Background Schistosomes are chronic intravascular helminth parasites of humans causing a heavy burden of disease worldwide. Diagnosis of schistosomiasis currently requires the detection of schistosome eggs in the feces and urine of infected individuals. This method unreliably measures disease burden due to poor sensitivity and wide variances in egg shedding. In vivo imaging of schistosome parasites could potentially better assess disease burden, improve management of schistosomiasis, facilitate vaccine development, and enhance study of the parasite's biology. Schistosoma mansoni (S. mansoni) have a high metabolic demand for glucose. In this work we investigated whether the parasite burden in mice could be assessed by positron emission tomography (PET) imaging with 2-deoxy-2[18F]fluoro-D-glucose (FDG). Methodology/Principal Findings Live adult S. mansoni worms FDG uptake in vitro increased with the number of worms. Athymic nude mice infected with S. mansoni 5–6 weeks earlier were used in the imaging studies. Fluorescence molecular tomography (FMT) imaging with Prosense 680 was first performed. Accumulation of the imaging probe in the lower abdomen correlated with the number of worms in mice with low infection burden. The total FDG uptake in the common portal vein and/or regions of elevated FDG uptake in the liver linearly correlated to the number of worms recovered from infected animals (R2 = 0.58, P<0.001, n = 40). FDG uptake showed a stronger correlation with the worm burden in mice with more than 50 worms (R2 = 0.85, P<0.001, n = 17). Cryomicrotome imaging confirmed that most of the worms in a mouse with a high infection burden were in the portal vein, but not in a mouse with a low infection burden. FDG uptake in recovered worms measured by well counting closely correlated with worm number (R2 = 0.85, P<0.001, n = 21). Infected mice showed a 32% average decrease in total FDG uptake after three days of praziquantel treatment (P = 0.12). The total FDG uptake in untreated mice increased on average by 36% over the same period (P = 0.052). Conclusion FDG PET may be useful to non-invasively quantify the worm burden in schistosomiasis-infected animals. Future investigations aiming at minimizing non-specific FDG uptake and to improve the recovery of signal from worms located in the lower abdomen will include the development of more specific radiotracers.
References
[1]
Chen M (2005) Use of praziquantel for clinical treatment and morbidity control of schistosomiasis japonica in China: a review of 30 years' experience. Acta Trop 96: 168–176. doi:10.1016/j.actatropica.2005.07.011.
[2]
Xiaonong Z, Minggang C, McManus D, Bergquist R (2002) Schistosomiasis control in the 21st century. Proceedings of the International Symposium on Schistosomiasis, Shanghai, July 4-6, 2001. Acta Trop 82: 95–114. doi: 10.1016/S0001-706X(02)00005-0
[3]
Hotez PJ, Molyneux DH, Fenwick A, Kumaresan J, Sachs SE, et al. (2007) Control of neglected tropical diseases. N Engl J Med 357: 1018–1027. doi:10.1056/NEJMra064142.
[4]
King CH, Dangerfield-Cha M (2008) The unacknowledged impact of chronic schistosomiasis. Chronic Illn 4: 65–79. doi:10.1177/1742395307084407.
[5]
Melman SD, Steinauer ML, Cunningham C, Kubatko LS, Mwangi IN, et al. (2009) Reduced Susceptibility to Praziquantel among Naturally Occurring Kenyan Isolates of Schistosoma mansoni. PLoS Negl Trop Dis 3: e504. doi:10.1371/journal.pntd.0000504.
[6]
Todd CW, Colley DG (2002) Practical and ethical issues in the development of a vaccine against schistosomiasis mansoni. Am J Trop Med Hyg 66: 348–358.
[7]
Zhu Y (2005) Immunodiagnosis and its role in schistosomiasis control in China: a review. Acta Trop 96: 130–136. doi:10.1016/j.actatropica.2005.07.007.
[8]
Jordan P, Webbe G, Sturrock RF (1993) Human schistosomiasis. CAB International. doi: 10.1017/s0022149x00013936
[9]
de Vlas SJ, Gryseels B (1992) Underestimation of Schistosoma mansoni prevalences. Parasitol. Today (Regul. Ed.) 8: 274–277. doi: 10.1016/0169-4758(92)90144-Q
[10]
Engels D, Sinzinkayo E, Gryseels B (1996) Day-to-day egg count fluctuation in Schistosoma mansoni infection and its operational implications. Am J Trop Med Hyg 54: 319–324.
[11]
Yu JM, de Vlas SJ, Yuan HC, Gryseels B (1998) Variations in fecal Schistosoma japonicum egg counts. Am J Trop Med Hyg 59: 370–375.
[12]
Utzinger J, Booth M, N'Goran EK, Müller I, Tanner M, et al. (2001) Relative contribution of day-to-day and intra-specimen variation in faecal egg counts of Schistosoma mansoni before and after treatment with praziquantel. Parasitology 122: 537–544. doi: 10.1017/S0031182001007752
[13]
Alan Wilson R, van Dam GJ, Kariuki TM, Farah IO, Deelder AM, et al. (2006) The detection limits for estimates of infection intensity in schistosomiasis mansoni established by a study in non-human primates. Int J Parasitol 36: 1241–1244. doi:10.1016/j.ijpara.2006.07.002.
