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Parasite pathogenesis: Breaching the wall for brain access

KRISHNAN, Aarti, SOLDATI-FAVRE, Dominique

Abstract

Parasite access to the central nervous system is a severe consequence of infection.

Toxoplasma gondii can achieve this by directly infecting, replicating in blood–brain barrier endothelial cells.

KRISHNAN, Aarti, SOLDATI-FAVRE, Dominique. Parasite pathogenesis: Breaching the wall for brain access. Nature Microbiology , 2016, vol. 1, no. 3, p. 16014

DOI : 10.1038/nmicrobiol.2016.14

Available at:

http://archive-ouverte.unige.ch/unige:81340

Disclaimer: layout of this document may differ from the published version.

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NATURE MICROBIOLOGY | VOL 1 | MARCH 2016 | www.nature.com/naturemicrobiology 1

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PUBLISHED: 24 FEBRUARY 2016 | ARTICLE NUMBER: 16014 | DOI: 10.1038/NMICROBIOL.2016.14

E

ntry of pathogens into the central nervous system (CNS) can result in devastating consequences. Despite the existence of a powerful immune system and cells specialized in protection against foreign invaders, pathogens have developed clever strategies to cross or circumvent these defences and ultimately access the brain. In this issue of Nature Microbiology, Konradt et al.1 report a new route of entry for the parasite Toxoplasma gondii — replication within and lysis of cerebral endothelial cells. This mechanism of entry into the CNS contrasts with the previously proposed ‘Trojan horse’ decoy strategy that recruits motile host immune cells2 and facilitates dissemination.

A key line of defence against CNS infection is the blood–brain barrier (BBB):

a structural and functional barrier composed of endothelial cells (ECs), pericytes and astrocyte end-feet that line cerebral blood vessels to regulate solute permeability, maintain homeostasis and protect the CNS (Fig. 1a). The restrictive properties of the BBB are quite formidable, making traversal a real challenge. So why and how exactly do parasites cross this intimidating barrier? As the best guarded organ of the body, the brain makes an ideal sanctuary for parasites such as T. gondii that seek long-term persistence in the host. This apicomplexan parasite is known for its capacity to penetrate host organs typically inaccessible to most pathogens. To favour its dissemination and ensure transmission, T. gondii can penetrate the intestinal epithelium and vertically transfer from a mother to the fetus by crossing the placenta. It can also cause severe ocular toxoplasmosis by entering the eye through the retina, known to possess an endothelial-retinal-barrier3, akin to the BBB.

T. gondii exploits both intracellular and extracellular (paracellular or transcellular) mechanisms of dissemination into various host organs4. An effective strategy to exit the site of infection and circulate within the lymphatic and cardiovascular system is to utilize natural cell trafficking pathways. T. gondii invades immune cells — predominantly leukocytes, dendritic cells

and macrophages — to use them as Trojan horses2, within which to disseminate to distal organs by inducing a hypermotile phenotype in the infected cell5 (Fig. 1b). In addition, the parasite can move across cellular barriers via the openings of endothelial tight junctions.

This paracellular route bypasses the need for parasite replication and is perhaps a useful adaptation to avoid damage to the host cell, reducing the inflammatory response6 (Fig. 1c).

Konradt et al.1 now describe an alternative strategy, commonly known as transcellular

traversal, to breach the BBB (Fig. 1d). They show that free T. gondii parasites are capable of actively invading, replicating within and lysing brain ECs to be released into the brain parenchyma. They intravenously infected live, anaesthetized mice with fluorescent parasites and visualized the process in vivo.

Observations in real-time were made using intravital multi-photon microscopy, which enabled high spatio-temporal resolution and captured key images of the cellular changes induced by host–T. gondii interactions.

Although a threshold level of parasitaemia

PARASITE PATHOGENESIS

Breaching the wall for brain access

Parasite access to the central nervous system is a severe complication of infection. Toxoplasma gondii can achieve this by directly infecting, replicating in and lysing blood–brain barrier endothelial cells.

