastigotesHostMonocytes and/or macrophagesPromotion of Th1 responses for parasite eliminationNaïve macrophages are primed to release IL-12, IL-1β, and TNF46Cronemberger-Andrade A. et al.Extracellular vesicles from Leishmania-infected macrophages confer an anti-infection cytokine-production profile to naive macrophages.PLoS Negl. Trop. Dis. 2014; 8: e3161Crossref PubMed Scopus (32) Google ScholarLeishmania donovaniPromastigotesParasiteMonocytes and/or macrophagesInvasion and persistence within host cells and delivery of virulence factorsLeishmania EF-1α and GP63 activate host PTPs in monocytes responding to IFNγ. GP63 can also influence exosome cargo selection and inhibit host miRNA processing.35Silverman J.M. et al.An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages.J. Cell Sci. 2010; 123: 842-852Crossref PubMed Scopus (342) Google Scholar, 36Silverman J.M. Reiner N.E. Leishmania exosomes deliver preemptive strikes to create an environment permissive for early infection.Front. Cell. Infect. Microbiol. 2011; 1: 26PubMed Google Scholar, 37Silverman J.M. et al.Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.J. Immunol. 2010; 185: 5011-5022Crossref PubMed Scopus (226) Google Scholar, 39Gomez M.A. et al.Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases.Sci. Signal. 2009; 2: ra58Crossref PubMed Scopus (145) Google Scholar, 40Hassani K. Olivier M. Immunomodulatory impact of Leishmania-induced macrophage exosomes: a comparative proteomic and functional analysis.PLoS Negl. Trop. Dis. 2013; 7: e2185Crossref PubMed Scopus (93) Google Scholar, 42Ghosh J. et al.Leishmania donovani targets Dicer1 to downregulate miR-122, lower serum cholesterol, and facilitate murine liver infection.Cell Host Microbe. 2013; 13: 277-288Abstract Full Text Full Text PDF PubMed Scopus (120) Google ScholarParasiteImmune cells, including macrophagesInduction of Leishmania peptide-carrying exosomes from monocytesOverall increase in IL-8 secretion by macrophages, which promotes neutrophil recruitment. Induces release of IL-10 in human monocytes while suppressing release of TNF.35Silverman J.M. et al.An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages.J. Cell Sci. 2010; 123: 842-852Crossref PubMed Scopus (342) Google Scholar, 36Silverman J.M. Reiner N.E. Leishmania exosomes deliver preemptive strikes to create an environment permissive for early infection.Front. Cell. Infect. Microbiol. 2011; 1: 26PubMed Google Scholar, 37Silverman J.M. et al.Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.J. Immunol. 2010; 185: 5011-5022Crossref PubMed Scopus (226) Google ScholarLeishmania majorPromastigotesParasiteMonocytes/macrophagesInvasion and persistence within host cells and delivery of virulence factorsLeishmania EF-1α and GP63 activate host PTPs in monocytes responding to IFNγ.39Gomez M.A. et al.Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases.Sci. Signal. 2009; 2: ra58Crossref PubMed Scopus (145) Google Scholar, 41Hassani K. et al.Absence of metalloprotease GP63 alters the protein content of Leishmania exosomes.PLoS ONE. 2014; 9: e95007Crossref PubMed Scopus (74) Google ScholarParasiteImmune cells, including macrophages and T cellsIncreased disease exacerbation and Th2 polarization in vivoIncrease in the number of IL-4-producing CD4+ T cells/decrease in the number of IFNγ-producing CD4+ T cells37Silverman J.M. et al.Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.J. Immunol. 2010; 185: 5011-5022Crossref PubMed Scopus (226) Google ScholarLeishmania mexicanaMacrophages exposed to promastigotesParasiteMacrophagesImmunomodulation of host signaling events promoting parasite survivalUpregulation of Adora2a by parasite-derived GP63 contained within host exosomes40Hassani K. Olivier M. Immunomodulatory impact of Leishmania-induced macrophage exosomes: a comparative proteomic and functional analysis.PLoS Negl. Trop. Dis. 2013; 7: e2185Crossref PubMed Scopus (93) Google ScholarPlasmodium bergheiInfected erythrocytesHostMacrophagesActivate systemic inflammation and T cell primingVia MyD88/TLR4 pathway and CD40/CD40L interactions77Couper K.N. et al.Parasite-derived plasma microparticles contribute significantly to malaria infection-induced inflammation through potent macrophage stimulation.PLoS Pathog. 