Development of experimental models of reactivated toxoplasmosis
Abstract
Toxoplasmosis is one of the most widespread zoonosis worldwide, since Toxoplasma gondii is a ubiquitous obligate intracellular protozoan parasite that infects up to one third of the human population. Although infection is usually asymptomatic in immunocompetent individuals, in vulnerabile categories such as the fetus and immunocompromised patients, toxoplasmosis can lead to severe consequences, in particular congenital and reactivated toxoplasmosis (RT). HAART and global increase in the number of immunocompromised patients undergoing organ and tissue transplantations, in which toxoplasmosis represents important opportunistic infection, shifted the focus of interest from HIV+ patients to transplant recipients. There is an urgent need for identifying novel potent and well-tolerated drugs, since available options for toxoplasmosis chemotherapy are limited, and associated with numerous side effects. Although potential chemotherapeutics are also investigated in vitro, results obtained in in vivo experimental models provide more valuable data. Iatrogenic immunosuppression in mice chronically infected with T. gondii is mostly based on administration of corticosteroids, such as dexamethasone in drinking water and hydrocortisone via subcutaneous injections. In addition, some models involve the use of cytostatics, mainly cyclophosphamide, which is among the most commonly used immunosuppressants in transplantation protocols. Large variations in dosing of immunosuppressants in models of RT call for their optimization. Cytostatics and corticosteroids, applied simultaneously in adequate doses and intervals would allow for simulation of the most frequently applied immunosuppressive regimens in human transplantation medicine. Although there is a variety of in vivo models of toxoplasmosis, a current trend of exponential increase in population of transplant recipients requires a better insight into possible ways of establishing a model of RT. Establishment of a sustainable model of RT would be of great importance in future studies focused on T. gondii infection, and above all, for conducting chemotherapy experiments oriented towards discovery of potential new candidates for the treatment of toxoplasmosis.
References
1. Montoya JG, Liesenfeld O. Toxoplasmosis. Lancet. 2004; 363(9425):1965–76.
2. Howe DK, Sibley LD. Toxoplasma gondii comprises three clonal lineages: correlation of parasite genotype with human disease. J Infect Dis. 1995; 172(6):1561-6.
3. Uzelac A, Klun I, Ćirković V, Bauman N, Bobić B, Štajner T, et al. Toxoplasma gondii genotypes circulating in Serbia-insight into the population structure and diversity of the species in Southeastern Europe, a region of intercontinental strain exchange. Microorganisms. 2021; 9(12):2526.
4. Dubey JP. Advances in the life cycle of Toxoplasma gondii. Int J Parasitol. 1998; 28(7):1019–24.
5. Weiss LM, Dubey JP. Toxoplasmosis: a history of clinical observations. Int J Parasitol. 2009; 39(8):895-901.
6. Remington JS, McLeod R, Thulliez P, Desmonts G. Toxoplasmosis. In: Remington JS, Klein J, editors. Infectious diseases of the fetus and newborn infant. 5th ed. Philadelphia, PA: WB Saunders; 2001. p.205-346.
7. Desmonts G, Couvreur J. Congenital toxoplasmosis. A prospective study of 378 pregnancies. N Engl J Med. 1974; 290(20):1110-6.
8. Passweg JR, Baldomero H, Bader P, Bonini C, Cesaro S, Dreger P, et al. Hematopoietic stem cell transplantation in Europe 2014: more than 40 000 transplants annually. Bone Marrow Transplant. 2016; 51(6):786-92.
9. Robert-Gangneux F, Sterkers Y, Yera H, Accoceberry I, Menotti J, Cassaing S, et al. Molecular diagnosis of toxoplasmosis in immunocompromised patients: a 3-year multicenter retrospective study. J Clin Microbiol. 2015; 53(5):1677-84.
