review · Biological reviews/Biological reviews of the Cambridge Philosophical Society
African trypanosomes cause sleeping sickness, entering the central nervous system after an initial presence in the blood and lymph. Although historically believed to cross the blood-brain barrier directly, experimental evidence indicates that the parasites bypass this barrier by crossing the blood-cerebrospinal fluid barrier at the choroid plexus instead. In experimental models, parasites appear in the cerebrospinal fluid and meninges rather than directly establishing within brain parenchyma. This evidence points to a distinct meningeal stage of infection, from which trypanosomes may enter the brain through the Virchow-Robin space. This intermediate stage also provides insight into healthy human carriers who live symptom-free for decades. Furthermore, the glymphatic pathway linking the meninges and the lymphatic system offers an explanation for blood relapse infections, presenting critical anatomical considerations for developing more effective anti-trypanosomal medicines.
Sleeping sickness causes fatal brain inflammation, yet how the parasite accesses brain tissue has remained controversial. Clarifying whether trypanosomes enter via the cerebrospinal fluid or directly through blood vessel walls alters our fundamental understanding of disease progression. This physiological insight explains how some individuals remain symptomless carriers and helps researchers identify precisely where therapeutic interventions must penetrate to eliminate latent infections.
The identification of a distinct meningeal stage provides drug developers with a targeted anatomical site for designing new anti-trypanosomal therapies. By showing that parasites bypass the blood-brain barrier to reside in the cerebrospinal fluid, this early-stage physiological research indicates that future therapeutics may need to target meningeal compartments rather than crossing the blood-brain barrier directly. The insights remain at a foundational research stage and require further preclinical validation.
AI-generated from the published abstract. Always read the original work before citing.
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.
This page summarises published work. The authoritative version sits with the publisher.
DOI: 10.1111/brv.12301
Is something wrong with this record? Report it or request removal.
Discussion
Have you built on this work, tried to replicate it, or seen it applied in practice? Share what you know. Verified researchers and MARATTO™ domain experts can open a discussion, and any member can reply. Contributions are reviewed before they appear.
No discussion yet. Open the first thread.
New to MARATTO™? Create a free account.