2010; 6: e1000744Crossref PubMed Scopus (172) Google ScholarPlasmodium falciparumInfected erythrocytesParasiteMonocytes and macrophagesTransfer of parasite material and parasite disseminationInnate cell activation. Cytokine induction in macrophages (IL-6, IL-12, IL-1β, and IL-10) in a dose-dependent manner.49Mantel P.Y. et al.Malaria-infected erythrocyte-derived microvesicles mediate cellular communication within the parasite population and with the host immune system.Cell Host Microbe. 2013; 13: 521-534Abstract Full Text Full Text PDF PubMed Scopus (276) Google ScholarParasiteInfected erythrocytesCommitment of asexual parasites to gametocytesTransfer of genetic information between parasites and budding of EVs via PfPTP249Mantel P.Y. et al.Malaria-infected erythrocyte-derived microvesicles mediate cellular communication within the parasite population and with the host immune system.Cell Host Microbe. 2013; 13: 521-534Abstract Full Text Full Text PDF PubMed Scopus (276) Google Scholar, 50Regev-Rudzki N. et al.Cell–cell communication between malaria-infected red blood cells via exosome-like vesicles.Cell. 2013; 153: 1120-1133Abstract Full Text Full Text PDF PubMed Scopus (392) Google ScholarPlasmodium vivaxPlatelets, erythrocytes, leukocytesHostHuman immune cells, erythrocytes, endothelial cellsHigher acute fever and greater duration of malaria symptoms in human patientsUnknown mechanism78Campos F.M. et al.Augmented plasma microparticles during acute Plasmodium vivax infection.Malar. J. 2010; 9: 327Crossref PubMed Scopus (105) Google ScholarTrichomonas vaginalisMature parasitesParasiteEctocervical cellsLimit neutrophil migration to site of infectionParasite-derived exosomes downregulate IL-8 secretion in ectocervical cells54Twu O. et al.Trichomonas vaginalis exosomes deliver cargo to host cells and mediate host:parasite interactions.PLoS Pathog. 2013; 9: e1003482Crossref PubMed Scopus (165) Google ScholarParasiteWeakly adherent strains of the parasitePromote adherence of weakly adherent strains and increase their virulenceUnknown mechanism54Twu O. et al.Trichomonas vaginalis exosomes deliver cargo to host cells and mediate host:parasite interactions.PLoS Pathog. 2013; 9: e1003482Crossref PubMed Scopus (165) Google ScholarTrypanosoma bruceiProcyclic forms of the parasite (pathogenic in bloodstream)ParasiteHost cellsImproved entry into host cells, enhanced parasite survivalAbundance of parasite-derived proteases (e.g., oligopeptidase B) favors parasite invasion51Atyame Nten C.M. et al.Excreted/secreted proteins from trypanosome procyclic strains.J. Biomed. Biotechnol. 2010; 2010: 212817Crossref PubMed Scopus (40) Google Scholar, 52Vartak D.G. Gemeinhart R.A. Matrix metalloproteases: underutilized targets for drug delivery.J. Drug Target. 2007; 15: 1-20Crossref PubMed Scopus (120) Google Scholar, 53Geiger A. et al.Exocytosis and protein secretion in Trypanosoma.BMC Microbiol. 2010; 10: 20Crossref PubMed Scopus (114) Google ScholarTrypanosoma cruziTrypomastigotesParasiteCD4+ T cells and macrophagesTh2 polarization leading to parasite dissemination and enhanced parasite survivalIncrease in IL-4 and IL-10 secretion and reduction in iNOS expression in CD4+ T cells and macrophages34Trocoli Torrecilhas A.C. et al.Trypanosoma cruzi: parasite shed vesicles increase heart parasitism and generate an intense inflammatory response.Microbes Infect. 2009; 11: 29-39Crossref PubMed Scopus (151) Google ScholarInfected lymphocytes, monocytes and erythrocytesParasiteRecipient immune cells and monocyte-derived complement factorsParasite invasion of host cells and inhibition of complement-induced parasite eliminationPlasma membrane-derived vesicles containing surface TGF-β, which promotes entry into host cells47Cestari I. et al.Trypanosoma cruzi immune evasion mediated by host cell-derived microvesicles.J. Immunol. 