Animal African trypanosomosis, caused by blood protozoan parasites transmitted mainly by tsetse flies, represents a major constraint for millions of cattle in sub-Saharan Africa. Exposed cattle include trypanosusceptible indicine breeds, severely affected by the disease, and West African taurine breeds called trypanotolerant owing to their ability to control parasite development, survive and grow in enzootic areas. Host biological factors that shape the trypanotolerant phenotype remain poorly understood. In order to improve knowledge on biological functions involved in bovine immunity, in trypanotolerance versus trypanosusceptibility, and also on virulent and pathogenic factors of the trypanosomes, we performed a whole blood transcriptome analysis of three trypanotolerant taurine breeds (N'Dama, Lagune and Baoulé), one susceptible zebu (Zebu Fulani) and one African taurine x zebu admixed breed (Borgou) during an infection by Trypanosoma congolense, using RNA sequencing. First, we identified bovine genes that were differentially expressed in five West African cattle breeds during an experimental infection by Trypanosoma congolense and their biological functions. We confirmed previous findings, naming an early activation of the innate immune response, followed by an activation of the humoral response and an inhibition of T cell functions at the chronic stage of infection. We also highlighted a strong disturbance in host metabolism and cellular energy production that seems to differentiate trypanotolerant and trypanosusceptible breeds. Moreover, we were able to identify more than four thousand genes expressed by the trypanosomes in their host blood and to highlight parasite top expressed genes. From the host point of view, this study showed the strong interplay between immunity and metabolism that could be involved in trypanotolerance and is an invaluable resource to analyze biology of the trypanosome bloodstream forms.