Murine Models for Trypanosoma brucei gambiense Disease Progression—From Silent to Chronic Infections and Early Brain Tropism

Abstract

BackgroundHuman African trypanosomiasis (HAT) caused by Trypanosoma brucei gambiense remains highly prevalent in west and central Africa and is lethal if left untreated. The major problem is that the disease often evolves toward chronic or asymptomatic forms with low and fluctuating parasitaemia producing apparently aparasitaemic serological suspects who remain untreated because of the toxicity of the chemotherapy. Whether the different types of infections are due to host or parasite factors has been difficult to address, since T. b. gambiense isolated from patients is often not infectious in rodents thus limiting the variety of isolates.Methodology/Principal findings T. b. gambiense parasites were outgrown directly from the cerebrospinal fluid of infected patients by in vitro culture and analyzed for their molecular polymorphisms. Experimental murine infections showed that these isolates could be clustered into three groups with different characteristics regarding their in vivo infection properties, immune response and capacity for brain invasion. The first isolate induced a classical chronic infection with a fluctuating blood parasitaemia, an invasion of the central nervous system (CNS), a trypanosome specific-antibody response and death of the animals within 6–8 months. The second group induced a sub-chronic infection resulting in a single wave of parasitaemia after infection, followed by a low parasitaemia with no parasites detected by microscope observations of blood but detected by PCR, and the presence of a specific antibody response. The third isolate induced a silent infection characterised by the absence of microscopically detectable parasites throughout, but infection was detectable by PCR during the whole course of infection. Additionally, specific antibodies were barely detectable when mice were infected with a low number of this group of parasites. In both sub-chronic and chronic infections, most of the mice survived more than one year without major clinical symptoms despite an early dissemination and growth of the parasites in different organs including the CNS, as demonstrated by bioluminescent imaging.Conclusions/SignificanceWhereas trypanosome characterisation assigned all these isolates to the homogeneous Group I of T. b. gambiense, they clearly induce very different infections in mice thus mimicking the broad clinical diversity observed in HAT due to T. b. gambiense. Therefore, these murine models will be very useful for the understanding of different aspects of the physiopathology of HAT and for the development of new diagnostic tools and drugs.

Trypanosoma brucei CYP51: Essentiality and Targeting Therapy in an Experimental Model

“…b . gambiense Feo also belongs to group 2 [37–39] (S1 Table). These pathogenic strains are currently conserved as frozen stabilates in our laboratory.…”

A new asymmetric division contributes to the continuous production of infective trypanosomes in the tsetse fly

“…Parasites from dissected organs were immediately air-dried, fixed in a methanol bath at -20°C for about 30 seconds and re-hydrated in phosphate-buffered saline for 10 minutes before immunostaining. A calflagin antiserum that labels all proteins of the calflagin family was used after a 30-second methanol fixation (Giroud et al, 2009). The anti-SCC1 antibody targets the sister chromatid cohesin component 1 found in the nucleus only during the S and G2 phases of the cell cycle (Sharma et al, 2008).…”

Ubiquitylation and Developmental Regulation of Invariant Surface Protein Expression in Trypanosomes

“…ISG65 and ISG75 are not subject to antigenic variation and are recognized by the host immune system (16,30). Stabilizing ISGs on the cell surface may allow recognition by the host immune system and clearance of the pathogen.…”