title: Trypanosoma brucei Invasion and T-Cell Infiltration of the Brain Parenchyma in Experimental Sleeping Sickness: Timing and Correlation with Functional Changes.
abstract: The 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.
  
  
  
  Using 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.
  
  
  
  Trypanosome 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.
  
  
  
  These 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.
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Claudia
authors.initials: C
authors.lastname: Laperchia
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Maria
authors.initials: M
authors.lastname: Palomba
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Paul F
authors.initials: PF
authors.lastname: Seke Etet
authors.affiliation: Institute of Biodiversity Animal Health and Comparative Medicine, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Jean
authors.initials: J
authors.lastname: Rodgers
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Barbara
authors.initials: B
authors.lastname: Bradley
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Paul
authors.initials: P
authors.lastname: Montague
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.
authors.forename: Gigliola
authors.initials: G
authors.lastname: Grassi-Zucconi
authors.affiliation: Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, Scotland, United Kingdom.
authors.forename: Peter G E
authors.identifier: 0000-0002-8420-8583
authors.initials: PG
authors.lastname: Kennedy
authors.affiliation: Department of Neuroscience, Biomedicine and Movement Sciences, University of Verona, Verona, Italy.|National Institute of Neuroscience (INN), Verona Unit, Verona, Italy.
authors.forename: Marina
authors.initials: M
authors.lastname: Bentivoglio
mesh_terms: D000818:Animals; D001812:Blood-Brain Barrier; D001921:Brain / Q000276:immunology* / Q000469:parasitology*; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology; D002908:Chronic Disease; D018509:DNA, Helminth / Q000302:isolation & purification; D004195:Disease Models, Animal; D006801:Humans; D009504:Neutrophils / Q000276:immunology; D059208:Parasite Load; D051381:Rats; D012890:Sleep; D012895:Sleep, REM; D013997:Time Factors; D014346:Trypanosoma brucei brucei / Q000235:genetics / Q000276:immunology*; D014353:Trypanosomiasis, African / Q000150:complications* / Q000276:immunology* / Q000469:parasitology
chemical_list: D018509:DNA, Helminth