Catalase compromises the development of the insect and mammalian stages of Trypanosoma brucei

Abstract

Catalase is a widespread heme‐containing enzyme, which converts hydrogen peroxide (H2O2) to water and molecular oxygen, thereby protecting cells from the toxic effects of H2O2. Trypanosoma brucei is an aerobic protist, which conspicuously lacks this potent enzyme, present in virtually all organisms exposed to oxidative stress. To uncover the reasons for its absence in T. brucei, we overexpressed different catalases in procyclic and bloodstream stages of the parasite. The heterologous enzymes originated from the related insect‐confined trypanosomatid Crithidia fasciculata and the human. While the trypanosomatid enzyme (cCAT) operates at low temperatures, its human homolog (hCAT) is adapted to the warm‐blooded environment. Despite the presence of peroxisomal targeting signal in hCAT, both human and C. fasciculata catalases localized to the cytosol of T. brucei. Even though cCAT was efficiently expressed in both life cycle stages, the enzyme was active in the procyclic stage, increasing cell's resistance to the H2O2 stress, yet its activity was suppressed in the cultured bloodstream stage. Surprisingly, following the expression of hCAT, the ability to establish the T. brucei infection in the tsetse fly midgut was compromised. In the mouse model, hCAT attenuated parasitemia and, consequently, increased the host's survival. Hence, we suggest that the activity of catalase in T. brucei is beneficial in vitro, yet it becomes detrimental for parasite's proliferation in both invertebrate and vertebrate hosts, leading to an inability to carry this, otherwise omnipresent, enzyme.

Cell-based and multi-omics profiling reveals dynamic metabolic repurposing of mitochondria to drive developmental progression of Trypanosoma brucei

“…Here, we show that ROS molecules produced during the RBP6 overexpression are important for the completion of the developmental program, as overexpression of cytosolic catalase hindered the in vitro-induced differentiation. In vivo, catalase expression also impeded the ability of T. brucei to establish infection in the midgut of the tsetse fly [67]. The ROS-induced signal transduction pathway likely takes place in the cytosol, because only the cytosolic ROS levels were decreased to the original values upon the catalase induction.…”

A Global Analysis of Enzyme Compartmentalization to Glycosomes

“…Examples of this can be found in the kinetoplastids, which include free living and monoxenous and dixenous parasites with a wide host range that is likely still incompletely defined [6]. For instance, the absence of the protective enzyme catalase in dixenous but not monoxenous kinetoplastid genomes may be a result of a requirement for low levels of the differentiation signal hydrogen peroxide for the dixenous organisms [40].…”

Catalase and Ascorbate Peroxidase in Euglenozoan Protists

“…The absence of CAT in certain parasitic trypanosomatids is likely due to an adaptation to their dixenous (two-hosts) lifestyle, as the transition in the development from the insect to the mammalian stages of T. brucei and Leishmania spp. seem to rely on H 2 O 2 production [39,45,46]. However, the lack of CAT in dixenous kinetoplastids is not universal, as exemplified by Trypanoplasma borelli harboring a glycosomal CAT [47].…”

“…Recently, it has been demonstrated that the human CAT and its orthologue from a monoxenous (insect-hosts only) trypanosomatid C. fasciculata have very different temperature optima [39]. In order to investigate the thermal properties of euglenozoan CAT in more detail, we examined its activity in C. thermophila and L. seymouri, both at their optimal cultivation temperature of 23 • C, as well as at 14 • C and 34 • C. These monoxenous species were selected because they have the highest expression and activity of CAT among the studied euglenozoans (Figure 3C,D; Supplementary Table S2), and are also thermo-tolerant, being able to withstand temperature changes [40,41].…”