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Organotypic endothelial adhesion molecules are key for Trypanosoma brucei tropism and virulence.

ABSTRACT: Trypanosoma brucei is responsible for lethal diseases in humans and cattle in Sub-Saharan Africa. These extracellular parasites extravasate from the blood circulation into several tissues. The importance of the vasculature in tissue tropism is poorly understood. Using intravital imaging and bioluminescence, we observe that gonadal white adipose tissue and pancreas are the two main parasite reservoirs. We show that reservoir establishment happens before vascular permeability is compromised, suggesting that extravasation is an active mechanism. Blocking endothelial surface adhesion molecules (E-selectin, P-selectins, or ICAM2) significantly reduces extravascular parasite density in all organs and delays host lethality. Remarkably, blocking CD36 has a specific effect on adipose tissue tropism that is sufficient to delay lethality, suggesting that establishment of the adipose tissue reservoir is necessary for parasite virulence. This work demonstrates the importance of the vasculature in a T. brucei infection and identifies organ-specific adhesion molecules as key players for tissue tropism.

SUBMITTER: De Niz M

PROVIDER: S-EPMC8480282 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Organotypic endothelial adhesion molecules are key for Trypanosoma brucei tropism and virulence.

De Niz Mariana M Brás Daniela D Ouarné Marie M Pedro Mafalda M Nascimento Ana M AM Henao Misikova Lenka L Franco Claudio A CA Figueiredo Luisa M LM

Cell reports 20210901 12

Trypanosoma brucei is responsible for lethal diseases in humans and cattle in Sub-Saharan Africa. These extracellular parasites extravasate from the blood circulation into several tissues. The importance of the vasculature in tissue tropism is poorly understood. Using intravital imaging and bioluminescence, we observe that gonadal white adipose tissue and pancreas are the two main parasite reservoirs. We show that reservoir establishment happens before vascular permeability is compromised, sugge ...[more]

PMID: 34551286

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Project description:Experiments on infections caused by trypanosomes are widely performed in Swiss white mice through various inoculation routes. To better understand the effect of route of trypanosome inoculation on disease outcomes in this model, we characterised the virulence of two isolates, Trypanosoma brucei KETRI 2710 and T. congolense KETRI 2765 in Swiss white mice. For each of the isolates, five routes of parasite inoculation, namely intraperitoneal (IP), subcutaneous (SC), intramuscular (IM) intradermal (ID) and intravenous (IV) were compared using groups (n = 6) of mice, with each mouse receiving 1x104 trypanosomes. We subsequently assessed impact of the routes on disease indices that included pre-patent period (PP), parasitaemia levels, Packed Cell Volume (PCV), bodyweight changes and survival time. Pre-patent period for IP inoculated mice was a mean ± SE of 3.8 ± 0.2 and 6.5 ± 0.0 for the T brucei and T. congolense isolates respectively; the PP for mice groups inoculated using other routes were not significantly different(p> 0.05) irrespective of route of inoculation and species of trypanosomes. With ID and IP routes, parasitaemia was significantly higher in T. brucei and significantly lower in T. congolense infected mice and the progression to peak parasitaemia routes showed no significant different between the routes of either species of trypanosome. The IM and ID routes in T. congolense inoculations, and IP and IV in T. b. brucei induced the fastest and slowest parasitaemia progressions respectively. There were significant differences in rates of reduction of PCV with time post infection in mice infected by the two species and which was more pronounced in sc and ip injected mice. No significant differences in mice body weight changes and survivorship was observed between the routes of inoculation. Inoculation route therefore appears to be a critical determinant of pathogenicity of Trypanosoma congolense and Trypanosoma brucei brucei in murine mouse model of African trypanosomiasis.

Project description:Trypanosoma brucei rhodesiense is the causative agent for Rhodesian human African trypanosomiasis. The disease is considered acute, but varying clinical outcomes including chronic infections have been observed. The basis for these different clinical manifestations is thought to be associated with a combination of parasite and host factors. In the current study, Trypanosoma brucei rhodesiense strains responsible for varying infection outcomes were sought using mouse model. Clinical rHAT parasite isolates were subjected to PCR tests to confirm presence of the serum resistance associated (SRA) gene. Thereafter, four T. b. rhodesiense isolates were subjected to a comparative pathogenicity study using female Swiss white mice; the parasite strains were compared on the basis of parasitaemia, host survival time, clinical and postmortem biomarkers of infection severity. Isolates identified to cause acute and chronic disease were compared for establishment in insect vector, tsetse fly. The mouse survival time was significantly different (Log-rankp = 0.0001). With mice infected with strain KETRI 3801 exhibiting the shortest survival time (20 days) as compared to those infected with KETRI 3928 that, as controls, survived past the 60 days study period. In addition, development of anaemia was rapid in KETRI 3801 and least in KETRI 3928 infections, and followed the magnitude of survival time. Notably, hepatosplenomegaly was pronounced with longer survival. Mouse weight and feed intake reduced (KETRI 3801 > KETRI 2636 > EATRO 1762) except in KETRI 3928 infections which remained similar to controls. Comparatively, acute to chronic infection outcomes is in the order of KETRI 3801 > KETRI 2636 > EATRO 1762 > KETRI 3928, indicative of predominant role of strain dependent factors. Further, KETRI 3928 strain established better in tsetse as compared to KETRI 3801, suggesting that transmission of strains causing chronic infections could be common. In sum, we have identified Trypanosoma brucei rhodesiense strains that cause acute and chronic infections in mice, that will be valuable in investigating pathogen - host interactions responsible for varying disease outcomes and transmission in African trypanosomiasis.

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Organotypic endothelial adhesion molecules are key for Trypanosoma brucei tropism and virulence.

Publications

Organotypic endothelial adhesion molecules are key for Trypanosoma brucei tropism and virulence.

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