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Olivera, Gabriela C.ORCID iD iconorcid.org/0000-0002-0179-4880
Alternative names
Publications (6 of 6) Show all publications
Ross, E. C., Olivera, G. C. & Barragan, A. (2022). Early passage of Toxoplasma gondii across the blood–brain barrier. Trends in Parasitology, 38(6), 450-461
Open this publication in new window or tab >>Early passage of Toxoplasma gondii across the blood–brain barrier
2022 (English)In: Trends in Parasitology, ISSN 1471-4922, E-ISSN 1471-5007, Vol. 38, no 6, p. 450-461Article, review/survey (Refereed) Published
Abstract [en]

The blood–brain barrier (BBB) efficiently protects the central nervous system (CNS) from infectious insults. Yet, the apicomplexan parasite Toxoplasma gondii has a remarkable capability to establish latent cerebral infection in humans and other vertebrates. In addition to the proposed mechanisms for access to the brain parenchyma, recent findings highlight a paramount role played by the BBB in restricting parasite passage and minimizing parasite loads in the brain. Consistent with clinically asymptomatic primary infections in humans, mounting evidence indicates that the original colonization of the brain by T. gondii encompasses previously unappreciated, nondisruptive translocation processes that precede the onset of parasite-limiting immune responses.

Keywords
Apicomplexa, coccidia, central nervous system infections, capillary permeability, transendothelial migration, host–parasite interactions
National Category
Microbiology in the medical area
Identifiers
urn:nbn:se:su:diva-204947 (URN)10.1016/j.pt.2022.02.003 (DOI)000804468600005 ()35227615 (PubMedID)2-s2.0-85125457108 (Scopus ID)
Available from: 2022-05-23 Created: 2022-05-23 Last updated: 2022-06-28Bibliographically approved
ten Hoeve, A. L., Braun, L., Rodriguez, M. E., Olivera, G. C., Bougdour, A., Belmudes, L., . . . Barragan, A. (2022). The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic cell-like migratory properties in infected macrophages. Cell Host and Microbe, 30(11), 1570-1588.e7
Open this publication in new window or tab >>The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic cell-like migratory properties in infected macrophages
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2022 (English)In: Cell Host and Microbe, ISSN 1931-3128, E-ISSN 1934-6069, Vol. 30, no 11, p. 1570-1588.e7Article in journal (Refereed) Published
Abstract [en]

Upon pathogen detection, macrophages normally stay sessile in tissues while dendritic cells (DCs) migrate to secondary lymphoid tissues. The obligate intracellular protozoan Toxoplasma gondii exploits the trafficking of mononuclear phagocytes for dissemination via unclear mechanisms. We report that, upon T. gondii infection, macrophages initiate the expression of transcription factors normally attributed to DCs, upregulate CCR7 expression with a chemotactic response, and perform systemic migration when adoptively transferred into mice. We show that parasite effector GRA28, released by the MYR1 secretory pathway, cooperates with host chromatin remodelers in the host cell nucleus to drive the chemotactic migration of parasitized macrophages. During in vivo challenge studies, bone marrow-derived macrophages infected with wild-type T. gondii outcompeted those challenged with MYR1- or GRA28-deficient strains in migrating and reaching secondary organs. This work reveals how an intracellular parasite hijacks chemotaxis in phagocytes and highlights a remarkable migratory plasticity in differentiated cells of the mononuclear phagocyte system.

Keywords
apicomplexa, cell motility, chemokine receptor 7, chemotaxis, host-pathogen, immune evasion, intracellular parasitism, mononuclear phagocyte, protozoa
National Category
Physical Sciences
Identifiers
urn:nbn:se:su:diva-211743 (URN)10.1016/j.chom.2022.10.001 (DOI)000919625100012 ()36309013 (PubMedID)2-s2.0-85141303354 (Scopus ID)
Available from: 2022-11-25 Created: 2022-11-25 Last updated: 2023-02-28Bibliographically approved
Olivera, G. C., Ross, E. C., Peuckert, C. & Barragan, A. (2021). Blood-brain barrier-restricted translocation of Toxoplasma gondii from cortical capillaries. eLIFE, 10, Article ID e69182.
Open this publication in new window or tab >>Blood-brain barrier-restricted translocation of Toxoplasma gondii from cortical capillaries
2021 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 10, article id e69182Article in journal (Refereed) Published
Abstract [en]

The cellular barriers of the central nervous system proficiently protect the brain parenchyma from infectious insults. Yet, the single-celled parasite Toxoplasma gondii commonly causes latent cerebral infection in humans and other vertebrates. Here, we addressed the role of the cerebral vasculature in the passage of T. gondii to the brain parenchyma. Shortly after inoculation in mice, parasites mainly localized to cortical capillaries, in preference over post-capillary venules, cortical arterioles or meningeal and choroidal vessels. Early invasion to the parenchyma (days 1-5) occurred in absence of a measurable increase in blood-brain barrier (BBB) permeability, perivascular leukocyte cuffs or hemorrhage. However, sparse focalized permeability elevations were detected adjacently to replicative parasite foci. Further, T. gondii triggered inflammatory responses in cortical microvessels and endothelium. Pro- and anti-inflammatory treatments of mice with LPS and hydrocortisone, respectively, impacted BBB permeability and parasite loads in the brain parenchyma. Finally, pharmacological inhibition or Cre/loxP conditional knockout of endothelial focal adhesion kinase (FAK), a BBB intercellular junction regulator, facilitated parasite translocation to the brain parenchyma. The data reveal that the initial passage of T. gondii to the central nervous system occurs principally across cortical capillaries. The integrity of the microvascular BBB restricts parasite transit, which conversely is exacerbated by the inflammatory response.

