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Publications (10 of 34) Show all publications
Hildebrandt, F., Mohammed, M., Dziedziech, A., Bhandage, A. K., Divne, A.-M., Barrenäs, F., . . . Ankarklev, J. (2023). scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics. Frontiers in Immunology, 14, Article ID 1224591.
Open this publication in new window or tab >>scDual-Seq of Toxoplasma gondii-infected mouse BMDCs reveals heterogeneity and differential infection dynamics
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2023 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 14, article id 1224591Article in journal (Refereed) Published
Abstract [en]

Dendritic cells and macrophages are integral parts of the innate immune system and gatekeepers against infection. The protozoan pathogen, Toxoplasma gondii, is known to hijack host immune cells and modulate their immune response, making it a compelling model to study host-pathogen interactions. Here we utilize single cell Dual RNA-seq to parse out heterogeneous transcription of mouse bone marrow-derived dendritic cells (BMDCs) infected with two distinct genotypes of T. gondii parasites, over multiple time points post infection. We show that the BMDCs elicit differential responses towards T. gondii infection and that the two parasite lineages distinctly manipulate subpopulations of infected BMDCs. Co-expression networks define host and parasite genes, with implications for modulation of host immunity. Integrative analysis validates previously established immune pathways and additionally, suggests novel candidate genes involved in host-pathogen interactions. Altogether, this study provides a comprehensive resource for characterizing host-pathogen interplay at high-resolution.

Keywords
Toxoplasma gondii, bone marrow-derived dendritic cells, BMDCs, host-pathogen interactions, immune modulation, scDual-Seq, Dual single-cell RNA-seq
National Category
Cell Biology Immunology Genetics
Identifiers
urn:nbn:se:su:diva-219761 (URN)10.3389/fimmu.2023.1224591 (DOI)001045246300001 ()37575232 (PubMedID)2-s2.0-85167593817 (Scopus ID)
Funder
Swedish Research Council, 2021-06602, 2022-00520, 2018-0241Swedish Society for Medical Research (SSMF)
Available from: 2023-07-28 Created: 2023-07-28 Last updated: 2024-01-17Bibliographically approved
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
Idro, R., Ogwang, R., Barragan, A., Raimondo, J. V. & Masocha, W. (2022). Neuroimmunology of Common Parasitic Infections in Africa. Frontiers in Immunology, 13, Article ID 791488.
Open this publication in new window or tab >>Neuroimmunology of Common Parasitic Infections in Africa
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2022 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 791488Article, review/survey (Refereed) Published
Abstract [en]

Parasitic infections of the central nervous system are an important cause of morbidity and mortality in Africa. The neurological, cognitive, and psychiatric sequelae of these infections result from a complex interplay between the parasites and the host inflammatory response. Here we review some of the diseases caused by selected parasitic organisms known to infect the nervous system including Plasmodium falciparumToxoplasma gondiiTrypanosoma brucei spp., and Taenia solium species. For each parasite, we describe the geographical distribution, prevalence, life cycle, and typical clinical symptoms of infection and pathogenesis. We pay particular attention to how the parasites infect the brain and the interaction between each organism and the host immune system. We describe how an understanding of these processes may guide optimal diagnostic and therapeutic strategies to treat these disorders. Finally, we highlight current gaps in our understanding of disease pathophysiology and call for increased interrogation of these often-neglected disorders of the nervous system.

Keywords
brain disorders, Plasmodium falciparum, Trypanosoma brucei spp, Toxoplasma gondii, Taenia solium, neuro-infections, immune system, glia
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-203169 (URN)10.3389/fimmu.2022.791488 (DOI)000761047100001 ()35222377 (PubMedID)
Available from: 2022-03-24 Created: 2022-03-24 Last updated: 2024-01-17Bibliographically 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
Ross, E. C., ten Hoeve, A. L., Saeij, J. P. J. & Barragan, A. (2022). Toxoplasma effector-induced ICAM-1 expression by infected dendritic cells potentiates transmigration across polarised endothelium. Frontiers in Immunology, 13, Article ID 950914.
Open this publication in new window or tab >>Toxoplasma effector-induced ICAM-1 expression by infected dendritic cells potentiates transmigration across polarised endothelium
2022 (English)In: Frontiers in Immunology, E-ISSN 1664-3224, Vol. 13, article id 950914Article in journal (Refereed) Published
Abstract [en]

The obligate intracellular parasite Toxoplasma gondii makes use of infected leukocytes for systemic dissemination. Yet, how infection impacts the processes of leukocyte diapedesis has remained unresolved. Here, we addressed the effects of T. gondii infection on the trans-endothelial migration (TEM) of dendritic cells (DCs) across polarised brain endothelial monolayers. We report that upregulated expression of leukocyte ICAM-1 is a feature of the enhanced TEM of parasitised DCs. The secreted parasite effector GRA15 induced an elevated expression of ICAM-1 in infected DCs that was associated with enhanced cell adhesion and TEM. Consequently, gene silencing of Icam-1 in primary DCs or deletion of parasite GRA15 reduced TEM. Further, the parasite effector TgWIP, which impacts the regulation of host actin dynamics, facilitated TEM across polarised endothelium. The data highlight that the concerted action of the secreted effectors GRA15 and TgWIP modulate the leukocyte-endothelial interactions of TEM in a parasite genotype-related fashion to promote dissemination. In addition to the canonical roles of endothelial ICAM-1, this study identifies a previously unappreciated role for leukocyte ICAM-1 in infection-related TEM.

