Original Article

Toxoplasma gondii Suppresses Th2-Induced by Trichinella spiralis Infection and Downregulates Serine Protease Genes Expression: A Critical Role in Vaccine Development


Background: Toxoplasma gondii coinfection can modify host immune responses and the severity and spread of other parasites. We investigated how T. gondii and Trichinella spiralis infections counter-regulate each other's immune responses.

Methods: The parasite burden, the expression of T. gondii rhoptry kinase ROP18 and T. spiralis putative serine protease (TsSP), the IgG1 and IgG2a responses, besides histopathological and immunohistochemical staining with iNOS and arginase were used to evaluate the dynamics of coinfection.

Results: Through their effects on host immune responsiveness, coinfection with T. gondii modified the virulence of T. spiralis infection. Coinfected animals with high and low doses of T. gondii demonstrated significant reductions in the T. spiralis burden of 75.2% and 68.2%, respectively. TsSP expression was downregulated in both groups by 96.2% and 86.7%, whereasROP18 expression was downregulated by only 6% and10.6%, respectively. In coinfected mice, elevated levels of T. gondii-specific IgG2a antibodies were detected. Th1 induced by T. gondii inhibits the Th2 response to T. spiralis in coinfected animals with high iNOS expression andlow-arginine1 expression.

Conclusion: T. gondii infection induces a shift toward a Th1-type immune response while suppressing a helminth-specific Th2 immune response, paving the way for developing novel vaccines and more efficient control strategies.

