A novel antibody surrogate biomarker to monitor parasite persistence in Trypanosoma cruzi-infected patients

Abstract

BackgroundTrypanosoma cruzi parasite, the causative agent of Chagas disease, infects about six million individuals in more than 20 countries. Monitoring parasite persistence in infected individuals is of utmost importance to develop and evaluate treatments to control the disease. Routine screening for infected human individuals is achieved by serological assays; PCR testing to monitor spontaneous or therapy-induced parasitological cure has limitations due to the low and fluctuating parasitic load in circulating blood. The aim of the present study is to evaluate a newly developed antibody profiling assay as an indirect method to assess parasite persistence based on waning of antibodies following spontaneous or therapy-induced clearance of the infection.Methodology/Principal findingsWe designed a multiplex serology assay, an array of fifteen optimized T. cruzi antigens, to evaluate antibody diversity in 1654 serum samples from chronic Chagas patients. One specific antibody response (antibody 3, Ab3) showed a strong correlation with T. cruzi parasite persistence as determined by T. cruzi PCR positive results. High and sustained Ab3 signal was strongly associated with PCR positivity in untreated patients, whereas significant decline in Ab3 signals was observed in BZN-treated patients who cleared parasitemia based on blood PCR results.Conclusion/SignificanceAb3 is a new surrogate biomarker that strongly correlates with parasite persistence in chronic and benznidazole-treated Chagas patients. We hypothesize that Ab3 is induced and maintained by incessant stimulation of the immune system by tissue-based and shed parasites that are not consistently detectable by blood based PCR techniques. Hence, a simple immunoassay measurement of Ab3 could be beneficial for monitoring the infectious status of seropositive patients.

Linear epitopes in Onchocerca volvulus vaccine candidate proteins and excretory‐secretory proteins

“…Biotinylated synthetic peptide OVOC9988; [25][26][27][28][29][30][31][32][33] was synthesized by standard procedures and purchased from…”

“…The fact that 80.6% of the onchocerciasis patients with negative Ov16 RDT were found to be positive for this polyglutamine peptide makes it an attractive complement for this serological test. Eventually, this peptide could be combined with other O. volvulus derived peptides to make up a classifier, an approach that was shown before to be of value to monitor parasite persistence in Chagas' Disease 31. Since the analysis on the eight selected vaccine candidates resulted in the identification of immunodominant linear epitopes, we also explored the entire list of vaccine candidates and ESP's for the presence of such immunodominant linear epitopes.…”

Chagas Disease Treatment Efficacy Biomarkers: Myths and Realities

“…More importantly, Ab3 could discriminate PCR-positive patients from PCRnegative treated patients (AUC 0.74). Ab3 efficiently detected parasite persistence in most of the T. cruzi-infected individuals and detected a large number of parasite persistent cases within the PCR-negative group, which shows this assay to be even more informative than PCR [49]. These results suggest that Ab3 could be a good surrogate biomarker; however, Ab3 titers should be evaluated before treatment and in a non-infected population.…”

“…In the search for the ideal antigens and antibodies, Zrein et al used an innovative multiparametric screening technology to identify antibodies that could be used as surrogate biomarkers [49]. After evaluating 15 antigens in a multiplex serology assay, Antibody 3 (Ab3), which recognizes T. cruzi putative microtubule-associated protein (MAP) (Antigen 3), showed a strong correlation (92%) with PCR-positive results in treated and untreated CD patients from the SaMi-Trop cohort study [64].…”

A Parasite Biomarker Set for Evaluating Benznidazole Treatment Efficacy in Patients with Chronic Asymptomatic Trypanosoma cruzi Infection

“…Serum biomarkers identified by surface-enhanced laser desorption ionization-time of flight (SELDI-TOF) mass spectrometry (such as MIPP1 alpha, C3a, apolipoprotein A1 [ApoA1], and C3 derivatives) have been proposed as confirmatory tests for Chagas disease (16). The use of the MultiCruzi assay, which is composed of 15 different antigens, allowed the selection of Ag3, which was detected with high titers by sera from most T. cruzi-infected individuals (17) and exhibited the highest titers in patients who had a positive PCR result when parasite detection was performed. Markers associated with cardiac dysfunction, such as NTproBNP, were also correlated with parasitemia and were elevated in patients with chronic Chagas cardiopathology (18).…”