Keywords
leukocyte, blood-brain barrier, apicomplexa, trans-endothelial migration, cell adhesion molecule (CAM), immune cell
National Category
Infectious Medicine
Identifiers
urn:nbn:se:su:diva-209445 (URN)10.3389/fimmu.2022.950914 (DOI)000841163400001 ()35990682 (PubMedID)2-s2.0-85136211762 (Scopus ID)
Available from: 2022-09-19 Created: 2022-09-19 Last updated: 2024-01-17Bibliographically 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
Ólafsson, E. B., ten Hoeve, A. L., Li-Wang, X., Westermark, L., Varas-Godoy, M. & Barragan, A. (2021). Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells. Journal of Cell Science, 134(5), Article ID jcs241752.
Open this publication in new window or tab >>Convergent Met and voltage-gated Ca2+ channel signaling drives hypermigration of Toxoplasma-infected dendritic cells
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2021 (English)In: Journal of Cell Science, ISSN 0021-9533, E-ISSN 1477-9137, Vol. 134, no 5, article id jcs241752Article in journal (Refereed) Published
Abstract [en]

Ras–Erk MAPK signaling controls many of the principal pathways involved in metazoan cell motility, drives metastasis of multiple cancer types and is targeted in chemotherapy. However, its putative roles in immune cell functions or in infections have remained elusive. Here, using primary dendritic cells (DCs) in an infection model with the protozoan Toxoplasma gondii, we show that two pathways activated by infection converge on Ras–Erk MAPK signaling to promote migration of parasitized DCs. We report that signaling through the receptor tyrosine kinase Met (also known as HGF receptor) contributes to T. gondii-induced DC hypermotility. Furthermore, voltage-gated Ca2+ channel (VGCC, subtype CaV1.3) signaling impacted the migratory activation of DCs via calmodulin–calmodulin kinase II. We show that convergent VGCC signaling and Met signaling activate the GTPase Ras to drive Erk1 and Erk2 (also known as MAPK3 and MAPK1, respectively) phosphorylation and hypermotility of T. gondii-infected DCs. The data provide a molecular basis for the hypermigratory mesenchymal-to-amoeboid transition (MAT) of parasitized DCs. This emerging concept suggests that parasitized DCs acquire metastasis-like migratory properties that promote infection-related dissemination.

Keywords
Receptor tyrosine kinase, Ca2+ signaling, Leukocyte motility, Amoeboid migration, Apicomplexa
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-193819 (URN)10.1242/jcs.241752 (DOI)000629619100003 ()32161101 (PubMedID)
Available from: 2021-06-08 Created: 2021-06-08 Last updated: 2022-03-21Bibliographically approved
Bhandage, A. K. & Barragan, A. (2021). GABAergic signaling by cells of the immune system: more the rule than the exception. Cellular and Molecular Life Sciences (CMLS), 78(15), 5667-5679
Open this publication in new window or tab >>GABAergic signaling by cells of the immune system: more the rule than the exception
2021 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 78, no 15, p. 5667-5679Article, review/survey (Refereed) Published
Abstract [en]

Gamma-aminobutyric acid (GABA) is best known as an essential neurotransmitter in the evolved central nervous system (CNS) of vertebrates. However, GABA antedates the development of the CNS as a bioactive molecule in metabolism and stress-coupled responses of prokaryotes, invertebrates and plants. Here, we focus on the emerging findings of GABA signaling in the mammalian immune system. Recent reports show that mononuclear phagocytes and lymphocytes, for instance dendritic cells, microglia, T cells and NK cells, express a GABAergic signaling machinery. Mounting evidence shows that GABA receptor signaling impacts central immune functions, such as cell migration, cytokine secretion, immune cell activation and cytotoxic responses. Furthermore, the GABAergic signaling machinery of leukocytes is implicated in responses to microbial infection and is co-opted by protozoan parasites for colonization of the host. Peripheral GABA signaling is also implicated in inflammatory conditions and diseases, such as type 1 diabetes, rheumatoid arthritis and cancer cell metastasis. Adding to its role in neurotransmission, growing evidence shows that the non-proteinogenic amino acid GABA acts as an intercellular signaling molecule in the immune system and, as an interspecies signaling molecule in host-microbe interactions. Altogether, the data raise the assumption of conserved GABA signaling in a broad range of mammalian cells and diversification of function in the immune system.

