Evaluation of Early Stage Immun Response in Experimental Chronic Toxoplasmosis Model

Öz

Encephalitic toxoplasmosis caused by Toxoplasma gondii is a disease that can cause death in immunocomprimised patient. Since experimental human studies are limited, experimental murine models are the most functional way for enlightening the mechanism of the host- pathogen interactions. C57BL/ 6 mice are susceptible for the toxoplasmosis compared the other mouse species. They may develop encephalitic toxoplasmosis without any immunocomprimised disease. Therefore, they generally infected with T. gondii for the host- pathogen interaction and immunopathogenesis studies. In present study, we investigate the role of the pro-inflammatory cytokines such as Interleukin- 12 IL-12 , Interferon-γ IFN-γ and Tumor Necrosis Factor-α TNF-α in ME49 infected C57BL/6 mice. ME49 infected mice sacrified at post-infection 30 days, then histopathological and immunoperoxidase tests applied for the cytokines and T. gondii antigen. Thus, there were T. gondii immunopositivity detected in cortex, amygdala, hippocampus, striatum and substantia nigra. IL-12, IFN-γ and TNF-α expressions showed correlation in those examined areas. In this context, it is thought that Type I proinflammatory cytokin levels are prominently increased during the early stage of encephalitic toxoplasmosis.

Anahtar Kelimeler

• Kırıkkale University,Faculty of VeterinaryMedicine,Department of Pathology,Kırıkkale,Turkey

Kronik Toksoplazmoz Modelinde Erken Dönem Bağışıklık Yanıtının Değerlendirilmesi

Öz

Ensefalitik toksoplazmoz, Toxoplasma gondii tarafından oluşturulan, ölümcül sonuçları olabilen ve özellikle de immun-baskılanmış bireylerin etkilendiği bir hastalıktır. Ancak insan çalışmalarının sınırlı olmasından dolayı konak- patojen ilişki mekanizmasının aydınlatılması için en iyi alternatif, deneysel fare çalışmaları olmaktadır. C57BL/6 fareler toksoplazmoza duyarlıdır ve T. gondii ile oluşan enfeksiyonlarında herhangi bir immun baskılayıcı etkiye maruz kalmadan da ensefalitik toksoplazmoz geliştirebilirler. Bu nedenle de özellikle T. gondii’ nin ME49 gibi tip II suşlarıyla oluşturulan immunopatogenez ve mekanizma çalışmalarında tercih edilmektedirler. Sunulan bu çalışmada; proinflamatuar sitokinler; İnterleukin- 12 IL-12 , İnterferon-γ IFN-γ ve Tümör Nekrozis Faktör-α TNF-α ’ nın, ME49 suşuyla enfekte edilmiş C57BL/ 6 farelerde görülen ensefalitik toksoplazmozdaki rolü araştırılmıştır. Bunun için, enfekte fareler enfeksiyonun 30. gününde sakrifiye edilmiş, hem histopatolojik hem de immunoperoksidaz testler uygulanmıştır. Sonuç olarak, yapılan ayrı ayrı boyamalarda; beyin korteks, amigdala, striatum ve substantia nigradaki T. gondii immunopozitiflikleriyle, IL-12, IFN-γ ve TNF-α sitokin ekspresyonlarının birbirleriyle korelasyon içinde olduğu gösterilmiştir. Sonuç olarak, bu çalışmada elde edilen bulgular, beyinde tip I proinflamatuar sitokinlerin T.gondii enfeksiyonunun erken aşamasında artış gösterdiklerini ortaya koymaktadır. Dipnot: Bu çalışma, çalışmayla Kırıkkale Üniversitesi Sağlık Bilimleri Enstitüsü “FARELERDE KRONİK ENSEFALİTİK Toxoplasma gondii Enfeksiyonunda, Konak-Parazit İlişkisi Ve Konak İmmun Yanıtının Fonksiyonel Nöropatoloji İle Araştırılması” adlı doktora tez çalışmasının ön bulgularını kapsamaktadır ve Kırıkkale Üniversitesi Bilimsel Araştırma Projeleri Birimi, Proje No:2016/ 040 ile desteklenmiştir.

