- Autores: David Jessula Levy, Amy Goundry, Raquel S S Laires, Tatiana F R Costa, Carlos Mendes Novo, Dennis J Grab, Jeremy C Mottram, Ana Paula C A Lima
- Ano de Publicação: 2021
- Journal: Plos Neglected Tropical Diseases, 15(6), art e0009526
- Link: https://doi.org/10.1371/journal.pntd.0009526
Trypanosoma brucei rhodesiense is one of the causative agents of Human African Trypanosomiasis (HAT), known as sleeping sickness. The parasite invades the central nervous system and causes severe encephalitis that is fatal if left untreated. We have previously identified ecotin-like inhibitors of serine peptidases, named ISPs, in trypanosomatid parasitic protozoa. Here, we investigated the role of ISP2 in bloodstream form T. b. rhodesiense. We generated gene-deficient mutants lacking ISP2 (Δisp2), which displayed a growth profile in vitro similar to that of wild-type (WT) parasites. C57BL/6 mice infected with Δisp2 displayed lower blood parasitemia, a delayed hind leg pathological phenotype and survived longer. The immune response was examined at two time-points that corresponded with two peaks of parasitemia. At 4 days, the spleens of Δisp2-infected mice had a greater percentage of NOS2+ myeloid cells, IFN-γ+-NK cells and increased TNF-α compared to those infected with WT and parasites re-expressing ISP2 (Δisp2:ISP2). By 13 days the increased NOS2+ population was sustained in Δisp2-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19+ B lymphocytes, and CD8+ and CD4+ T lymphocytes. Taken together, these findings indicate that ISP2 contributes to T. b. rhodesiense virulence in mice and attenuates the inflammatory response during early infection.
Trypanosoma brucei rhodesiense are protozoan parasites that cause deadly diseases in humans. The parasites are transmitted by the bite of infected tsetse flies and can penetrate the brain, causing severe inflammation, accompanied by motor disability, neurological disorders and death. It is important to understand how and which parasite factors contribute to infection in order to improve treatment alternatives. In their genome, these parasites have genes called ISPs similar to genes of bacteria, which encode proteins that inhibit serine peptidases of the trypsin family. Here, we studied the role of ISP2 in T. b. rhodesiense by analyzing parasite knock-out mutants for isp2 in experimental infections in mice. We found that ISP2 contributes to blood parasitemia, to the clinical signs of motor disability, and to reduce the levels of the inflammatory response of the host, therefore, contributing to infection.
Trypanosoma brucei; parasite; Trypanosomiasis; inhibitors of serine peptidases; ISPs; Africa; Human African Trypanosomiasis; sleeping sickness.