Immune Response and Pathogen Invasion at the Choroid Plexus in the Onset of Cerebral Toxoplasmosis

Overview

Journal J Neuroinflammation

Publisher Biomed Central

Date 2022 Jan 14

PMID 35027063

Authors

Caio Andreeta Figueiredo

Johannes Steffen

Lorena Morton

Sushmitha Arumugam

Oliver Liesenfeld

Maria A Deli

Andrea Kroger

Thomas Schuler

Ildiko Rita Dunay

Affiliations

Soon will be listed here.

Abstract

Background: Toxoplasma gondii (T. gondii) is a highly successful parasite being able to cross all biological barriers of the body, finally reaching the central nervous system (CNS). Previous studies have highlighted the critical involvement of the blood-brain barrier (BBB) during T. gondii invasion and development of subsequent neuroinflammation. Still, the potential contribution of the choroid plexus (CP), the main structure forming the blood-cerebrospinal fluid (CSF) barrier (BCSFB) have not been addressed.

Methods: To investigate T. gondii invasion at the onset of neuroinflammation, the CP and brain microvessels (BMV) were isolated and analyzed for parasite burden. Additionally, immuno-stained brain sections and three-dimensional whole mount preparations were evaluated for parasite localization and morphological alterations. Activation of choroidal and brain endothelial cells were characterized by flow cytometry. To evaluate the impact of early immune responses on CP and BMV, expression levels of inflammatory mediators, tight junctions (TJ) and matrix metalloproteinases (MMPs) were quantified. Additionally, FITC-dextran was applied to determine infection-related changes in BCSFB permeability. Finally, the response of primary CP epithelial cells to T. gondii parasites was tested in vitro.

Results: Here we revealed that endothelial cells in the CP are initially infected by T. gondii, and become activated prior to BBB endothelial cells indicated by MHCII upregulation. Additionally, CP elicited early local immune response with upregulation of IFN-γ, TNF, IL-6, host-defence factors as well as swift expression of CXCL9 chemokine, when compared to the BMV. Consequently, we uncovered distinct TJ disturbances of claudins, associated with upregulation of MMP-8 and MMP-13 expression in infected CP in vivo, which was confirmed by in vitro infection of primary CP epithelial cells. Notably, we detected early barrier damage and functional loss by increased BCSFB permeability to FITC-dextran in vivo, which was extended over the infection course.

Conclusions: Altogether, our data reveal a close interaction between T. gondii infection at the CP and the impairment of the BCSFB function indicating that infection-related neuroinflammation is initiated in the CP.

Citing Articles

Infection with Toxoplasma gondii triggers coagulation at the blood-brain barrier and a reduction in cerebral blood flow.

Hoover E, Schneider C, Crouzet C, Lima T, Velez D, Tran C J Neuroinflammation. 2025; 22(1):3.

PMID: 39780244 PMC: 11708167. DOI: 10.1186/s12974-024-03330-1.

Choroid Plexus Pathophysiology.

Courtney Y, Hochstetler A, Lehtinen M Annu Rev Pathol. 2024; 20(1):193-220.

PMID: 39383438 PMC: 11884907. DOI: 10.1146/annurev-pathmechdis-051222-114051.

The Brazilian Toxoplasma gondii strain BRI caused greater inflammation and impairment in anxiogenic behavior in mice, which was reverted by rosuvastatin treatment.

Evangelista F, de Laet SantAna P, Ferreira W, Ferreira T, Dos Santos M, de Souza A Parasitol Res. 2023; 123(1):64.

PMID: 38117414 DOI: 10.1007/s00436-023-08038-4.

Reduced neural progenitor cell count and cortical neurogenesis in guinea pigs congenitally infected with Toxoplasma gondii.

Grochow T, Beck B, Renteria-Solis Z, Schares G, Maksimov P, Strube C Commun Biol. 2023; 6(1):1209.

PMID: 38012384 PMC: 10682419. DOI: 10.1038/s42003-023-05576-6.

Toxoplasma gondii infection of the central nervous system and suicide: A case-control study of decedents.

Mendoza-Larios L, Garcia-Dolores F, Sanchez-Anguiano L, Antuna-Salcido E, Hernandez-Tinoco J, Rocha-Salais A Eur J Microbiol Immunol (Bp). 2023; 13(3):77-82.

PMID: 37982867 PMC: 10668923. DOI: 10.1556/1886.2023.00033.

References

Tenter A, Heckeroth A, Weiss L . Toxoplasma gondii: from animals to humans. Int J Parasitol. 2000; 30(12-13):1217-58. PMC: 3109627. DOI: 10.1016/s0020-7519(00)00124-7. View

Lachenmaier S, Deli M, Meissner M, Liesenfeld O . Intracellular transport of Toxoplasma gondii through the blood-brain barrier. J Neuroimmunol. 2010; 232(1-2):119-30. PMC: 4116595. DOI: 10.1016/j.jneuroim.2010.10.029. View

Meeker R, Williams K, Killebrew D, Hudson L . Cell trafficking through the choroid plexus. Cell Adh Migr. 2012; 6(5):390-6. PMC: 3496674. DOI: 10.4161/cam.21054. View

