<i>Toxoplasma gondii</i> modulates the dynamics of human monocyte adhesion to vascular endothelium under fluidic shear stress

Harker, Katherine S.; Ueno, Norikiyo; Wang, Tingting; C, Bonhomme; Liu, Wendy; Lodoen, Melissa B.

doi:10.1189/jlb.1012517

Cited by 39 publications

(64 citation statements)

References 55 publications

(75 reference statements)

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“…In the present study, we have demonstrated that the hypermotility of T. gondii-infected human monocytes is linked to a dysregulation in integrin-dependent cell adhesion through defects in FAK-regulated focal adhesions. Notably, T. gondii infection did not affect the expression of integrins on the cell surface or the ability of integrins to become activated through inside-out signaling (27). Rather, T. gondii impeded outside-in signaling and integrin clustering upon ligand engagement.…”

Section: Discussionmentioning

confidence: 89%

“…Several studies have demonstrated that immune cells infected with T. gondii become hypermotile (27)(28)(29)(30)(31)(32)(33)(34)41), an effect that has been proposed to facilitate the dissemination of the intracellular parasite in the infected host. In the present study, we have demonstrated that the hypermotility of T. gondii-infected human monocytes is linked to a dysregulation in integrin-dependent cell adhesion through defects in FAK-regulated focal adhesions.…”

Section: Discussionmentioning

confidence: 99%

“…The membranes were then probed with HRP-conjugated anti-mouse or anti-rabbit IgG (Jackson Immuno Research, West Grove, PA) and visualized using enhanced chemiluminescence (GE Healthcare Life Sciences, Pittsburgh, PA). Images were captured by a Nikon camera as previously described (27). Band intensity was quantified using ImageJ Gel tools (NIH, Bethesda, MD).…”

Section: Western Blotting and Densitometrymentioning

confidence: 99%

“…We have previously reported that T. gondiiinfected monocytes exhibit an impairment of integrin clustering, and in conditions of shear stress, infected cells roll and crawl on vascular endothelium at higher velocities and over greater distances than uninfected monocytes (27,28 …”

Section: Introductionmentioning

confidence: 99%

“…In this model, an infected cell can act as a Trojan horse for T. gondii in the bloodstream or tissues (26). Several studies have demonstrated that T. gondii infection of monocytes (27,28), neutrophils (29), NK cells (30), and DCs (31-34) induces a hypermotility phenotype in these cells.…”

Section: Introductionmentioning

confidence: 99%

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Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

Cook¹,

Ueno²,

Lodoen

2018

Journal of Biological Chemistry

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The motility of blood monocytes is orchestrated by the activity of cell surface integrins, which translate extracellular signals into cytoskeletal changes to mediate adhesion and migration. Toxoplasma gondii is an intracellular parasite that infects migratory cells and enhances their motility, but the mechanisms underlying T. gondii-induced hypermotility are incompletely understood. We have investigated the molecular basis for the hypermotility of primary human peripheral blood monocytes and THP-1 cells infected with T. gondii. Compared to uninfected monocytes, T. gondii infection of monocytes reduced cell spreading and the number of activated β1 integrin clusters in contact with fibronectin during settling, an effect not observed in monocytes treated with LPS or E. coli. Furthermore, T. gondii infection disrupted the phosphorylation of focal adhesion kinase (FAK) at tyrosine 397 (Y397) and Y925 and of the related protein proline-rich tyrosine kinase (Pyk2) at Y402. The localization of paxillin, FAK, and vinculin to focal adhesions and the colocalization of these proteins with activated β1 integrins were also impaired in T. gondiiinfected monocytes. Using time-lapse confocal microscopy of THP-1 cells expressing eGFP-FAK during settling on fibronectin, we found that T. gondii-induced monocyte hypermotility was characterized by a reduced number of eGFP-FAKcontaining clusters over time compared to uninfected cells. This study demonstrates an integrin conformation-independent regulation of the β1 integrin adhesion pathway, providing further insight into the molecular mechanism of T. gondiiinduced monocyte hypermotility.

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Section: Discussionmentioning

confidence: 89%

Section: Discussionmentioning

confidence: 99%

Section: Western Blotting and Densitometrymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

Cook¹,

Ueno²,

Lodoen

2018

Journal of Biological Chemistry

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Understanding the mechanisms underlying the disruption of the blood–brain barrier in parasitic infections

Jamil Al‐Obaidi,

Desa

2024

J of Neuroscience Research

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Parasites have a significant impact on the neurological, cognitive, and mental well‐being of humans, with a global population of over 1 billion individuals affected. The pathogenesis of central nervous system (CNS) injury in parasitic diseases remains limited, and prevention and control of parasitic CNS infections remain significant areas of research. Parasites, encompassing both unicellular and multicellular organisms, have intricate life cycles and possess the ability to infect a diverse range of hosts, including the human population. Parasitic illnesses that impact the central and peripheral nervous systems are a significant contributor to morbidity and mortality in low‐ to middle‐income nations. The precise pathways through which neurotropic parasites infiltrate the CNS by crossing the blood–brain barrier (BBB) and cause neurological harm remain incompletely understood. Investigating brain infections caused by parasites is closely linked to studying neuroinflammation and cerebral impairment. The exact molecular and cellular mechanisms involved in this process remain incomplete, but understanding the exact mechanisms could provide insight into their pathogenesis and potentially reveal novel therapeutic targets. This review paper explores the underlying mechanisms involved in the development of neurological disorders caused by parasites, including parasite‐derived elements, host immune responses, and modifications in tight junctions (TJs) proteins.

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Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers

Ross

Hoeve

Barragán

2021

Cell. Mol. Life Sci.

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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.

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Toxoplasma gondii modulates the dynamics of human monocyte adhesion to vascular endothelium under fluidic shear stress

Cited by 39 publications

References 55 publications

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

Toxoplasma gondii disrupts β1 integrin signaling and focal adhesion formation during monocyte hypermotility

Understanding the mechanisms underlying the disruption of the blood–brain barrier in parasitic infections

Integrin-dependent migratory switches regulate the translocation of Toxoplasma-infected dendritic cells across brain endothelial monolayers

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