2012; 188: 1942-1952Crossref PubMed Scopus (117) Google Scholar, 48Cestari I. Ramirez M.I. Inefficient complement system clearance of Trypanosoma cruzi metacyclic trypomastigotes enables resistant strains to invade eukaryotic cells.PLoS ONE. 2010; 5: e9721Crossref PubMed Scopus (41) Google ScholarFungiCryptococcus neoformansExosomes secreted during the fungal cell phasePathogenHost cells – unknownPromote colonization of infected tissuesRelease virulence factors – glucosylceramide and GXM72Rodrigues M.L. et al.Extracellular vesicles produced by Cryptococcus neoformans contain protein components associated with virulence.Eukaryot. Cell. 2008; 7: 58-67Crossref PubMed Scopus (378) Google ScholarPathogenMacrophagesStimulate fungal killingEnhanced IL-10 and TGF-β secretion and increased nitric oxide production by macrophages75Oliveira D.L. et al.Extracellular vesicles from Cryptococcus neoformans modulate macrophage functions.Infect. Immun. 2010; 78: 1601-1609Crossref PubMed Scopus (174) Google ScholarMalassezia sympodialisYeast – skin-living flora componentPathogenPBMCsExacerbation of atopic dermatitisPromote IL-4 and TNF secretion from PBMCs74Gehrmann U. et al.Nanovesicles from Malassezia sympodialis and host exosomes induce cytokine responses – novel mechanisms for host–microbe interactions in atopic eczema.PLoS ONE. 2011; 6: e21480Crossref PubMed Scopus (99) Google ScholarParacoccidioides brasiliensisYeast phase exosomesPathogenImmune cellsPotential to skew to a suppressive Th2 responseEnriched in α-Gal, which may bind host lectins potentially improving infectivity by fungi69Vallejo M.C. et al.The pathogenic fungus Paracoccidioides brasiliensis exports extracellular vesicles containing highly immunogenic α-galactosyl epitopes.Eukaryot. Cell. 2011; 10: 343-351Crossref PubMed Scopus (113) Google ScholarHelminthsHeligmosomoides polygyrusIntestinal tract of adult nematodeParasiteIntestinal epithelial cells of the hostSuppress classical inflammation and danger responses, promoting parasite survivalSuppression of host targets including IL-33R and DUSP159Buck A.H. et al.Exosomes secreted by nematode parasites transfer small RNAs to mammalian cells and modulate innate immunity.Nat. Commun. 2014; 5: 5488Crossref PubMed Scopus (470) Google ScholarSchistosoma japonicumAdult wormsParasiteMacrophagesPolarization of host macrophages to M1 phenotypeUnknown mechanism58Wang L. et al.Exosome-like vesicles derived by Schistosoma japonicum adult worms mediates M1 type immune activity of macrophage.Parasitol. Res. 2015; 114: 1865-1873Crossref PubMed Scopus (86) Google Scholara Details in each column (from left to right) describe: the parasite species, the life stage and/or cellular origin of the EV, the proposed beneficiary (host or parasite), the proposed target and functional outcome, the mechanistic data in support of this function, and the primary literature reference. Open table in a new tab In mammalian systems EVs represent a mechanism of cell-to-cell communication through the direct stimulation of cells by receptor-mediated contact and/or through the transfer of genetic material, proteins, and lipids. Several distinct types of EV have been described, including those derived from the endocytic pathway, exosomes, versus those derived from shedding of the plasma membrane. We refer to the latter as microvesicles but note that these have been called by many names in the literature, including ectosomes, plasma membrane-derived vesicles, and microparticles [14Raposo G. Stoorvogel W. Extracellular vesicles: exosomes, microvesicles, and friends.J. Cell Biol. 2013; 200: 373-383Crossref PubMed Scopus (5145) Google Scholar]. Exosomes are endocytic vesicles approximately 40–100 nm in size that are released from most cell types [15Thery C. Exosomes: secreted vesicles and intercellular communications.F1000 Biol. Rep. 2011; 3: 15Crossref PubMed Scopus (699) Google Scholar]. Their biogenesis is initiated by inward budding of multivesicular endosomes (Figure 1). Consequently, exosomes express markers of their parent cells, but are also specifically enriched in other molecules associated with their biogenesis or that are selectively packaged into them; for example, by the endosomal sorting complexes required for transport (ESCRT) pathway (reviewed in [16Hanson P.I. Cashikar A. Multivesicular body morphogenesis.Annu. Rev. Cell Dev. Biol. 2012; 28: 337-362Crossref PubMed Scopus (403) Google Scholar]). Microvesicles can be difficult to distinguish from exosomes, but are generally up to 1 μm and bud from the plasma membrane, incorporating certain lipids, surface proteins, and other molecules before fission [17Muralidharan-Chari V. et al.Microvesicles: mediators of extracellular communication during cancer