Invasion of Trypanosoma cruzi into host cells is impaired by N-propionylmannosamine and other N-acylmannosamines

Abstract

The etiologic agent of Chagas' disease, Trypanosoma cruzi, is widely distributed in South America, affecting millions of people with thousands of deaths every year. Adherence of the infectious trypomastigote to host cells is mediated by sialic acid. T. cruzi cannot synthesize sialic acids on their own but cleave them from the host cells and link them to glycans on the surface of the parasites using the trans-sialidase, a GPI-anchored enzyme. The infectivity of the protozoan parasites strongly depends on the activity of this enzyme. In this report, we investigated whether the transfer of sialic acids from the host to the parasites can be attenuated using novel sialic acid precursors. The cell line 86-HG-39 was infected with T. cruzi and treated with defined N-acylmannosamine analogues bearing an elongated N-acyl side-chain. By treatment of these cells the number of T. cruzi infected cell was reduced up to 60%. We also showed that the activity of the bacterial sialidase C was reduced with N-glycan substrates with elongated N-acyl side chains of the terminal sialic acids. The affinity of this sialidase decreased with the length of the N-acyl side-chain. The data presented suggest that N-acyl modified sialic acid precursors can change the transfer of sialic acids leading to modification of infection. Since the chemotherapy of this disease is inefficient and afflicted by side effects, the need of effective drugs is lasting. These findings propose a new path to prevent the dissemination of T. cruzi in the human hosts. These compounds or further modified analogues might be a basis for the search of new agents against Chagas' disease.

N-Glycosylation Profile of Undifferentiated and Adipogenically Differentiated Human Bone Marrow Mesenchymal Stem Cells: Towards a Next Generation of Stem Cell Markers

“…The cells were pelleted and frozen in 100 mL PBS at -80°C until analysis. Membrane extraction was performed according to Lieke et al [29]. Cell pellets were thawed and suspended in 2 mL of homogenization buffer (pH 7.6), consisting of 1 mM NaHCO 3 (Merck), 150 mM KCl, 2 mM CaCl 2 (both Roth) and protease inhibitors (EDTA-free; Roche Applied Science).…”

Virulence factors of Trypanosoma cruzi: who is who?

“…Nevertheless, specific TS inhibitors were shown to reduce parasite cell infection [70]. Also treatment of cells with modified precursors of sialic acid reduce cell invasion [71]. TS may also function as a counter-receptor for parasite binding to alpha 2,3-sialyl receptors on host cells as a prelude to TCT invasion.…”

Production, purification and crystallization of atrans-sialidase fromTrypanosoma vivax

“…It is tempting to speculate that the differences between the trans-sialidases encoded by intracellular and extracellular trypanosomes might be related to the distinct functions that these enzymes play in the divergent life cycles of these two classes of parasite. Indeed, for the intracellular trypanosome T. cruzi it has been shown that TcTS is essential for host immune evasion and cell invasion by the parasite (Lieke et al, 2011;Giorgi & de Lederkremer, 2011). The biological role of TvTS1 is less well defined.…”