Host Cell Autophagy Is Induced by Toxoplasma gondii and Contributes to Parasite Growth

Abstract

Autophagy has been shown to contribute to defense against intracellular bacteria and parasites. In comparison, the ability of such pathogens to manipulate host cell autophagy to their advantage has not been examined. Here we present evidence that infection by Toxoplasma gondii, an intracellular protozoan parasite, induces host cell autophagy in both HeLa cells and primary fibroblasts, via a mechanism dependent on host Atg5 but independent of host mammalian target of rapamycin suppression. Infection led to the conversion of LC3 to the autophagosome-associated form LC3-II, to the accumulation of LC3-containing vesicles near the parasitophorous vacuole, and to the relocalization toward the vacuole of structures labeled by the phosphatidylinositol 3-phosphate indicator YFP-2؋FYVE. The autophagy regulator beclin 1 was concentrated in the vicinity of the parasitophorous vacuole in infected cells. Inhibitor studies indicated that parasite-induced autophagy is dependent on calcium signaling and on abscisic acid. At physiologically relevant amino acid levels, parasite growth became defective in Atg5-deficient cells, indicating a role for host cell autophagy in parasite recovery of host cell nutrients. A flow cytometric analysis of cell size as a function of parasite content revealed that autophagy-dependentparasitegrowthcorrelateswithautophagydependent consumption of host cell mass that is dependent on parasite progression. These findings indicate a new role for autophagy as a pathway by which parasites may effectively compete with the host cell for limiting anabolic resources.

Mycobacterial Induction of Autophagy Varies by Species and Occurs Independently of Mammalian Target of Rapamycin Inhibition

“…An examination of the complete panel of non-pathogenic and pathogenic mycobacteria used in this study indicated that all species tested could induce the phosphorylation of S6. These results are especially interesting in light of recent work showing that Toxoplama gondii infection can induce autophagy without a change in the levels of phosphorylated S6 or 4E-BP1 (32).…”

Microfilariae of Brugia malayi Inhibit the mTOR Pathway and Induce Autophagy in Human Dendritic Cells

“…Indeed, autophagy is an important mechanism used by host immune cells to kill intracellular pathogens (e.g., Helicobacter pylori [51], Leishmania amazonensis [52], and Toxoplasma gondii [53]) or to provide some defense against intracellular pathogens (50). Furthermore, various bacteria and viruses regulate autophagy to avoid degradation through this pathway (54,55).…”

Autophagy in protists

“…175 In general, autophagy contributes to increase the pool of nutrients derived from autolysosomes via the recycling of autophagy degradation products. Wang et al 174 showed that the host cell autophagy machinery is stimulated by Toxoplasma in order to exploit the nutritive function of autophagy and therefore boost its multiplication. Infection results in lipidation of LC3 and the accumulation of PtdIns(3)P or LC3-containing vesicles near the PV.…”

“…174 Upon infection of host cells and formation of the PV, the parasite undergoes a phase of rapid proliferation. This rapid growth is dependent on the host cell for the supply of nutrients, such as amino acids, lipids and purines.…”