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The Role of Small Extracellular Vesicles in Viral-Protozoan Symbiosis: Lessons From Trichomonasvirus in an Isogenic Host Parasite Model.

ABSTRACT: The protozoan parasite Trichomonas vaginalis (TV), exclusively adapted to the human genital tract, is one of the most common sexually transmitted pathogens. Adding to the complexity of the host-pathogen interactions, the parasite harbors TV-specific endosymbiont viruses (Trichomonasvirus, TVV). It was reported that small extracellular vesicles (sEVs) released by TV play a role in host immunity; however, the role of the viral endosymbiosis in this process remained unknown. We hypothesized that the virus may offer evolutionary benefit to its protozoan host at least in part by altering the immunomodulatory properties of sEVs spreading from the site of infection to non-infected immune effector cells. We infected human vaginal epithelial cells, the natural host of the parasite, with TV natively harboring TVV and an isogenic derivative of the parasite cured from the viral infection. sEVs were isolated from vaginal cell culture 24 h post TV infection and from medium where the isogenic TV strains were cultured in the absence of the human host. sEVs from TVV-negative but not TVV-positive parasites cultured alone caused NF-?B activation and increase of IL-8 and RANTES expression by uterine endocervical cells, which provide innate immune defense at the gate to the upper reproductive tract. Similarly, mononuclear leukocytes increased their IL-8, IL-6 and TNF-? output in response to sEVs from virus-negative, but not isogenic virus-positive parasites, the latter exosomes being immunosuppressive in comparison to TV medium control. The same phenomenon of suppressed immunity induced by the TVV-positive compared to TVV-negative phenotype was seen when stimulating the leukocytes with sEVs originating from infected vaginal cultures. In addition, the sEVs from the TVV-positive infection phenotype suppressed immune signaling of a toll-like receptor ligand derived from mycoplasma, another frequent TV symbiont. Quantitative comparative proteome analysis of the secreted sEVs from virus-positive versus virus-negative TV revealed differential expression of two functionally uncharacterized proteins and five proteins involved in Zn binding, protein binding, electron transfer, transferase and catalytic activities. These data support the concept that symbiosis with viruses may provide benefit to the protozoan parasite by exploiting sEVs as a vehicle for inter-cellular communications and modifying their protein cargo to suppress host immune activation.

SUBMITTER: Govender Y

PROVIDER: S-EPMC7674494 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The Role of Small Extracellular Vesicles in Viral-Protozoan Symbiosis: Lessons From Trichomonasvirus in an Isogenic Host Parasite Model.

Govender Yashini Y Chan Tiffany T Yamamoto Hidemi S HS Budnik Bogdan B Fichorova Raina N RN

Frontiers in cellular and infection microbiology 20201105

The protozoan parasite Trichomonas vaginalis (TV), exclusively adapted to the human genital tract, is one of the most common sexually transmitted pathogens. Adding to the complexity of the host-pathogen interactions, the parasite harbors TV-specific endosymbiont viruses (Trichomonasvirus, TVV). It was reported that small extracellular vesicles (sEVs) released by TV play a role in host immunity; however, the role of the viral endosymbiosis in this process remained unknown. We hypoth ...[more]

PMID: 33224901

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Project description:The protozoan parasite Trichomonas vaginalis (TV), exclusively adapted to the human genital tract, is one of the most common sexually transmitted pathogens. Adding to the complexity of the host-pathogen interactions, the parasite harbors TV-specific endosymbiont viruses (Trichomonasvirus, TVV). It was reported that small extracellular vesicles (exosomes) released by TV play a role in host immunity; however, the role of the viral endosymbiosis in this process remained unknown. We hypothesized that the virus may offer evolutionary benefit to its protozoan host at least in part by altering the immunomodulatory properties of exosomes spreading from the site of infection to non-infected immune effector cells. We infected human vaginal epithelial cells, the natural host of the parasite, with TV natively harboring TVV and an isogenic derivative of the parasite cured from the viral infection. Exosomes were isolated from vaginal cell culture 24 h post TV infection and from medium where the isogenic TV strains were cultured in the absence of the human host. Exosomes from TVV-negative but not TVV-positive parasites cultured alone caused NF-kB activation and increase of IL-8 and RANTES expression by uterine endocervical cells, which provide innate immune defense at the gate to the upper reproductive tract. Similarly, mononuclear leukocytes increased their IL-8, IL-6 and TNF-a output in response to exosomes from virus-negative, but not isogenic virus-positive parasites, the latter exosomes being immunosuppressive in comparison to TV medium control. The same phenomenon of suppressed immunity induced by the TVV-positive compared to TVV-negative phenotype was seen when stimulating the leukocytes with exosomes originating from infected vaginal cultures. In addition, the exosomes from the TVV-positive infection phenotype suppressed immune signaling of a toll-like receptor ligand derived from mycoplasma, another frequent TV symbiont. Quantitative comparative proteome analysis of exosomes from viruspositive versus virus-negative TV revealed differential expression of two functionally uncharacterized proteins and five proteins involved in Zn binding, protein binding, electron transfer, transferase and catalytic activities. These data support the concept that symbiosis with viruses may provide benefit to the protozoan parasite by exploiting exosomes as a vehicle for inter-cellular communications and modifying their protein cargo to suppress host immune activation.

Project description:We have previously shown that the microfilarial (mf) stage of Brugia malayi can inhibit the mammalian target of rapamycin (mTOR; a conserved serine/threonine kinase critical for immune regulation and cellular growth) in human dendritic cells (DC) and we have proposed that this mTOR inhibition is associated with the DC dysfunction seen in filarial infections. Extracellular vesicles (EVs) contain many proteins and nucleic acids including microRNAs (miRNAs) that might affect a variety of intracellular pathways. Thus, EVs secreted from mf may elucidate the mechanism by which the parasite is able to modulate the host immune response during infection. EVs, purified from mf of Brugia malayi and confirmed by size through nanoparticle tracking analysis, were assessed by miRNA microarrays (accession number GSE157226) and shown to be enriched (>2-fold, p-value<0.05, FDR = 0.05) for miR100, miR71, miR34, and miR7. The microarray analysis compared mf-derived EVs and mf supernatant. After confirming their presence in EVs using qPCR for these miRNA targets, web-based target predictions (using MIRPathv3, TarBAse and MicroT-CD) predicted that miR100 targeted mTOR and its downstream regulatory protein 4E-BP1. Our previous data with live parasites demonstrated that mf downregulate the phosphorylation of mTOR and its downstream effectors. Additionally, our proteomic analysis of the mf-derived EVs revealed the presence of proteins commonly found in these vesicles (data are available via ProteomeXchange with identifier PXD021844). We confirmed internalization of mf-derived EVs by human DCs and monocytes using confocal microscopy and flow cytometry, and further demonstrated through flow cytometry, that mf-derived EVs downregulate the phosphorylation of mTOR in human monocytes (THP-1 cells) to the same degree that rapamycin (a known mTOR inhibitor) does. Our data collectively suggest that mf release EVs that interact with host cells, such as DC, to modulate host responses.

Dataset Information

The Role of Small Extracellular Vesicles in Viral-Protozoan Symbiosis: Lessons From Trichomonasvirus in an Isogenic Host Parasite Model.

Publications

The Role of Small Extracellular Vesicles in Viral-Protozoan Symbiosis: Lessons From <i>Trichomonasvirus</i> in an Isogenic Host Parasite Model.

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