The host Rab9a/Rab32 axis is actively recruited to the Trypanosoma cruzi parasitophorous vacuole and benefits the infection cycle

• Published in: Molecular microbiology 2024-11, Vol.122 (5), p.643-659
• Main Authors: Salassa, Betiana Nebaí, Cueto, Juan Agustín, Vanrell, María Cristina, López, María Belén, Descoteaux, Albert, Labriola, Carlos Alberto, Romano, Patricia Silvia
• Format: Article
• Language: English
• Subjects: Animals; Chagas disease; Chagas Disease - parasitology; Cruzipain; Cysteine Endopeptidases; Cytoplasm; Endocytosis; Host-Parasite Interactions; host‐pathogen communication; Humans; Infections; Mammalian cells; Membrane trafficking; Membranes; Molecular machines; Parasites; Parasitophorous vacuole; Phagocytes; Protein biosynthesis; Protein synthesis; Protein transport; Proteins; Protozoa; Protozoan Proteins - genetics; Protozoan Proteins - metabolism; rab GTP-Binding Proteins - metabolism; Rab32 protein; Rab9a protein; Trypanosoma cruzi; Trypanosoma cruzi - genetics; Trypanosoma cruzi - metabolism; Trypanosoma cruzi - physiology; Trypomastigotes; Vacuoles; Vacuoles - metabolism; Vacuoles - parasitology; Vector-borne diseases; Virulence factors
• ISSN: 0950-382X; 1365-2958; 1365-2958
• DOI: 10.1111/mmi.15217

Trypanosoma cruzi, the etiological agent of Chagas disease is a protozoan parasite that infects phagocytic and non‐phagocytic mammalian cells. At early stages of infection, trypomastigotes, the infective forms of this parasite, localize in a vesicular compartment called the T. cruzi parasitophorous vacuole until the exit of parasites to the host cell cytoplasm where continue their infective cycle. Rab proteins participate in the membrane traffic's molecular machinery, functioning as central regulators of vesicle recognition and transport. In previous work, we demonstrated that endocytic Rabs are key factors of the T. cruzi infection process in non‐phagocytic cells, regulating the formation and the maturation of the vacuole. In this work, we identified and characterized other molecular components of the vesicular transport pathways and their participation in the T. cruzi infection. We found that Rab9a and Rab32, two regulators of the endocytic and autophagic pathways, were actively recruited to the T. cruzi vacuoles and favored the late stages of the infective process. The recruitment was specific and dependent on T. cruzi protein synthesis. Interestingly, Rab32 association depends on the presence of Rab9a in the vacuolar membrane, while the inhibition of the cysteine‐protease cruzipain, a T. cruzi virulence factor, significantly decreases both Rab9a and Rab32 association with the vacuole. In summary, this work showed for the first time that specific molecules produced and secreted by the parasite can subvert intracellular components of host cells to benefit the infection. These new data shed light on the complex map of interactions between T. cruzi and the host cell and introduce concepts that can be useful in finding new forms of intervention against this parasite in the future. This work shows the beneficial effect of the Rab9a/Rab32 functional axis on the Trypanosoma cruzi intracellular cycle for the first time. During the infection, T. cruzi recruits the host Rab9a and Rab32 to the parasitophorous vacuole at precise times. Cruzipain and other T. cruzi virulence factors are involved in controlling the host Rab9a and Rab32 association to favor the infection.