A brain cyst load-associated antigen is a Toxoplasma gondii biomarker for serodetection of persistent parasites and chronic infection View Full Text


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Article Info

DATE

2021-02-09

AUTHORS

Céline Dard, Christopher Swale, Marie-Pierre Brenier-Pinchart, Dayana C. Farhat, Valeria Bellini, Marie Gladys Robert, Dominique Cannella, Hervé Pelloux, Isabelle Tardieux, Mohamed-Ali Hakimi

ABSTRACT

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. More... »

PAGES

25

Identifiers

URI

http://scigraph.springernature.com/pub.10.1186/s12915-021-00959-9

DOI

http://dx.doi.org/10.1186/s12915-021-00959-9

DIMENSIONS

https://app.dimensions.ai/details/publication/pub.1135236379

PUBMED

https://www.ncbi.nlm.nih.gov/pubmed/33557824


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20 schema: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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27 ELISA
28 Mag2
29 T. gondii
30 Toxoplasma gondii
31 antibodies
32 antigen
33 background
34 balance
35 biomarkers
36 bradyzoites
37 cells
38 challenges
39 chronic diseases
40 chronic infection
41 collection
42 combination
43 combinatorial strategies
44 compartments
45 context
46 cyst envelope
47 cyst structure
48 design
49 detection
50 developmental stages
51 different genetic backgrounds
52 discovery
53 disease
54 disruption
55 distinct genetic programs
56 envelope
57 epitope mapping
58 equilibrium
59 form
60 form of toxoplasmosis
61 generation
62 generation of antibodies
63 genetic background
64 genetic program
65 gondii
66 growth
67 host cells
68 host model
69 human patients
70 human population
71 humans
72 immune balance
73 immune equilibrium
74 infection
75 laboratory mice
76 large collection
77 life-threatening disease
78 major challenge
79 mapping
80 markers
81 mature bradyzoites
82 medicine
83 metazoans
84 mice
85 microbes
86 model
87 nervous system
88 parasites
89 parasitism
90 past infection
91 patients
92 people
93 peptides
94 persistent parasites
95 perspective
96 phase
97 polypeptide
98 population
99 predictive medicine
100 presence
101 principles
102 program
103 proof
104 proof of principle
105 protein
106 protozoan Toxoplasma gondii
107 recombinant polypeptides
108 reverse transition
109 risk
110 sensitive ELISA
111 sensitive serological marker
112 serodetection
113 serological markers
114 serological survey
115 serological tests
116 serum
117 silent phase
118 specific combinations
119 stage
120 strategies
121 structure
122 survey
123 system
124 tachyzoites
125 test
126 third
127 tissue
128 toxoplasmosis
129 transition
130 uncontrolled growth
131 vitro
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