Anahtar Kelimeler

• Toxoplasma gondii,ensefalitik toksoplazmoz,IL-12,IFN-γ,TNF-α

Kaynakça

1. Andrade RM, Wessendarp M, Gubbels MJ, STRIEPEN B, Subauste CS (2006). CD40 induces macrophage anti-Toxoplasma gondii activity by triggering autophagy-dependent fusion of pathogen-containing vacuoles and lysosomes. J Clin Invest, 116, 2366–2377.
2. Araujo FG, Slifer T (2003). Different strains of Toxoplasma gondii induce different cytokine responses in CBA/Ca mice, Infect. Immun, 71, 4171–4174.
3. Atmaca HT, Kul O, Karakus E, Terzi OS, Canpolat S, Anteplioglu T (2014). Astrocytes, microglia/macrophages, and neurons expressing Toll- like receptor 11 contribute to innate immunity against encephalitic Toxoplasma gondii infection. Neuroscience, 269, 184-191.
4. Barr BC, Anderson ML, Blanchard PC, Daft BM, Kinde H, Conrad PA (1990). Bovine fetal encephalitis and myocarditis associated with protozoal infections. Veterinary Pathology, 27, 354-361.
5. Chardes T, Buzoni-Gatel D, Lepage A, Bernard F, Bout D (1994). Toxoplasmagondii oral infection induces specific cytotoxic CD8_/_+ Thy-1+ gutintraepithelial lymphocytes, lytic for parasite-infected enterocytes. J Immunol,153, 4596–603.
6. Denkers EY, Gazzinelli RT (1998). Regulation and function of T-cell- mediated immunity during Toxoplasma gondii infection. Clin Microbiol Rev, 11, 569-588.
7. Dubey JP (1997). Tissue cyst tropism in Toxoplasma gondii: a comparison of tissue cyst formation in organs of cats, and rodents fed oocysts. Parasitology, 115, 15–20
8. Dubey JP (1998). Advances in the life cycle of Toxoplasma gondii. Int J Parasitol, 28, 1019–1024.

