Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection

Abstract

Globally, nearly 2 billion people are infected with the intracellular protozoan Toxoplasma gondii1. This persistent infection can cause severe disease in immunocompromised people and is epidemiologically linked to major mental illnesses2 and cognitive impairment3. There are currently no options for curing this infection. The lack of effective therapeutics is due partly to a poor understanding of essential pathways that maintain this long-term infection. Although it is known that Toxoplasma replicates slowly within intracellular cysts demarcated with a cyst wall, precisely how it sustains itself and remodels organelles in this niche is unknown. Here we identify a key role for proteolysis within the parasite lysosomal organelle (the vacuolar compartment or VAC) in turnover of autophagosomes and persistence during neural infection. We found that disrupting a VAC-localized cysteine protease compromised VAC digestive function and markedly reduced chronic infection. Death of parasites lacking the VAC protease was preceded by accumulation of undigested autophagosomes in the parasite cytoplasm. These findings suggest an unanticipated function for parasite lysosomal degradation in chronic infection and identify an intrinsic role for autophagy in the T. gondii parasite and its close relatives. This work also identifies a key element of Toxoplasma persistence and suggests that VAC proteolysis is a prospective target for pharmacologic development.

Intersection of endocytic and exocytic systems in Toxoplasma gondii

“…In T. gondii ingestion, proteins acquired from the host cell cytosol are trafficked across the PV and parasite plasma membrane to a lysosome‐like compartment within the parasite termed the vacuolar compartment/plant‐like vacuole (VAC/PLV) for degradation . The ability to deliver host cytosol and/or parasite‐derived material to the VAC for digestion contributes to the acute stage infection and is especially important for chronic infection . However, how ingested cargoes are delivered to the VAC is not known.…”

“…3 The ability to deliver host cytosol and/or parasite-derived material to the VAC for digestion contributes to the acute stage infection and is especially important for chronic infection. 3,4 However, how ingested cargoes are delivered to the VAC is not known.…”

The 14th International Workshops on Opportunistic Protists (IWOP 14)

“…Two significant studies tackled the basic physiology of tissue cysts and bradyzoites. Recently published work (Di Cristina et al 2017) in presentation [1757 described the role of the cysteine protease VAC in autophagosomemediated turnover during persistent infection. In other work, insights into the regulation of amylopectin, a starchlike glucose polymer, that accumulates in bradyzoites, were presented Guerardel et al 2005).…”

A proteomic analysis unravels novel CORVET and HOPS proteins involved inToxoplasma gondiisecretory organelles biogenesis

“…Interestingly, in T. gondii , proteins acquired from the host cell cytosol are degraded in the VAC during or immediately following invasion and intersect with exocytic trafficking of microneme proteins (Dou, McGovern, Di Cristina, & Carruthers, ; McGovern, Rivera‐Cuevas, Kannan, Narwold Jr., & Carruthers, ). This process is important for both acute and chronic stages of the infection (Di Cristina et al, ). Most microneme (e.g., M2AP, MIC3, and MIC6) and rhoptry proteins (e.g., ROP1 and ROP13) have N‐terminal pro‐domains that are cleaved off in a post‐Golgi compartment or within the immature secretory organelles (Dogga et al, ; Miller, Thathy, Ajioka, Blackman, & Kim, ; Soldati, Lassen, Dubremetz, & Boothroyd, ; Turetzky, Chu, Hajagos, & Bradley, ).…”