10. Gajurel K, Dhakal R, Montoya JG. Toxoplasma prophylaxis in haematopoietic cell transplant recipients: a review of the literature and recommendations. Curr Opin Infect Dis. 2015; 28(4):283-92.
11. Robert-Gangneux F, Meroni V, Dupont D, Botterel F, Garcia JMA, Brenier-Pinchart MP, et al. Toxoplasmosis in transplant recipients, Europe, 2010-2014. Emerg Infect Dis. 2018; 24(8):1497-504.
12. Štajner T, Vujić D, Srbljanović J, Bauman N, Zečević Ž, Simić M, et al. Risk of reactivated toxoplasmosis in haematopoietic stem cell transplant recipients: a prospective cohort study in a setting withholding prophylaxis. Clin Microbiol Infect. 2022; 28(5):733.e1-733.e5.
13. Štajner T, Nestorović E, Jovanović S, Dakić Z, Srbljanović J, Terzić D, et al. Molecular monitoring of Toxoplasma infection after orthotopic heart transplantation. 15th International Congress of Parasitology; 2022 Aug 21-26; Copenhagen, Denmark; Abstract book (O057 / #1307)
14. Dunay IR, Gajurel K, Dhakal R, Liesenfeld O, Montoya JG. Treatment of toxoplasmosis: historical perspective, animal models, and current clinical practice. Clin Microbiol Rev. 2018; 31(4):e00057-17.
15. Shammaa AM, Powell TG, Benmerzouga I. Adverse outcomes associated with the treatment of Toxoplasma infections. Sci Rep. 2021; 11(1):1035.
16. Silva LA, Reis-Cunha JL, Bartholomeu DC, Vítor RW. Genetic polymorphisms and phenotypic profiles of sulfadiazine-resistant and sensitive Toxoplasma gondii isolates obtained from newborns with congenital toxoplasmosis in Minas Gerais, Brazil. PLoS One. 2017; 12(1):e0170689.
17. Villena I, Aubert D, Leroux B, Dupouy D, Talmud M, Chemla C, et al. Pyrimethamine-sulfadoxine treatment of congenital toxoplasmosis: follow-up of 78 cases between 1980 and 1997. Reims Toxoplasmosis Group. Scand J Infect Dis. 1998; 30(3):295-300.
18. Konstantinović N, Guegan H, Štajner T, Belaz S, Robert-Gangneux F. Treatment of toxoplasmosis: current options and future perspectives. Food Waterborne Parasitol. 2019; 15:e00036.
19. Szabo EK, Finney CAM. Toxoplasma gondii: one organism, multiple models. Trends Parasitol. 2017; 33(2):113-27.
20. Watson GF, Davis PH. Systematic review and meta-analysis of variation in Toxoplasma gondii cyst burden in the murine model. Exp Parasitol. 2019; 196:55-62.
21. Saraf P, Shwab EK, Dubey JP, Su C. On the determination of Toxoplasma gondii virulence in mice. Exp Parasitol. 2017; 174:25-30.
22. Djurković-Djaković O, Nikolić T, Robert-Gangneux F, Bobić B, Nikolić A. Synergistic effect of clindamycin and atovaquone in acute murine toxoplasmosis. Antimicrob Agents Chemother. 1999; 43(9):2240-4.
23. Ferreira RA, Oliveira AB, Gualberto SA, Vitor RW. Activity of natural and synthetic naphthoquinones against Toxoplasma gondii, in vitro and in murine models of infection. Parasite. 2002; 9(3):261-9.
24. Ferreira RA, Oliveira AB, Ribeiro MF, Tafuri WL, Vitor RW. Toxoplasma gondii: in vitro and in vivo activities of the hydroxynaphthoquinone 2-hydroxy-3-(1'-propen-3-phenyl)-1,4-naphthoquinone alone or combined with sulfadiazine. Exp Parasitol. 2006; 113(2):125-9.