progression.J. Cell Sci. 2010; 123: 1603-1611Crossref PubMed Scopus (712) Google Scholar]. As reports in the literature do not always identify vesicular origin, here we refer to parasite exosomes or 'exosome-like vesicles' if they have been described as such in the primary literature or parasite microvesicles if they are suggested to derive from the plasma membrane, or 'EVs' if the origin is unclear. In recent years, the literature surrounding EV function has exploded as their ubiquity in many biological and disease contexts has been realized [18Harding C.V. et al.Exosomes: looking back three decades and into the future.J. Cell Biol. 2013; 200: 367-371Crossref PubMed Scopus (298) Google Scholar]. Historically, these were first identified in reticulocytes as a mechanism to release transferrin receptors during maturation [19Pan B.T. Johnstone R.M. Fate of the transferrin receptor during maturation of sheep reticulocytes in vitro: selective externalization of the receptor.Cell. 1983; 33: 967-978Abstract Full Text PDF PubMed Scopus (1228) Google Scholar, 20Harding C. et al.Receptor-mediated endocytosis of transferrin and recycling of the transferrin receptor in rat reticulocytes.J. Cell Biol. 1983; 97: 329-339Crossref PubMed Scopus (1100) Google Scholar] and then became of interest to immunologists as they contain MHCs and can present antigens [21Raposo G. et al.B lymphocytes secrete antigen-presenting vesicles.J. Exp. Med. 1996; 183: 1161-1172Crossref PubMed Scopus (2444) Google Scholar]. However, following the report that functional mRNAs and miRNAs are transferred between mast cells via exosomes [22Valadi H. et al.Exosome-mediated transfer of mRNAs and microRNAs is a novel mechanism of genetic exchange between cells.Nat. Cell Biol. 2007; 9: 654-659Crossref PubMed Scopus (8874) Google Scholar], there was further momentum in studying EVs as a mechanism of cell–cell communication. In this context, they have been shown to have various functions in immune cell activation and suppression [23Deng Z.B. et al.Exosome-like nanoparticles from intestinal mucosal cells carry prostaglandin E2 and suppress activation of liver NKT cells.J. Immunol. 2013; 190: 3579-3589Crossref PubMed Scopus (63) Google Scholar, 24Montecalvo A. et al.Mechanism of transfer of functional microRNAs between mouse dendritic cells via exosomes.Blood. 2012; 119: 756-766Crossref PubMed Scopus (984) Google Scholar] and are also proposed to play a role in disease development and tissue homeostasis, [25Aswad H. et al.Exosomes participate in the alteration of muscle homeostasis during lipid-induced insulin resistance in mice.Diabetologia. 2014; 57: 2155-2164Crossref PubMed Scopus (108) Google Scholar]. An ever-expanding literature has also demonstrated various roles of EVs in diseases including cancer, since tumors also secrete these vesicles with oncogenes [26Saleem S.N. Abdel-Mageed A.B. Tumor-derived exosomes in oncogenic reprogramming and cancer progression.Cell. Mol. Life Sci. 2015; 72: 1-10Crossref PubMed Scopus (83) Google Scholar], such as those seen in gastrointestinal stromal tumor cell lines [27Atay S. et al.Oncogenic KIT-containing exosomes increase gastrointestinal stromal tumor cell invasion.Proc. Natl. Acad. Sci. U.S.A. 2014; 111: 711-716Crossref PubMed Scopus (126) Google Scholar]. Exosomes and other EVs are now part of larger clinical initiatives to test their properties in drug delivery, their use as diagnostic biomarkers, and their potential as therapeutics. While most of this work has focused on oncology [28Fong M.Y. et al.Breast-cancer-secreted miR-122 reprograms glucose metabolism in premetastatic niche to promote metastasis.Nat. Cell Biol. 2015; 17: 183-194Crossref PubMed Scopus (734) Google Scholar, 29Zocco D. et al.Extracellular vesicles as shuttles of tumor biomarkers and anti-tumor drugs.Front. Oncol. 