1. Labeaud AD, Malhotra I, King MJ, et al. Do antenatal parasite infections deval-ue childhood vaccination? PLoS Negl Trop Dis. 2009; 3 (5): e442.
2. Thumbi SM, Bronsvoort BMC, Poole EJ, et al. Parasite co-infections and their impact on survival of indigenous cattle. PLoS One. 2014; 9 (2): e76324.
3. Griffiths EC, Pedersen AB, Fenton A, et al. The nature and consequences of coinfection in humans. J Infect. 2011; 63 (3):200–206.
4. Cox FE. Concomitant infections, para-sites, and immune responses. Parasitol-ogy. 2001;122 (S1): S23–S38.
5. Babu S, Nutman TB. Immune responses to helminth infection. In: Rich RR, Fleisher TA, Shearer WT, Schroeder HW, Frew AJ, Weyand CM, eds. Clinical Immunology. 5th ed. Elsevier; 2019. p. 437–447.
6. Ashour DS. Trichinella spiralis immuno-modulation: An interactive multifactori-al process. Expert Rev Clin Immunol. 2013; 9 (7):669–675.
7. Ortega-Pierres G, Vaquero-Vera A, Fon-seca-Linan R, et al. Induction of protec-tion in murine experimental models against Trichinella spiralis: An up-to-date review. J Helminthol. 2015; 89 (5): 526–539.
8. Zhao Z, Sun HQ, Wei SS, et al. Multiple B-cell epitope vaccine induces a Staphy-lococcus enterotoxin B-specific IgG1 pro-tective response against MRSA infection. Sci Rep.2015; 5:12371.
9. Dubey, JP. The history of Toxoplasma gondii–the first 100 years. J Eukaryot Mi-crobiol.2008;55 (6): 467–475.
10. Bahia-Oliveira LM, da Silva JA, Peixoto-Rangel AL, et al. Host immune response to Toxoplasma gondii and Ascaris lumbri-coides in an endemic area: Evidence of parasite co-immunomodulation proper-ties influencing the outcome of both in-fections. Mem Inst Oswaldo Cruz. 2009; 104 (2): 273–280.
11. Owyang AM, Zaph C, Wilson EH, et al. Interleukin 25 regulates type 2 cytokine-dependent immunity and limits chronic inflammation in the gastrointestinal tract. J Exp Med. 2006; 203 (4): 843–849.
12. Mulcahy G, Joyce P, Dalton JP. Immu-nology of Fasciola hepatica infection. In: J.P. Dalton, ed. Fasciolosis;1999. p. 341–375.
13. Khan A, Taylor S, Ajioka JW, et al. Se-lection at a single locus leads to wide-spread expansion of Toxoplasma gondii lineages that are virulent in mice. PLoS Genet.2009; 5 (3): e1000404.
14. Sun GG, Song YY, Jiang P, et al. Char-acterization of a Trichinella spiralis puta-tive serine protease. Study of its poten-tial as sero-diagnostic tool. PLoS Negl Trop Dis. 2018; 12 (5): e0006485.
15. Nishi L, Santana PL, Evangelista FF, et al. Rosuvastatin reduced brain parasite burden in a chronic toxoplasmosis in vivo model and influenced the neuro-pathological pattern of ME-49 strain. Parasitology. 2020;147 (3): 303–309.
16. AbdelHamed EF, Mostafa NE, Fawzy EM, et al. The delayed death-causing nature of Rosmarinus officinalis leaf ex-tracts and their mixture within experi-mental chronic toxoplasmosis: Thera-peutic and prophylactic implications. Acta Tropica. 2021; 221:105992.
17. AbdelHamed EF, Mostafa NE, Saleh AA, et al. Artesunate loaded nanofiber and its combinations with spiramycin for treatment of murine toxoplasmosis. J Egypt Soc Parasitol. 2019; 49 (1): 135–144.
18. Li F, Wang ZQ, Cui J. Early detection by polymerase chain reaction of migra-tory Trichinella spiralis larvae in blood of experimentally infected mice. Food-borne Pathog Dis.2010; 7 (8):887–892.
19. Angkasekwinai P, Sodthawon W, Jeerawattanawart S, et al. ILC2s activat-ed by IL-25 promote antigen-specific Th2 and Th9 functions that contribute to the control of Trichinella spiralis infec-tion. PLoS One. 2017; 12 (9): e0184684.
20. Bruschi F, Bianchi C, Fornaro M, et al. Pinto B Matrix metalloproteinase (MMP)-2 and MMP-9 as inflammation markers of Trichinella spiralis and Trichinel-la pseudospiralis infections in mice. Para-sit Immunol. 2014; 36 (10): 540–549.
21. Kapel CMO, Gamble HR. Infectivity, persistence, and antibody response to domestic and sylvatic Trichinella spp. In experimentally infected pigs. Int J Para-sitol.2000; 30 (2):215–221.
22. Barakat AMA. Some diagnostic studies on male New Zealand rabbit experi-mentally infected with Toxoplasma gondii strain. Glob Vet. 2007; 1 (1):17–23.
23. Fux B, Nawas J, Khan A, et al. Toxoplas-ma gondii strains defective in oral transmission are also defective in de-velopmental stage differentiation. In-fect Immun.2007; 75 (5):2580–2590.