Keywords
apicomplexa, blood-brain barrier, CNS infection, Toxoplasma gondii, biological barriers, inflammation, Mouse
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-201404 (URN)10.7554/eLife.69182 (DOI)000734653800001 ()34877929 (PubMedID)
Available from: 2022-02-08 Created: 2022-02-08 Last updated: 2023-04-17Bibliographically approved
Bhandage, A. K., Olivera, G. C., Kanatani, S., Thompson, E., Loré, K., Varas-Godoy, M. & Barragan, A. (2020). A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites. eLIFE, 9, Article ID e60528.
Open this publication in new window or tab >>A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites
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2020 (English)In: eLIFE, E-ISSN 2050-084X, Vol. 9, article id e60528Article in journal (Refereed) Published
Abstract [en]

Gamma-aminobutyric acid (GABA) serves diverse biological functions in prokaryotes and eukaryotes, including neurotransmission in vertebrates. Yet, the role of GABA in the immune system has remained elusive. Here, a comprehensive characterization of human and murine myeloid mononuclear phagocytes revealed the presence of a conserved and tightly regulated GABAergic machinery with expression of GABA metabolic enzymes and transporters, GABA-A receptors and regulators, and voltage-dependent calcium channels. Infection challenge with the common coccidian parasites Toxoplasma gondii and Neospora caninum activated GABAergic signaling in phagocytes. Using gene silencing and pharmacological modulators in vitro and in vivo in mice, we identify the functional determinants of GABAergic signaling in parasitized phagocytes and demonstrate a link to calcium responses and migratory activation. The findings reveal a regulatory role for a GABAergic signaling machinery in the host-pathogen interplay between phagocytes and invasive coccidian parasites. The co-option of GABA underlies colonization of the host by a Trojan horse mechanism.

National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-188736 (URN)10.7554/eLife.60528 (DOI)000595496600001 ()33179597 (PubMedID)
Available from: 2021-01-18 Created: 2021-01-18 Last updated: 2022-02-25Bibliographically approved
Ross, E. C., Olivera, G. C. & Barragan, A. (2019). Dysregulation of focal adhesion kinase upon Toxoplasma gondii infection facilitates parasite translocation across polarised primary brain endothelial cell monolayers. Cellular Microbiology, 21(9), Article ID e13048.
Open this publication in new window or tab >>Dysregulation of focal adhesion kinase upon Toxoplasma gondii infection facilitates parasite translocation across polarised primary brain endothelial cell monolayers
2019 (English)In: Cellular Microbiology, ISSN 1462-5814, E-ISSN 1462-5822, Vol. 21, no 9, article id e13048Article in journal (Refereed) Published
Abstract [en]

The apicomplexan parasite Toxoplasma gondii invades tissues and traverses non-permissive biological barriers in infected humans and other vertebrates. Following ingestion, the parasite penetrates the intestinal wall and disseminates to immune-privileged sites such as the brain parenchyma, after crossing the blood-brain barrier. In the present study, we have established a protocol for high-purification of primary mouse brain endothelial cells to generate stably polarised monolayers that allowed assessment of cellular barrier traversal by T. gondii. We report that T. gondii tachyzoites translocate across polarised monolayers of mouse brain endothelial cells and human intestinal Caco2 cells without significantly perturbing barrier impermeability and with minimal change in transcellular electrical resistance. In contrast, challenge with parasite lysate or LPS increased barrier permeability by destabilising intercellular tight junctions (TJs) and accentuated transmigration of T. gondii. Conversely, reduced phosphorylation of the TJ-regulator focal adhesion kinase (FAK) was observed dose-dependently upon challenge of monolayers with live T. gondii but not with parasite lysate or LPS. Pharmacological inhibition of FAK phosphorylation reversibly altered barrier integrity and facilitated T. gondii translocation. Finally, gene silencing of FAK by shRNA facilitated transmigration of T. gondii across epithelial and endothelial monolayers. Jointly, the data demonstrate that T. gondii infection transiently alters the TJ stability through FAK dysregulation to facilitate transmigration. This work identifies the implication of the TJ regulator FAK in the transmigration of T. gondii across polarised cellular monolayers and provides novel insights in how microbes overcome the restrictiveness of biological barriers.

Keywords
Apicomplexa, biological barriers, blood-brain barrier, host-pathogen, protein tyrosine kinase 2, tight junction proteins
National Category
Cell and Molecular Biology Cell Biology
Identifiers
urn:nbn:se:su:diva-172966 (URN)10.1111/cmi.13048 (DOI)000482477200003 ()31099453 (PubMedID)
Available from: 2019-09-16 Created: 2019-09-16 Last updated: 2022-04-26Bibliographically approved
ten Hoeve, A. L., Olivera, G. C., Saeij, J. P. .., Hakimi, M.-A. & Barragan, A.The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic cell-like migratory properties in infected macrophages.
Open this publication in new window or tab >>The Toxoplasma effector GRA28 promotes parasite dissemination by inducing dendritic cell-like migratory properties in infected macrophages
Show others...
(English)Manuscript (preprint) (Other academic)
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-203088 (URN)
Available from: 2022-03-22 Created: 2022-03-22 Last updated: 2022-03-24
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0002-0179-4880

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