Role of the inhibitor of serine peptidase 2

• Published in: PLoS neglected tropical diseases 2021-06, Vol.15 (6)
• Main Authors: Grab, Dennis J, Goundry, Amy, Costa, Tatiana F. R, Mottram, Jeremy C, Levy, David Jessula, Novo, Carlos Mendes, Laires, Raquel S. S, Lima, Ana Paula C. A
• Format: Article
• Language: English
• Subjects: African trypanosomiasis; Development and progression; Host-parasite relationships; Inflammation; Parasitological research; Physiological aspects; Protease inhibitors; Trypanosoma brucei; Virulence (Microbiology)
• ISSN: 1935-2727

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 ([DELTA]isp2), which displayed a growth profile in vitro similar to that of wild-type (WT) parasites. C57BL/6 mice infected with [DELTA]isp2 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 [DELTA]isp2-infected mice had a greater percentage of NOS2.sup.+ myeloid cells, IFN-[gamma].sup.+ -NK cells and increased TNF-[alpha] compared to those infected with WT and parasites re-expressing ISP2 ([DELTA]isp2:ISP2). By 13 days the increased NOS2.sup.+ population was sustained in [DELTA]isp2-infected mice, along with increased percentages of monocyte-derived dendritic cells, as well as CD19.sup.+ B lymphocytes, and CD8.sup.+ and CD4.sup.+ 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.