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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 the essential pathways that maintain 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 pharmacological development.

SUBMITTER: Di Cristina M

PROVIDER: S-EPMC5527684 | biostudies-literature | 2017 Jun

REPOSITORIES: biostudies-literature

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Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection.

Di Cristina Manlio M Dou Zhicheng Z Lunghi Matteo M Kannan Geetha G Huynh My-Hang MH McGovern Olivia L OL Schultz Tracey L TL Schultz Aric J AJ Miller Alyssa J AJ Hayes Beth M BM van der Linden Wouter W Emiliani Carla C Bogyo Matthew M Besteiro Sébastien S Coppens Isabelle I Carruthers Vern B VB

Nature microbiology 20170619

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 the essential pathways that maintain long-term infection. Although i ...[more]

PMID: 28628099

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Project description:The seroepidemiology of infection with Toxoplasma gondii (T. gondii) in alcohol consumers is largely undeveloped. In light of this, we sought to determine the seroprevalence of T. gondii infection in alcohol consumers in Durango, Mexico, and the association of T. gondii seroprevalence with characteristics of the population studied. Anti-T. gondii IgG and IgM antibodies were searched in sera of participants using commercially available enzyme immunoassays. Bivariate and logistic regression analyses were then used to determine the association between T. gondii infection and the characteristics of the population studied. Of the 1544 people studied (mean age: 39.4±14.0 years), 173 (11.2%) tested positive for anti-T. gondii IgG antibodies. We were able to test 167 of the 173 anti-T. gondii IgG positive sera for anti-T. gondii IgM antibodies. Fifty-five (32.9%) of these 167 serum samples were positive for anti-T. gondii IgM antibodies. Bivariate analysis showed that visual impairment, history of surgery, and hepatitis were negatively associated with T. gondii IgG seropositivity (P<0.05). In women, seropositivity to T. gondii was positively associated with a history of pregnancy (P<0.05). Logistic regression analysis showed that T. gondii seropositivity was associated with the variables consumption of armadillo meat (OR = 2.33; 95% CI: 1.04-5.22; P = 0.03), and the use of latrines for elimination of excretes (OR = 2.27; 95% CI: 1.07-4.80; P = 0.03); and high (>150 IU/ml) anti-T. gondii IgG antibodies were associated with consumption of both armadillo meat (OR = 2.25; 95% CI: 1.01-5.02; P = 0.04) and crowding at home (OR = 1.63; 95% CI: 1.02-2.61; P = 0.03). We found a distinct T. gondii seroprevalence in people with alcohol consumption from those previously found in population groups in the region. This is the first study that illustrates the association between high anti-T. gondii antibodies and crowding in Mexico, and the second study on the association between T. gondii infection and consumption of armadillo meat and the use of latrines in this country. We conclude that epidemiology of T. gondii infection in people with alcohol consumption deserves further investigation.

Project description:BackgroundBiomarker discovery remains a major challenge for predictive medicine, in particular, in the context of chronic diseases. This is true for the widespread protozoan Toxoplasma gondii which establishes long-lasting parasitism in metazoans, humans included. This microbe successively unfolds distinct genetic programs that direct the transition from high to low replicative potential inside host cells. As a slow-replicating cell, the T. gondii bradyzoite developmental stage persists enclosed in a cyst compartment within tissues including the nervous system, being held by a sustained immune equilibrium which accounts for the prolonged clinically silent phase of parasitism. Serological surveys indicate that nearly one third of the human population has been exposed to T. gondii and possibly host bradyzoites. Because any disruption of the immune balance drives the reverse transition from bradyzoite to fast replicating tachyzoite and uncontrolled growth of the latter, these people are at risk for life-threatening disease. While serological tests for discriminating recent from past infection are available, there is yet no immunogenic biomarker used in the serological test to allow ascertaining the presence of persistent bradyzoites.ResultsCapitalizing on genetically engineered parasites induced to produce mature bradyzoites in vitro, we have identified the BCLA/MAG2 protein being restricted to the bradyzoite and the cyst envelope. Using laboratory mice as relevant T. gondii host models, we demonstrated that BCLA/MAG2 drives the generation of antibodies that recognize bradyzoite and the enveloping cyst structure. We have designed an ELISA assay based on a bacterially produced BCLA recombinant polypeptide, which was validated using a large collection of sera from mice of different genetic backgrounds and infected with bcla+ or bcla-null cystogenic and non-cystogenic T. gondii strains. To refine the design of the ELISA assay, we applied high-resolution BCLA epitope mapping and identified a specific combination of peptides and accordingly set up a selective and sensitive ELISA assay which allowed the detection of anti-BCLA/MAG2 antibodies in the sera of human patients with various forms of toxoplasmosis.ConclusionsWe brought proof of principle that anti-BCLA/MAG2 antibodies serve as specific and sensitive serological markers in the perspective of a combinatorial strategy for detection of persistent T. gondii parasitism.

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Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection.

Publications

Toxoplasma depends on lysosomal consumption of autophagosomes for persistent infection.

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