25. Mui EJ, Schiehser GA, Milhous WK, Hsu H, Roberts CW, Kirisits M, et al. Novel triazine JPC-2067-B inhibits Toxoplasma gondii in vitro and in vivo. PLoS Negl Trop Dis. 2008; 2(3):e190.
26. Doggett JS, Nilsen A, Forquer I, Wegmann KW, Jones-Brando L, Yolken RH, et al. Endochin-like quinolones are highly efficacious against acute and latent experimental toxoplasmosis. Proc Natl Acad Sci U S A. 2012; 109(39):15936-41.
27. El-Zawawy LA, El-Said D, Mossallam SF, Ramadan HS, Younis SS. Preventive prospective of triclosan and triclosan-liposomal nanoparticles against experimental infection with a cystogenic ME49 strain of Toxoplasma gondii. Acta Trop. 2015; 141(Pt A):103-11.
28. El-Zawawy LA, El-Said D, Mossallam SF, Ramadan HS, Younis SS. Triclosan and triclosan-loaded liposomal nanoparticles in the treatment of acute experimental toxoplasmosis. Exp Parasitol. 2015; 149:54-64.
29. Opsenica DM, Radivojević J, Matić IZ, Štajner T, Knežević-Ušaj S, Djurković-Djaković O, et al. Tetraoxanes as inhibitors of apicomplexan parasites Plasmodium falciparum and Toxoplasma gondii growth and anti-cancer molecules. J Serb Chem Soc. 2015; 80(11):1339–59.
30. Johnson LL. SCID mouse models of acute and relapsing chronic Toxoplasma gondii infections. Infect Immun. 1992; 60(9):3719-24.
31. Rutaganira FU, Barks J, Dhason MS, Wang Q, Lopez MS, Long S, et al. Inhibition of calcium dependent protein kinase 1 (CDPK1) by pyrazolopyrimidine analogs decreases establishment and reoccurrence of central nervous system disease by Toxoplasma gondii. J Med Chem. 2017; 60(24):9976-89.
32. Suzuki Y, Kang H, Parmley S, Lim S, Park D. Induction of tumor necrosis factor-alpha and inducible nitric oxide synthase fails to prevent toxoplasmic encephalitis in the absence of interferon-gamma in genetically resistant BALB/c mice. Microbes Infect. 2000; 2(5):455-62.
33. Dunay IR, Chan WC, Haynes RK, Sibley LD. Artemisone and artemiside control acute and reactivated toxoplasmosis in a murine model. Antimicrob Agents Chemother. 2009; 53(10):4450-6.
34. Schöler N, Krause K, Kayser O, Müller RH, Borner K, Hahn H, et al. Atovaquone nanosuspensions show excellent therapeutic effect in a new murine model of reactivated toxoplasmosis. Antimicrob Agents Chemother. 2001; 45(6):1771-9.
35. Dunay IR, Heimesaat MM, Bushrab FN, Müller RH, Stocker H, Arasteh K, et al. Atovaquone maintenance therapy prevents reactivation of toxoplasmic encephalitis in a murine model of reactivated toxoplasmosis. Antimicrob Agents Chemother. 2004; 48(12):4848-54.
36. Silva LA, Brandão GP, Pinheiro BV, Vitor RW. Immunosuppression with cyclophosphamide favors reinfection with recombinant Toxoplasma gondii strains. Parasite. 2012; 19(3):249-57.
37. Huo XX, Wang L, Chen ZW, Chen H, Xu XC, Zhang AM, et al. Preventive effect of pidotimod on reactivated toxoplasmosis in mice. Parasitol Res. 2013; 112(8):3041-51.
38. Zhang YH, Chen H, Chen Y, Wang L, Cai YH, Li M, et al. Activated microglia contribute to neuronal apoptosis in Toxoplasmic encephalitis. Parasit Vectors. 2014; 7:372.