Samak G, Gangwar R, Crosby L, Desai L, Wilhelm K, Waters C . Cyclic stretch disrupts apical junctional complexes in Caco-2 cell monolayers by a JNK-2-, c-Src-, and MLCK-dependent mechanism. Am J Physiol Gastrointest Liver Physiol. 2014; 306(11):G947-58. PMC: 4042113. DOI: 10.1152/ajpgi.00396.2013. View

Dubey J . History of the discovery of the life cycle of Toxoplasma gondii. Int J Parasitol. 2009; 39(8):877-82. DOI: 10.1016/j.ijpara.2009.01.005. View

Nakagawa S, Deli M, Kawaguchi H, Shimizudani T, Shimono T, Kittel A . A new blood-brain barrier model using primary rat brain endothelial cells, pericytes and astrocytes. Neurochem Int. 2008; 54(3-4):253-63. DOI: 10.1016/j.neuint.2008.12.002. View

Dellacasa-Lindberg I, Hitziger N, Barragan A . Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging. Microbes Infect. 2007; 9(11):1291-8. DOI: 10.1016/j.micinf.2007.06.003. View

Dando S, Mackay-Sim A, Norton R, Currie B, St John J, Ekberg J . Pathogens penetrating the central nervous system: infection pathways and the cellular and molecular mechanisms of invasion. Clin Microbiol Rev. 2014; 27(4):691-726. PMC: 4187632. DOI: 10.1128/CMR.00118-13. View

Lauer A, Tenenbaum T, Schroten H, Schwerk C . The diverse cellular responses of the choroid plexus during infection of the central nervous system. Am J Physiol Cell Physiol. 2017; 314(2):C152-C165. DOI: 10.1152/ajpcell.00137.2017. View

10.

Mogk S, Meiwes A, Bosselmann C, Wolburg H, Duszenko M . The lane to the brain: how African trypanosomes invade the CNS. Trends Parasitol. 2014; 30(10):470-7. DOI: 10.1016/j.pt.2014.08.002. View

11.

Coombes J, Charsar B, Han S, Halkias J, Chan S, Koshy A . Motile invaded neutrophils in the small intestine of Toxoplasma gondii-infected mice reveal a potential mechanism for parasite spread. Proc Natl Acad Sci U S A. 2013; 110(21):E1913-22. PMC: 3666704. DOI: 10.1073/pnas.1220272110. View

12.

Kratzer I, Vasiljevic A, Rey C, Fevre-Montange M, Saunders N, Strazielle N . Complexity and developmental changes in the expression pattern of claudins at the blood-CSF barrier. Histochem Cell Biol. 2012; 138(6):861-79. PMC: 3483103. DOI: 10.1007/s00418-012-1001-9. View

13.

Mendez O, Koshy A . Toxoplasma gondii: Entry, association, and physiological influence on the central nervous system. PLoS Pathog. 2017; 13(7):e1006351. PMC: 5519211. DOI: 10.1371/journal.ppat.1006351. View

14.

Baruch K, Deczkowska A, David E, Castellano J, Miller O, Kertser A . Aging. Aging-induced type I interferon response at the choroid plexus negatively affects brain function. Science. 2014; 346(6205):89-93. PMC: 4869326. DOI: 10.1126/science.1252945. View

15.

Baruch K, Ron-Harel N, Gal H, Deczkowska A, Shifrut E, Ndifon W . CNS-specific immunity at the choroid plexus shifts toward destructive Th2 inflammation in brain aging. Proc Natl Acad Sci U S A. 2013; 110(6):2264-9. PMC: 3568380. DOI: 10.1073/pnas.1211270110. View

16.

Zhou B, Flodby P, Luo J, Castillo D, Liu Y, Yu F . Claudin-18-mediated YAP activity regulates lung stem and progenitor cell homeostasis and tumorigenesis. J Clin Invest. 2018; 128(3):970-984. PMC: 5824875. DOI: 10.1172/JCI90429. View

17.

Vandenbroucke R . A Hidden Epithelial Barrier in the Brain with a Central Role in Regulating Brain Homeostasis. Implications for Aging. Ann Am Thorac Soc. 2016; 13 Suppl 5:S407-S410. DOI: 10.1513/AnnalsATS.201609-676AW. View

18.

Dias M, Mapunda J, Vladymyrov M, Engelhardt B . Structure and Junctional Complexes of Endothelial, Epithelial and Glial Brain Barriers. Int J Mol Sci. 2019; 20(21). PMC: 6862204. DOI: 10.3390/ijms20215372. View

19.

Gorle N, Blaecher C, Bauwens E, Vandendriessche C, Balusu S, Vandewalle J . The choroid plexus epithelium as a novel player in the stomach-brain axis during Helicobacter infection. Brain Behav Immun. 2017; 69:35-47. DOI: 10.1016/j.bbi.2017.12.010. View

20.

Butcher B, Fox B, Rommereim L, Kim S, Maurer K, Yarovinsky F . Toxoplasma gondii rhoptry kinase ROP16 activates STAT3 and STAT6 resulting in cytokine inhibition and arginase-1-dependent growth control. PLoS Pathog. 2011; 7(9):e1002236. PMC: 3169547. DOI: 10.1371/journal.ppat.1002236. View