24. Sánchez V, de-la-Torre A, Gómez-Marín JE. Characterization of ROP18 alleles in human toxoplasmosis. Parasi-tol Int. 2014; 63 (2): 463–469.
25. Song YY, Zhang Y, Ren HN, et al. Characterization of a serine protease inhibitor from Trichinella spiralis and its participation in larval invasion of host’s intestinal epithelial cells. Parasites Vec-tors. 2018; 11: 499.
26. Yuan JS, Reed A, Chen F, Stewart CN. Statistical analysis of real-time PCR data. BMC Bioinform. 2006; 7:85.
27. Suvarna SK, Layton C, Bancroft JD. Bancroft’s theory and practice of histo-logical techniques. 7thed. 2013.
28. Cattoretti G, Becker MH, Key G, et al. Monoclonal antibodies against recom-binant parts of the Ki-67 antigen (MIB 1 and MIB 3) detect proliferating cells in microwave-processed formalin-fixed paraffin sections. J Pathol. 1992;168 (4): 357–363. doi:10.1002/path.1711680404
29. Hsu SM, Raine L, Fanger H. Use of avi-din-biotin-peroxidase complex (ABC) in immunoperoxidase techniques: A com-parison between ABC and unlabeled antibody (PAP) procedures. J Histo-chem Cytochem. I981; 29 (4):577–580.
30. Miller CMD, Smith NC, Ikin RJ, et al. Immunological interactions between 2 common pathogens, Th1-inducing pro-tozoan Toxoplasma gondii and the Th2-inducing Helminth Fasciola hepatica. PLoS One.2009; 4 (5): e5692.
31. Hoeve MA, Mylonas KJ, Fairlie-Clarke KJ, et al. Plasmodium chabaudi limits early Nippostrongylus brasiliensis-induced pul-monary immune activation and Th2 po-larization in co-infected mice. BMC Immunol. 2009; 10:60.
32. Karadjian G, Berrebi D, Dogna N, et al. Co-infection restrains Litomosoides sigmo-dont is filarial load and plasmodial P. yoelii but not P. chabaudi parasitaemia in mice. Parasite. 2014; 21:16.
33. Ahmed N, French T, Rausch S, et al. Hartmann S. Toxoplasma co-infection prevents Th2 differentiation and leads to a helminth-specific Th1 response. Front Cell Infect Microbiol. 2017; 7:341. doi:10.3389/fcimb.2017.00341
34. Kugler DG, Flomerfelt FA, Costa DL, et al. Systemic Toxoplasma infection trig-gers a long-term defect in the genera-tion and function of naive T lympho-cytes. J Exp Med. 2016; 213 (13): 3041–3056.
35. Lei T, Wang H, Liu J, et al. ROP18 is a key factor responsible for virulence dif-ference between Toxoplasma gondii and Neospora caninum. PLoS One. 2014; 9 (6): e99744.
36. Yi N, Yu P, Wu L, et al. RNAi-mediated silencing of Trichinella spiralis serpin-type serine protease inhibitors results in a reduction in larval infectivity. Vet Res.2020; 51: 139.
37. Meira CS, Pereira-Chioccola VL, Vidal JE, et al. Cerebral and ocular toxoplas-mosis related with IFN-γ, TNF-α, and IL-10 levels. Front Microbiol. 2014; 5: 492.
38. Munoz M, Liesenfeld O, Heimesaat MM. Immunology of Toxoplasma gondii. Im-munol. Rev.2011; 240 (1): 269–285.
39. Bokken GC, van Eerden E, Opsteegh M, et al. Specific serum antibody responses following a Toxoplasma gondii and Trichi-nella spiralis co-infection in swine. Vet Parasitol. 2012; 184 (2–4):126–132.
40. Xu F, Cheng R, Miao S, et al. Prior Tox-oplasma gondii infection ameliorates liver fibrosis induced by Schistosoma japonicum through inhibiting Th2 response and improving balance of intestinal flora in mice. Int J Mol Sci.2020; 21 (8): 2711.
41. Aliberti J. Host persistence: Exploitation of anti-inflammatory pathways by Toxo-plasma gondii. Nat Rev Immunol. 2005; 5 (2): 162–170.
42. Butcher BA, Fox BA, Rommereim LM, et al. Toxoplasma gondii rhoptry kinase ROP16 activates STAT3 and STAT6 re-sulting in cytokine inhibition and ar-ginase-1-dependent growth control. PLoSPathog.2011; 7 (9): e1002236.
43. Howe DK, Honoré S, Derouin F, et al. Determination of genotypes of Toxo-plasma gondii strains isolated from pa-tients with toxoplasmosis. J Clin Micro-biol.1997; 35 (6): 1411–1414.
IssueVol 18 No 2 (2023) QRcode
SectionOriginal Article(s)
DOI https://doi.org/10.18502/ijpa.v18i2.13183
Coinfection Toxoplasma gondii Trichinella spiralis Arginase1

Rights and permissions
Creative Commons License This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
How to Cite
Fakhry Abdel Hamed E, ElSayed Mostafa N, Fawzy E, Ibrahim M, Ibrahim B, Radwan M, Salama M. Toxoplasma gondii Suppresses Th2-Induced by Trichinella spiralis Infection and Downregulates Serine Protease Genes Expression: A Critical Role in Vaccine Development. Iran J Parasitol. 2023;18(2):172-181.