Aarti Krishnan and Dominique Soldati-Favre

Endothelial cell tight junction

Pericyte Neuron

Astrocyte

Microglia

Macrophage

Dendritic cell RBC

Endothelial cells

Extracellular T. gondii

Astrocyte

end–foot Tight

junction

Replication

a b

c

d

Lysis Brain

parenchyma Blood Brain parenchyma

Brain parenchyma

Blood Blood Intracellular

T. gondii

Figure 1 | Toxoplasma gondii entry into the CNS. a, Structure of the blood–brain barrier (BBB), composed of endothelial cells, pericytes, and astrocyte end feet. b–d, Modes of pathogen entry through the BBB:

The ‘Trojan horse’ mechanism, exploiting natural immune cells (b); paracellular transmigration through endothelial tight junctions by free parasites (c); and transcellular traversal, which requires parasite replication and endothelial cell lysis for entry into the brain (d).

© 2016 Macmillan Publishers Limited. All rights reserved

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2 NATURE MICROBIOLOGY | VOL 1 | MARCH 2016 | www.nature.com/naturemicrobiology

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is necessary for crossing the BBB, the authors noticed that it is not sufficient, and replication within the ECs is an important prerequisite. This was confirmed using transgenic, replication-deficient parasites7 that could invade cerebral ECs but not traverse the BBB.

To explain the observed preferential localization of parasites within cerebral micro-vessels of less than 10 μm in diameter, the authors analysed the impact of blood flow rates and shear force on EC invasion.

In vivo, brain ECs are usually exposed to shear forces, enhancing the barrier properties of the BBB and dislodging invading parasites. Using primary human umbilical vein endothelial cells cultured in a microfluidic chamber with varied shear stress8, the authors observed that free parasites indeed adhere better when subject to lower shear forces. In particular, the conditions for adhesion and invasion are better at bifurcations, where velocities are lower and therefore less challenging.

The lysis of ECs mediated by T. gondii egress was surprisingly not accompanied by local haemorrhaging or inflammatory

response. Inflammation is an essential response to CNS damage, crucial for the clearance of pathogens and potentially toxic cellular debris9. However, as the authors discuss, T. gondii-induced EC lysis could be a relatively isolated and rare event, or T. gondii may have evolved mechanisms to limit bystander damage.

In all, Konradt and colleagues provide novel insights into CNS entry by extracellular T. gondii parasites. Extracellular invasion into the brain follows high

parasitaemia, and the cerebral capillaries lined by endothelial cells are the portals for entry. The Trojan horse mechanism remains the plausible mode of dissemination from the site of infection and parasite propagation to the brain, however its importance in traversing the BBB in the face of this new route remains unclear.

Our poor understanding of host–pathogen interactions in the CNS underpins the lack of treatments available for chronic stage infections. Peeking into the future, elucidating modes of pathogen entry into the brain could have important implications for the development of new therapeutic approaches

to treat severe encephalitis. From a broader perspective, this study by Konradt et al.

elegantly illustrates how live-cell imaging and the use of transgenic animals and fluorescent parasites can help uncover key mechanisms of parasite invasion. This approach could be extended to other extracellular pathogenic organisms, such as Trypanosoma brucei and Acanthamoeba, whose strategies for CNS entry are also poorly understood. ❐ Aarti Krishnan and Dominique Soldati-Favre are in the Department of Microbiology and Molecular Medicine, University of Geneva, CMU, 1 Rue Michel-Servet, CH-1211 Geneva 4, Switzerland.

e-mail: Aarti.Krishnan@unige.ch References

1. Konradt, C. et al. Nature Microbiol. 1, 16001 (2016).

2. Lambert, H. & Barragan, A. Cell. Microbiol. 12, 292–300 (2010).

3. Butler, N. J., Furtado, J. M., Winthrop, K. L. & Smith, J. R.

Clin. Exp. Ophthalmol. 41, 95–108 (2013).

4. Harker, K. S., Ueno, N. & Lodoen, M. B. Parasite Immunol.

37, 141–149 (2015).

5. Ueno, N. et al. Immunol. Cell Biol. 93, 508–513 (2015).

6. Antonio, B., Brossier, F. & Sibley, L. D. Cell. Microbiol.

7, 561–568 (2005).

7. Fox, B. A. & Bzik, D. J. Nature 415, 926–929 (2002).

8. Harker, K. S. et al. mBio 5, e01111–e01113 (2014).

9. Sofroniew, M. V. Nature Rev. Neurosci. 16, 249–263 (2015).

© 2016 Macmillan Publishers Limited. All rights reserved

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