9. Dubey JP (2010). Toxoplasmosis of Animals and Humans, 2nd ed, CRC Press Taylor & Francis Group, Beltsville, Maryland, USA, p: 1-29.
10. Dubey JP, Navarro IT, Sreekumar C, Dahl E, Freire RL, Kawabata HH, Vianna MC, Kwok OC, Shen SK, Thulliez P, Lehmann T. (2004). Toxoplasma gondii infections in cats from Parana, Brazil: seroprevalence, tissue distribution, and biologic and genetic characterization of isolates. J. Parasitol, 90, 721–726.
11. Dupont CD, Christian DA, Hunter CA (2012). Immune response and immunopathology during toxoplasmosis. Semin Immunopathol, 34, 793–813.
12. Frenkel JK, Dubey JP, Miller NL (1970). Toxoplasma gondii in cats: fecal stages identified as coccidian oocysts. Science, 167, 893–896.
13. Gaddi PJ AND Yap GS (2007) Cytokine regulation of immunopathology in toxoplasmosis. Immunol Cell Biol, 85, 155-159.
14. Gazzinelli RT, Wysocka M, Hayashi S, Denkers EY, Hieny S, Caspar P, Trinchieri G, Sher A (1994). Parasite-induced IL-12 stimulates early IFN-gamma synthesis and resistance during acute infection with Toxoplasma gondii. J Immunol, 153, 2533–2543.
15. Hermes G, Ajoka JW, Kelly KA, Mui E, Roberts F, Kasza K, Mayr T, Kirisits MJ, Wollmann R, Ferguson DJ, Roberts CW, Hwang JH, Trendler T, Kennan RP, Suzuki Y, Reardon C, Hickey WF, Chen L, Mcleod R (2008). Neurological and behavioral abnormalities, ventricular dilatation, altered cellular functions, inflammation, and neuronal injury in brains of mice due to common, persistent, parasitic infection. J Neuroinflammation, 5, 48..
16. Hunter CA, Roberts CW, Murray M, Alexander J (1992). Detection of cytokine mRNA in the brains of mice with toxoplasmic encephalitis. Parasite Immunol, 14, 405–413.
17. Hunter CA, Subauste CS, Van Cleave VH, Remington JS (1994). Production of gamma interferon by natural killer cells from Toxoplasma gondii-infected SCID mice: regulation by interleukin-10, interleukin-12, and tumor necrosis factor alpha. Infect Immun, 62, 2818–2824.
18. Jacobs L, Moyle GG, RIS RR (1963). The prevalence of toxoplasmosis in New Zealand sheep and cattle. Am. J. Vet. Res, 24, 673–675.
19. Jones JL, Hanson DL, Chu SY, Ciesielski CA, Kaplan JE, Ward JW, Navin TR (1996). Toxoplasmic encephalitis in HIV-infected persons: Risk factors and trends. AIDS, 10, 1393–1399.
20. Kawai T, Akira S (2006). TLR signaling. Cell Death Differ, 13, 816-825.
21. Kocak OM, Atmaca HT, Terzi OS, Buyukkayaer S, Ozdemir H, Uzunalioglu T, Dincel GC, Bal E, Kul O (2012). Experimental Chronic Toxoplasmosis Model in Mice: Brain Lesions and Related Behavioral Changes, Archives of Neuropsychiatry, 49, 139-144.
22. Lieberman LA, Hunter CA (2002). The role of cytokines and their signaling pathways in the regulation of immunity to Toxoplasma gondii. Int Rev Immunol, 21, 373–403.
23. Lindsay DS, Dubey JP (2014). Toxoplasmosis in wild and domestic animals In: Toxoplasma gondii: the model apicomplexan. Ed. LM WEISS, K KIM, 2nd ed, Elsevier, Amsterdam. The Netherlands, p: 194-209.
24. Luder CG, Lang C, Giraldo-Velasquez M, Algner M, Gerdes J, Groszs U (2003). Toxoplasma gondii inhibits MHC class II expression in neural antigen-presenting cells by down-regulating the class II transactivator CIITA. J Neuroimmunol,134, 12–24.
25. Montoya JG, Liesenfeld O (2004). Toxoplasmosis. Lancet, 363, 1965- 1976.
26. Mordue DG, Sibley LD (2003). A novel population of Gr-1+-activated macrophagesinduced during acute toxoplasmosis. J Leukoc Biol,74, 1015-1025.
27. Mosmann TR, Cherwinskih H, Bond MW, Giedlin MA, Coffman RL (1986). Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J. Immunol, 136, 2348 –2357.
28. Nash PB, Purner MB, Leon RP, Clarke P, Duke RC, Curiel TJ (1998). Toxoplasma gondii-infected cells are resistant to multiple inducers of apoptosis. J Immunol,160, 1824–30.
29. Opal SV, Depalo VA (2000). Anti-Inflammatory Cytokines. CHEST 117, 1162–1172.
30. Parlog A, Schluter D, Dunay IR (2015). Toxoplasma gondii-induced neuronal alterations. Parasite Immunol, 37, 159–170.
31. Schade B, Fischer HG (2001). Toxoplasma gondii induction of interleukin- 12is associated with acute virulence in mice and depends on the host genotype. Vet. Parasitol, 100, 63–74.
32. Sibley LD, Adams LB, Fukutomi Y, Krahenbuhl JL (1991). Tumor necrosis factor-alpha triggers antitoxoplasmal activity of IFN-gamma primed macrophages, J Immunol, 147, 2340–2345.
33. Sukthana Y (2006). Toxoplasmosis: beyond animals to humans. Trends Parasitol, 22, 137–42.
34. Suzuki Y (2002). Immunopathogenesis of cerebral toxoplasmosis. J Infect Dis, 186, 234– 240.
35. Wilson EH, Hunter C (2004). The role of astrocytes in the immunopathogenesis of toxoplasmic encephalitis. Int J Parasitol, 34, 543–548.