title: African trypanosomes and brain infection - the unsolved question.
abstract: African trypanosomes induce sleeping sickness. The parasites are transmitted during the blood meal of a tsetse fly and appear primarily in blood and lymph vessels, before they enter the central nervous system. During the latter stage, trypanosomes induce a deregulation of sleep-wake cycles and some additional neurological disorders. Historically, it was assumed that trypanosomes cross the blood-brain barrier and settle somewhere between the brain cells. The brain, however, is a strictly controlled and immune-privileged area that is completely surrounded by a dense barrier that covers the blood vessels: this is the blood-brain barrier. It is known that some immune cells are able to cross this barrier, but this requires a sophisticated mechanism and highly specific cell-cell interactions that have not been observed for trypanosomes within the mammalian host. Interestingly, trypanosomes injected directly into the brain parenchyma did not induce an infection. Likewise, after an intraperitoneal infection of rats, Trypanosoma brucei brucei was not observed within the brain, but appeared readily within the cerebrospinal fluid (CSF) and the meninges. Therefore, the parasite did not cross the blood-brain barrier, but the blood-CSF barrier, which is formed by the choroid plexus, i.e. the part of the ventricles where CSF is produced from blood. While there is no question that trypanosomes are able to invade the brain to induce a deadly encephalopathy, controversy exists about the pathway involved. This review lists experimental results that support crossing of the blood-brain barrier and of the blood-CSF barrier and discuss the implications that either pathway would have on infection progress and on the survival strategy of the parasite. For reasons discussed below, we prefer the latter pathway and suggest the existence of an additional distinct meningeal stage, from which trypanosomes could invade the brain via the Virchow-Robin space thereby bypassing the blood-brain barrier. We also consider healthy carriers, i.e. people living symptomless with the disease for up to several decades, and discuss implications the proposed meningeal stage would have for new anti-trypanosomal drug development. Considering the re-infection of blood, a process called relapse, we discuss the likely involvement of the newly described glymphatic connection between the meningeal space and the lymphatic system, that seems also be important for other infectious diseases.
authors.affiliation: Department of Natural Sciences, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, 72076, Hoppe-Seyler-Str. 4, Germany.
authors.forename: Stefan
authors.initials: S
authors.lastname: Mogk
authors.affiliation: Department of Natural Sciences, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, 72076, Hoppe-Seyler-Str. 4, Germany.
authors.forename: Christian M
authors.initials: CM
authors.lastname: Boßelmann
authors.affiliation: Department of Natural Sciences, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, 72076, Hoppe-Seyler-Str. 4, Germany.|Department of Basic Sciences, School of Medicine, University of Kinshasa, BP 834 KIN XI, Kinshasa, D.R. Congo.
authors.forename: Celestin N
authors.initials: CN
authors.lastname: Mudogo
authors.affiliation: Department of Natural Sciences, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, 72076, Hoppe-Seyler-Str. 4, Germany.
authors.forename: Jasmin
authors.initials: J
authors.lastname: Stein
authors.affiliation: Medical Department, Institute of Pathology and Neuropathology, University of Tübingen, Tübingen, 72076, Liebermeister Str. 8, Germany.
authors.forename: Hartwig
authors.initials: H
authors.lastname: Wolburg
authors.affiliation: Department of Natural Sciences, Interfaculty Institute of Biochemistry, University of Tübingen, Tübingen, 72076, Hoppe-Seyler-Str. 4, Germany.|Medical Department, School of Medicine, Tongji University, 1239 Siping Road, Shanghai, P.R. China.
authors.forename: Michael
authors.initials: M
authors.lastname: Duszenko
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier / Q000469:parasitology*; D001921:Brain / Q000469:parasitology*; D002490:Central Nervous System / Q000469:parasitology; D006790:Host-Parasite Interactions; D006801:Humans; D014353:Trypanosomiasis, African / Q000469:parasitology / Q000635:transmission*
keywords: African sleeping sickness; HAT; Trypanosoma brucei; brain infection; trypanosomiasis