2014; 4: 267Crossref PubMed Scopus (77) Google Scholar], these vesicles also have exciting implications across a range of infectious diseases [30Schorey J.S. et al.Exosomes and other extracellular vesicles in host–pathogen interactions.EMBO Rep. 2015; 16: 24-43Crossref PubMed Scopus (453) Google Scholar]. Here we detail the recent literature describing their roles in eukaryotic parasite infection, focusing on the communicative relationship between parasites and hosts. Furthermore we highlight the importance of EVs in the future identification of novel therapeutic targets and the development of vaccine strategies. Several protozoan parasites have been shown to release exosomes and/or microvesicles, including Leishmania species [31Silverman J.M. et al.Proteomic analysis of the secretome of Leishmania donovani.Genome Biol. 2008; 9: R35Crossref PubMed Scopus (228) Google Scholar] and T. cruzi [32Bayer-Santos E. et al.Proteomic analysis of Trypanosoma cruzi secretome: characterization of two populations of extracellular vesicles and soluble proteins.J. Proteome Res. 2013; 12: 883-897Crossref PubMed Scopus (183) Google Scholar, 33Garcia-Silva M.R. et al.Extracellular vesicles shed by Trypanosoma cruzi are linked to small RNA pathways, life cycle regulation, and susceptibility to infection of mammalian cells.Parasitol. Res. 2014; 113: 285-304Crossref PubMed Scopus (101) Google Scholar, 34Trocoli Torrecilhas A.C. et al.Trypanosoma cruzi: parasite shed vesicles increase heart parasitism and generate an intense inflammatory response.Microbes Infect. 2009; 11: 29-39Crossref PubMed Scopus (151) Google Scholar], the parasites that cause human leishmaniasis and Chagas disease, respectively. Seminal reports showed that promastigote and amastigote forms of Leishmania donovani and Leishmania major can release exosomes that are detected in host cells and selectively induce IL-8 secretion from macrophages [35Silverman J.M. et al.An exosome-based secretion pathway is responsible for protein export from Leishmania and communication with macrophages.J. Cell Sci. 2010; 123: 842-852Crossref PubMed Scopus (342) Google Scholar, 36Silverman J.M. Reiner N.E. Leishmania exosomes deliver preemptive strikes to create an environment permissive for early infection.Front. Cell. Infect. Microbiol. 2011; 1: 26PubMed Google Scholar] (Figure 2A) . The subsequent chemokinetic recruitment of neutrophils has been proposed as a 'Trojan horse' effect, whereby Leishmania can invade these cells and gain access to macrophages on phagocytosis of the infected neutrophils [37Silverman J.M. et al.Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.J. Immunol. 2010; 185: 5011-5022Crossref PubMed Scopus (226) Google Scholar, 38van Zandbergen G. et al.Cutting edge: neutrophil granulocyte serves as a vector for Leishmania entry into macrophages.J. Immunol. 2004; 173: 6521-6525Crossref PubMed Scopus (326) Google Scholar]. Leishmania exosomes have also been shown to induce the release of the immunosuppressive cytokine IL-10 and inhibit the inflammatory cytokine tumor necrosis factor (TNF) in human monocyte-derived DCs in response to interferon gamma (IFNγ). Pretreatment of mice with exosomes derived from L. major and L. donovani resulted in exacerbated infection and pathogenesis in vivo, associated with enhanced IL-10 production and a skewed Th2 response, preventing parasite expulsion as a type 1 response is normally required for clearance [37Silverman J.M. et al.Leishmania exosomes modulate innate and adaptive immune responses through effects on monocytes and dendritic cells.J. Immunol. 2010; 185: 5011-5022Crossref PubMed Scopus (226) Google Scholar]. Specific components of Leishmania exosome cargo have also been identified and shown to be involved in immunomodulation, including elongation factor 1 alpha (EF-1α) and the membrane-bound metalloprotease GP63 [39Gomez M.A. et al.Leishmania GP63 alters host signaling through cleavage-activated protein tyrosine phosphatases.Sci. Signal. 2009; 2: ra58Crossref PubMed Scopus (145) Google Scholar]. These have both been associated with a depression in signalling events during a proinflammatory IFNγ response by monocytes (and potentially subsequent Th1 polarization) [36Silverman J.M. Reiner N.E. Leishmania exosomes deliver preemptive strikes to create an environment permissive for early infection.Front. Cell. Infect. Microbiol. 2011; 1: 26PubMed Google Scholar, 40Hassani K. Olivier M. Immunomodulatory impact of Leishmania-induced macrophage exosomes: a comparative proteomic and functional analysis.PLoS Negl. Trop. Dis. 2013; 7: e2185Crossref PubMed Scopus (93) Google Scholar]. GP63 is also associated with numerous downstream modulatory effects during Leishmania infecti
Referência(s)