[14]
Bergquist NR (1992) Present aspects of immunodiagnosis of schistosomiasis. Mem Inst Oswaldo Cruz 87 : Suppl 429–38. doi: 10.1590/S0074-02761992000800004
[15]
Ross AG, Sleigh AC, Li Y, Davis GM, Williams GM, et al. (2001) Schistosomiasis in the People's Republic of China: prospects and challenges for the 21st century. Clin Microbiol Rev 14: 270–295. doi:10.1128/CMR.14.2.270-295.2001.
[16]
Wu G (2002) A historical perspective on the immunodiagnosis of schistosomiasis in China. Acta Trop 82: 193–198. doi: 10.1016/S0001-706X(02)00010-4
Robinson MW, Dalton JP, Donnelly S (2008) Helminth pathogen cathepsin proteases: it's a family affair. Trends Biochem Sci 33: 601–608. doi:10.1016/j.tibs.2008.09.001.
[20]
Ben-Haim S, Ell P (2009) 18F-FDG PET and PET/CT in the evaluation of cancer treatment response. J Nucl Med 50: 88–99. doi:10.2967/jnumed.108.054205.
[21]
Schiepers C, Hoh CK (1998) Positron emission tomography as a diagnostic tool in oncology. Eur Radiol 8: 1481–1494. doi: 10.1007/s003300050579
[22]
Bueding E (1950) Carbohydrate metabolism of schistosoma mansoni. J Gen Physiol 33: 475–495. doi: 10.1085/jgp.33.5.475
[23]
Muzic RF, Cornelius S (2001) COMKAT: compartment model kinetic analysis tool. J Nucl Med 42: 636–645.
[24]
Weber S, Bauer A (2004) Small animal PET: aspects of performance assessment. Eur J Nucl Med Mol Imaging 31: 1545–1555. doi:10.1007/s00259-004-1683-x.
[25]
Roy D, Steyer GJ, Gargesha M, Stone ME, Wilson DL (2009) 3D cryo-imaging: a very high-resolution view of the whole mouse. Anat Rec (Hoboken) 292: 342–351. doi:10.1002/ar.20849.
[26]
Wilson RA (2009) The saga of schistosome migration and attrition. Parasitology 136: 1581–1592. doi:10.1017/S0031182009005708.
[27]
Blum G, Weimer RM, Edgington LE, Adams W, Bogyo M (n.d.) Comparative Assessment of Substrates and Activity Based Probes as Tools for Non-Invasive Optical Imaging of Cysteine Protease Activity. PLoS One 4: doi:10.1371/journal.pone.0006374.
[28]
Abouzied MM, Crawford ES, Nabi HA (2005) 18F-FDG Imaging: Pitfalls and Artifacts. J Nucl Med Technol 33: 145–155.
[29]
Prabhakar HB, Sahani DV, Fischman AJ, Mueller PR, Blake MA (2007) Bowel hot spots at PET-CT. Radiographics 27: 145–159. doi:10.1148/rg.271065080.
[30]
Miraldi F, Vesselle H, Faulhaber PF, Adler LP, Leisure GP (1998) Elimination of artifactual accumulation of FDG in PET imaging of colorectal cancer. Clin Nucl Med 23: 3–7. doi: 10.1097/00003072-199801000-00002
[31]
Brindley PJ, Strand M, Norden AP, Sher A (1989) Role of host antibody in the chemotherapeutic action of praziquantel against Schistosoma mansoni: identification of target antigens. Mol Biochem Parasitol 34: 99–108. doi: 10.1016/0166-6851(89)90001-7
[32]
Phillips SM, DiConza JJ, Gold JA, Reid WA (1977) Schistosomiasis in the congenitally athymic (nude) mouse. I. Thymic dependency of eosinophilia, granuloma formation, and host morbidity. J Immunol 118: 594–599.
[33]
Cheever AW, Eltoum IA, Andrade ZA, Cox TM (1993) Biology and pathology of Schistosoma mansoni and Schistosoma japonicum infections in several strains of nude mice. Am J Trop Med Hyg 48: 496–503.
[34]
Zhao S, Kuge Y, Kohanawa M, Takahashi T, Kawashima H, et al. (2007) Extensive FDG uptake and its modification with corticosteroid in a granuloma rat model: an experimental study for differentiating granuloma from tumors. Eur J Nucl Med Mol Imaging 34: 2096–2105. doi:10.1007/s00259-007-0529-8.
[35]
Shibuya K, Yoshida E, Nishikido F, Suzuki T, Tsuda T, et al. (2007) Limit of Spatial Resolution in FDG-PET due to Annihilation Photon Non-Collinearity. World Congress on Medical Physics and Biomedical Engineering 2006. pp. 1667–1671. Available: http://dx.doi.org/10.1007/978-3-540-3684？1-0_411. Accessed 11 Feb 2010.
[36]
Machado-Silva JR, Galv？o C, de Oliveira RM, Presgrave OA, Gomes DC (1995) Schistosoma mansoni Sambon, 1907: comparative morphological studies of some Brazilian strains. Rev Inst Med Trop Sao Paulo 37: 441–447. doi: 10.1590/S0036-46651995000500010
[37]
Panin VY, Kehren F, Michel C, Casey M (2006) Fully 3-D PET reconstruction with system matrix derived from point source measurements. IEEE Trans Med Imaging 25: 907–921. doi: 10.1109/TMI.2006.876171