39. Mahmoud ME, Ihara F, Fereig RM, Nishimura M, Nishikawa Y. Induction of depression-related behaviors by reactivation of chronic Toxoplasma gondii infection in mice. Behav Brain Res. 2016; 298(Pt B):125-33.
40. Mokua Mose J, Muchina Kamau D, Kagira JM, Maina N, Ngotho M, Njuguna A, et al. Development of neurological mouse model for toxoplasmosis using Toxoplasma gondii isolated from chicken in Kenya. Patholog Res Int. 2017; 2017:4302459.
41. Hofflin JM, Conley FK, Remington JS. Murine model of intracerebral toxoplasmosis. J Infect Dis. 1987; 155(3):550-7.
42. Nicoll S, Wright S, Maley SW, Burns S, Buxton D. A mouse model of recrudescence of Toxoplasma gondii infection. J Med Microbiol. 1997; 46(3):263-6.
43. Djurković-Djaković O, Milenković V. Murine model of drug induced reactivation of Toxoplasma gondii. Acta Protozool. 2001; 40(2):99–106.
44. Kang KN, Choi IU, Shin DW, Lee YH. Cytokine and antibody responses of reactivated murine toxoplasmosis upon administration of dexamathasone. Korean J Parasitol. 2006; 44(3):209-19.
45. Dellacasa-Lindberg I, Hitziger N, Barragan A. Localized recrudescence of Toxoplasma infections in the central nervous system of immunocompromised mice assessed by in vivo bioluminescence imaging. Microbes Infect. 2007; 9(11):1291-8.
46. Takashima Y, Suzuki K, Xuan X, Nishikawa Y, Unno A, Kitoh K. Detection of the initial site of Toxoplasma gondii reactivation in brain tissue. Int J Parasitol. 2008; 38(5):601-7.
47. Djurković-Djaković O, Milenković V, Nikolić A, Bobić B, Grujić J. Efficacy of atovaquone combined with clindamycin against murine infection with a cystogenic (Me49) strain of Toxoplasma gondii. J Antimicrob Chemother. 2002; 50(6):981-7.
48. Sumyuen MH, Garin YJ, Derouin F. Effect of immunosuppressive drug regimens on acute and chronic murine toxoplasmosis. Parasitol Res. 1996; 82(8):681-6.
49. Carreras E, Dufour C, Mohty M, Kröger N, editors. The EBMT handbook: hematopoietic stem cell transplantation and cellular therapies. 7th ed. Cham (CH): Springer; 2019.
50. Chu E, Sartorelli AC. Cancer chemotherapy. In: Katzung BG, editor. Basic and clinical pharmacology. 9th ed. New York: Mc Graw Hill; 2004. p.898-930.
51. Zuluaga AF, Salazar BE, Rodriguez CA, Zapata AX, Agudelo M, Vesga O. Neutropenia induced in outbred mice by a simplified low-dose cyclophosphamide regimen: characterization and applicability to diverse experimental models of infectious diseases. BMC Infect Dis. 2006; 6:55.
52. Huyan XH, Lin YP, Gao T, Chen RY, Fan YM. Immunosuppressive effect of cyclophosphamide on white blood cells and lymphocyte subpopulations from peripheral blood of Balb/c mice. Int Immunopharmacol. 2011; 11(9):1293-7.
53. McConkey CA, Delorme-Axford E, Nickerson CA, Kim KS, Sadovsky Y, Boyle JP, et al. A three-dimensional culture system recapitulates placental syncytiotrophoblast development and microbial resistance. Sci Adv. 2016; 2(3):e1501462.
54. Piñero J, Furlong LI, Sanz F. In silico models in drug development: where we are. Curr Opin Pharmacol. 2018; 42:111-21.
55. Lopes CS, Silva TL, de Almeida JCN, Costa LVS, Mineo TWP, Mineo JR. Transmission of Toxoplasma gondii infection due to bone marrow transplantation: validation by an experimental model. Front Med (Lausanne). 2019; 6:227.