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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\u2013wake cycles and some additional neurological disorders. Historically, it was assumed that trypanosomes cross the blood\u2013brain barrier and settle somewhere between the brain cells. The brain, however, is a strictly controlled and immune\u2010privileged area that is completely surrounded by a dense barrier that covers the blood vessels: this is the blood\u2013brain barrier. It is known that some immune cells are able to cross this barrier, but this requires a sophisticated mechanism and highly specific cell\u2013cell 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, <jats:italic><jats:styled-content style=\"fixed-case\">T<\/jats:styled-content>rypanosoma brucei brucei<\/jats:italic> was not observed within the brain, but appeared readily within the cerebrospinal fluid (<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content>) and the meninges. Therefore, the parasite did not cross the blood\u2013brain barrier, but the blood\u2013<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content> barrier, which is formed by the choroid plexus, i.e. the part of the ventricles where <jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content> 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\u2013brain barrier and of the blood\u2013<jats:styled-content style=\"fixed-case\">CSF<\/jats:styled-content> 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 <jats:italic>via<\/jats:italic> the <jats:styled-content style=\"fixed-case\">V<\/jats:styled-content>irchow\u2013<jats:styled-content style=\"fixed-case\">R<\/jats:styled-content>obin space thereby bypassing the blood\u2013brain 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\u2010trypanosomal drug development. Considering the re\u2010infection 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.<\/jats:p>","DOI":"10.1111\/brv.12301","type":"journal-article","created":{"date-parts":[[2016,10,14]],"date-time":"2016-10-14T10:22:55Z","timestamp":1476440575000},"page":"1675-1687","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":50,"title":["African trypanosomes and brain infection\u00a0\u2013\u00a0the unsolved question"],"prefix":"10.1111","volume":"92","author":[{"given":"Stefan","family":"Mogk","sequence":"first","affiliation":[{"name":"Department of Natural Sciences, Interfaculty Institute of Biochemistry University of T\u00fcbingen  T\u00fcbingen 72076 Hoppe\u2010Seyler\u2010Str. 4 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christian M.","family":"Bo\u00dfelmann","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Interfaculty Institute of Biochemistry University of T\u00fcbingen  T\u00fcbingen 72076 Hoppe\u2010Seyler\u2010Str. 4 Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Celestin N.","family":"Mudogo","sequence":"additional","affiliation":[{"name":"Department of Natural Sciences, Interfaculty Institute of Biochemistry University of T\u00fcbingen  T\u00fcbingen 72076 Hoppe\u2010Seyler\u2010Str. 4 Germany"},{"name":"Department of Basic Sciences, School of Medicine University of Kinshasa  BP 834 KIN XI Kinshasa D.R. 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