Keywords
Neurotransmission, Inflammation, Macrophage, Toxoplasma, Apicomplexa, Host-pathogen, Voltage-dependent calcium channel, Cation-chloride cotransporter
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-195815 (URN)10.1007/s00018-021-03881-z (DOI)000663996600001 ()34152447 (PubMedID)
Available from: 2021-08-31 Created: 2021-08-31 Last updated: 2022-02-28Bibliographically approved
Bhandage, A. K., Friedrich, L. M., Kanatani, S., Jakobsson-Björkén, S., Escrig-Larena, J. I., Wagner, A. K., . . . Barragan, A. (2021). GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii. Journal of Leukocyte Biology, 110(4), 617-628
Open this publication in new window or tab >>GABAergic signaling in human and murine NK cells upon challenge with Toxoplasma gondii
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2021 (English)In: Journal of Leukocyte Biology, ISSN 0741-5400, E-ISSN 1938-3673, Vol. 110, no 4, p. 617-628Article in journal (Refereed) Published
Abstract [en]

Protective cytotoxic and proinflammatory cytokine responses by NK cells impact the outcome of infections by Toxoplasma gondii, a common parasite in humans and other vertebrates. However, T. gondii can also sequester within NK cells and downmodulate their effector functions. Recently, the implication of GABA signaling in infection and inflammation-related responses of mononuclear phagocytes and T cells has become evident. Yet, the role of GABAergic signaling in NK cells has remained unknown. Here, we report that human and murine NK cells synthesize and secrete GABA in response to infection challenge. Parasitized NK cells secreted GABA, whereas activation stimuli, such as IL-12/IL-18 or parasite lysates, failed to induce GABA secretion. GABA secretion by NK cells was associated to a transcriptional up-regulation of GABA synthesis enzymes (glutamate decarboxylases [GAD65/67]) and was abrogated by GAD inhibition. Further, NK cells expressed GABA-A receptor subunits and GABA signaling regulators, with transcriptional modulations taking place upon challenge with T. gondii. Exogenous GABA and GABA-containing supernatants from parasitized dendritic cells (DCs) impacted NK cell function by reducing the degranulation and cytotoxicity of NK cells. Conversely, GABA-containing supernatants from NK cells enhanced the migratory responses of parasitized DCs. This enhanced DC migration was abolished by GABA-A receptor antagonism or GAD inhibition and was reconstituted by exogenous GABA. Jointly, the data show that NK cells are GABAergic cells and that GABA hampers NK cell cytotoxicity in vitro. We hypothesize that GABA secreted by parasitized immune cells modulates the immune responses to T. gondii infection.

Keywords
Apicomplexa, cell migration, GABA-Areceptor, Host-pathogen, immunomodulation, Lymphocyte, neurotransmitter
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-195877 (URN)10.1002/JLB.3HI0720-431R (DOI)000653260100001 ()34028876 (PubMedID)
Available from: 2021-08-26 Created: 2021-08-26 Last updated: 2022-02-25Bibliographically approved
Ross, E. C., ten Hoeve, A. L. & Barragan, A. (2021). Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers. Cellular and Molecular Life Sciences (CMLS), 78, 5197-5212
Open this publication in new window or tab >>Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers
2021 (English)In: Cellular and Molecular Life Sciences (CMLS), ISSN 1420-682X, E-ISSN 1420-9071, Vol. 78, p. 5197-5212Article in journal (Refereed) Published
Abstract [en]

Multiple cellular processes, such as immune responses and cancer cell metastasis, crucially depend on interconvertible migration modes. However, knowledge is scarce on how infectious agents impact the processes of cell adhesion and migration at restrictive biological barriers. In extracellular matrix, dendritic cells (DCs) infected by the obligate intracellular protozoan Toxoplasma gondii undergo mesenchymal-to-amoeboid transition (MAT) for rapid integrin-independent migration. Here, in a cellular model of the blood–brain barrier, we report that parasitised DCs adhere to polarised endothelium and shift to integrin-dependent motility, accompanied by elevated transendothelial migration (TEM). Upon contact with endothelium, parasitised DCs dramatically reduced velocities and adhered under both static and shear stress conditions, thereby obliterating the infection-induced amoeboid motility displayed in collagen matrix. The motility of adherent parasitised DCs on endothelial monolayers was restored by blockade of β1 and β2 integrins or ICAM-1, which conversely reduced motility on collagen-coated surfaces. Moreover, parasitised DCs exhibited enhanced translocation across highly polarised primary murine brain endothelial cell monolayers. Blockade of β1, β2 integrins, ICAM-1 and PECAM-1 reduced TEM frequencies. Finally, gene silencing of the pan-integrin-cytoskeleton linker talin (Tln1) or of β1 integrin (Itgb1) in primary DCs resulted in increased motility on endothelium and decreased TEM. Adding to the paradigms of leukocyte diapedesis, the findings provide novel insights in how an intracellular pathogen impacts the migratory plasticity of leukocytes in response to the cellular environment, to promote infection-related dissemination.

Keywords
Leukocyte, Blood-brain barrier, Apicomplexa, Immune cell, Cell migration, Cell adhesion molecule
National Category
Biological Sciences
Identifiers
urn:nbn:se:su:diva-195882 (URN)10.1007/s00018-021-03858-y (DOI)000652959400001 ()34023934 (PubMedID)
Available from: 2021-08-26 Created: 2021-08-26 Last updated: 2022-04-26Bibliographically approved
Organisations
Identifiers
ORCID iD: ORCID iD iconorcid.org/0000-0001-7746-9964

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