From the blood to the brain: avenues of eukaryotic pathogen dissemination to the central nervous system

Ueno, Norikiyo; Lodoen, Melissa B.

doi:10.1016/j.mib.2015.05.006

Cited by 23 publications

(19 citation statements)

References 63 publications

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“…T. gondii causes chronic CNS infection and neuroinflammation after ingestion of oocysts in contaminated food or water 115 . Ingested oocysts develop into fast-dividing tachyzoites that invade the gut epithelium and lamina propria, replicate asexually through a process called endodyogeny and then exit and infect myeloid cells, which allow dissemination to multiple tissue sites in the body (including the eye, heart, liver, lung, lymph nodes, muscles and CNS) 116 . The life cycle of T. gondii requires infection of feline prey intermediate hosts, whose ingestion leads to infection of feline definitive hosts 117 .…”

Section: Inflammation-induced Cns Dysfunction In Parenchymal Infectionmentioning

confidence: 99%

Infectious immunity in the central nervous system and brain function

2017

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Inflammation is emerging as a critical mechanism underlying neurological disorders of various etiologies, yet its role in altering brain function as a consequence of neuroinfectious disease remains unclear. Although acute alterations in mental status due to inflammation are a hallmark of central nervous system (CNS) infections with neurotropic pathogens, post-infectious neurologic dysfunction has traditionally been attributed to irreversible damage caused by the pathogens themselves. More recently, studies indicate that pathogen eradication within the CNS may require immune responses that interfere with neural cell function and communication without affecting their survival. In this Review we explore inflammatory processes underlying neurological impairments caused by CNS infection and discuss their potential links to established mechanisms of psychiatric and neurodegenerative diseases.

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Section: Inflammation-induced Cns Dysfunction In Parenchymal Infectionmentioning

confidence: 99%

Infectious immunity in the central nervous system and brain function

2017

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“…The mechanisms used by circulating eukaryotic pathogens to evade host immunity, cross the blood-brain barrier (BBB), and invade the CNS are remarkably complex and diverse (Ueno and Lodoen, 2015). Normally the brain microvascular endothelial cells that constitute the BBB prevent harmful substances from invading the CNS by restricting movement across the barrier; however, some microorgansims have evolved stealth-like mechanisms that allow them to breach the BBB.…”

Section: Introductionmentioning

confidence: 99%

The Metalloprotease, Mpr1, Engages AnnexinA2 to Promote the Transcytosis of Fungal Cells across the Blood-Brain Barrier

Pombejra

Salemi

Phinney

et al. 2017

Front. Cell. Infect. Microbiol.

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Eukaryotic pathogens display multiple mechanisms for breaching the blood-brain barrier (BBB) and invading the central nervous system (CNS). Of the fungal spp., that cause disease in mammals, only some cross brain microvascular endothelial cells which constitute the BBB, and invade the brain. Cryptococcus neoformans, the leading cause of fungal meningoencephalitis, crosses the BBB directly by transcytosis or by co-opting monocytes. We previously determined that Mpr1, a secreted fungal metalloprotease, facilitates association of fungal cells to brain microvascular endothelial cells and we confirmed that the sole expression of CnMPR1 endowed S. cerevisiae with an ability to cross the BBB. Here, the gain of function conferred onto S. cerevisiae by CnMPR1 (i.e., Sc strain) was used to identify targets of Mpr1 that might reside on the surface of the BBB. Following biotin-labeling of BBB surface proteins, Sc-associated proteins were identified by LC-MS/MS. Of the 62 proteins identified several were cytoskeleton-endocytosis-associated including AnnexinA2 (AnxA2). Using an in vitro model of the human BBB where AnxA2 activity was blocked, we found that the lack of AnxA2 activity prevented the movement of S. cerevisiae across the BBB (i.e., transcytosis of Sc strain) but unexpectedly, TEM analysis revealed that AnxA2 was not required for the association or the internalization of Sc. Additionally, the co-localization of AnxA2 and Sc suggest that successful crossing of the BBB is dependent on an AxnA2-Mpr1-mediated interaction. Collectively the data suggest that AnxA2 plays a central role in fungal transcytosis in human brain microvascular endothelial cells. The movement and exocytosis of Sc is dependent on membrane trafficking events that involve AnxA2 but these events appear to be independent from the actions of AnxA2 at the host cell surface. We propose that Mpr1 activity promotes cytoskeleton remodeling in brain microvascular endothelial cells and thereby engages AnxA2 in order to facilitate fungal transcytosis of the BBB.

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“…However, routes and mechanisms used by the parasite to gain entry into the brain remain to be fully clarified [18–20]. The timing of parasite neuroinvasion following infection is also controversial [21, 22], and even parasite entry into the brain parenchyma has been recently questioned [19, 20, 23]. Importantly, neurological signs and symptoms are considered characteristic of the second stage of HAT, but their onset and evolution in relation to the disease second stage, which have obvious diagnostic and therapeutic implications, remain to be determined [5].…”

Section: Introductionmentioning

confidence: 99%

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

et al. 2016

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BackgroundThe timing of Trypanosoma brucei entry into the brain parenchyma to initiate the second, meningoencephalitic stage of human African trypanosomiasis or sleeping sickness is currently debated and even parasite invasion of the neuropil has been recently questioned. Furthermore, the relationship between neurological features and disease stage are unclear, despite the important diagnostic and therapeutic implications.MethodologyUsing a rat model of chronic Trypanosoma brucei brucei infection we determined the timing of parasite and T-cell neuropil infiltration and its correlation with functional changes. Parasite DNA was detected using trypanosome-specific PCR. Body weight and sleep structure alterations represented by sleep-onset rapid eye movement (SOREM) periods, reported in human and experimental African trypanosomiasis were monitored. The presence of parasites, as well as CD4+ and CD8+ T-cells in the neuropil was assessed over time in the brain of the same animals by immunocytochemistry and quantitative analyses.Principal findingsTrypanosome DNA was present in the brain at day 6 post-infection and increased more than 15-fold by day 21. Parasites and T-cells were observed in the parenchyma from day 9 onwards. Parasites traversing blood vessel walls were observed in the hypothalamus and other brain regions. Body weight gain was reduced from day 7 onwards. SOREM episodes started in most cases early after infection, with an increase in number and duration after parasite neuroinvasion.ConclusionThese findings demonstrate invasion of the neuropil over time, after an initial interval, by parasites and lymphocytes crossing the blood-brain barrier, and show that neurological features can precede this event. The data thus challenge the current clinical and cerebrospinal fluid criteria of disease staging.

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From the blood to the brain: avenues of eukaryotic pathogen dissemination to the central nervous system

Cited by 23 publications

References 63 publications

Infectious immunity in the central nervous system and brain function

Infectious immunity in the central nervous system and brain function

The Metalloprotease, Mpr1, Engages AnnexinA2 to Promote the Transcytosis of Fungal Cells across the Blood-Brain Barrier

Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes

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