Trichobilharzia regenti (Schistosomatidae) percutaneously infects birds and mammals and invades their central nervous system (CNS). Here, we characterized the peripheral immune response of infected mice and showed how it was influenced by the parasite-induced inflammation in the skin and the CNS. As revealed by flow cytometry, T cells expanded in the spleen and the CNS-draining lymph nodes 7-14 days post-infection. Both T-bet+ and GATA-3+ T cells were markedly elevated suggesting a mixed type 1/2 immune response. However, it dropped after 7 dpi most likely being unaffected by the neuroinflammation. Splenocytes from infected mice produced a high amount of IFN-γ and, to a lesser extent, IL-10, IL-4 and IL-17 after in vitro stimulation by cercarial homogenate. Nevertheless, it had only a limited capacity to alter the maturation status of bone marrow-derived dendritic cells (BMDCs), contrary to the recombinant T. regenti cathepsin B2, which also strongly augmented expression of Ccl5, Cxcl10, Il12a, Il33 and Il10 by BMDCs. Taken together, mice infected with T. regenti developed the mixed type 1/2 immune response, which was driven by the early skin inflammation rather than the late neuroinflammation. Parasite peptidases might play an active role in triggering the host immune response.

Department of Parasitology Faculty of Science Charles University Prague Czech Republic

Institute of Immunology and Microbiology 1st Faculty of Medicine Charles University and General University Hospital Prague Prague Czech Republic

Zobrazit více v PubMed

Finsterer J, Auer H. Parasitoses of the human central nervous system. J Helminthol. 2013;87(3):257-270.

Carson MJ, Doose JM, Melchior B, Schmid CD, Ploix CC. CNS immune privilege: hiding in plain sight. Immunol Rev. 2006;213(1):48-65.

Louveau A, Harris TH, Kipnis J. Revisiting the mechanisms of CNS immune privilege. Trends Immunol. 2015;36(10):569-577.

Klein RS, Hunter CA. Protective and pathological immunity during central nervous system infections. Immunity. 2017;46(6):891-909.

McSorley HJ, Maizels RM. Helminth infections and host immune regulation. Clin Microbiol Rev. 2012;25(4):585-608.

Verma A, Prasad KN, Cheekatla SS, Nyati KK, Paliwal VK, Gupta RK. Immune response in symptomatic and asymptomatic neurocysticercosis. Med Microbiol Immunol. 2011;200(4):255-261.

Arce-Sillas A, Álvarez-Luquín DD, Cárdenas G, et al. Interleukin 10 and dendritic cells are the main suppression mediators of regulatory T cells in human neurocysticercosis. Clin Exp Immunol. 2016;183(2):271-279.

Adalid-Peralta L, Fleury A, García-Ibarra TM, et al. Human neurocysticercosis: in vivo expansion of peripheral regulatory T cells and their recruitment in the central nervous system. J Parasitol. 2012;98(1):142-148.

Chavarría A, Roger B, Fragoso G, et al. Th2 profile in asymptomatic Taenia solium human neurocysticercosis. Microbes Infect. 2003;5(12):1109-1115.

Janecek E, Beineke A, Schnieder T, Strube C. Neurotoxocarosis: marked preference of Toxocara canis for the cerebrum and T. cati for the cerebellum in the paratenic model host mouse. Parasit Vectors. 2014;7(1):194.

Ruiz-Manzano RA, Hernández-Cervantes R, Del Río-Araiza VH, Palacios-Arreola MI, Nava-Castro KE, Morales-Montor J. Immune response to chronic Toxocara canis infection in a mice model. Parasite Immunol. 2019;41(12):e12672.

Hrádková K, Horák P. Neurotropic behaviour of Trichobilharzia regenti in ducks and mice. J Helminthol. 2002;76(2):137-141.

Mikeš L, Zídková L, Kašný M, Dvořák J, Horák P. In vitro stimulation of penetration gland emptying by Trichobilharzia szidati and T. regenti (Schistosomatidae) cercariae. Quantitative collection and partial characterization of the products. Parasitol Res. 2005;96(4):230-241.

Dolečková K, Kašný M, Mikeš L, et al. The functional expression and characterisation of a cysteine peptidase from the invasive stage of the neuropathogenic schistosome Trichobilharzia regenti. Int J Parasitol. 2009;39(2):201-211.

Kouřilová P, Syrůček M, Kolářová L. The severity of mouse pathologies caused by the bird schistosome Trichobilharzia regenti in relation to host immune status. Parasitol Res. 2004;93(1):8-16.

Kouřilová P, Hogg KG, Kolářová L, Mountford AP. Cercarial dermatitis caused by bird schistosomes comprises both immediate and late phase cutaneous hypersensitivity reactions. J Immunol. 2004;172(6):3766-3774.

Horák P, Mikeš L, Lichtenbergová L, Skála V, Soldánová M, Brant SV. Avian schistosomes and outbreaks of cercarial dermatitis. Clin Microbiol Rev. 2015;28(1):165-190.

Soldánová M, Selbach C, Kalbe M, Kostadinova A, Sures B. Swimmer’s itch: etiology, impact, and risk factors in Europe. Trends Parasitol. 2013;29(2):65-74.

Macháček T, Turjanicová L, Bulantová J, Hrdý J, Horák P, Mikeš L. Cercarial dermatitis: a systematic follow-up study of human cases with implications for diagnostics. Parasitol Res. 2018;117(12):3881-3895.

Lichtenbergová L, Lassmann H, Jones MK, Kolářová L, Horák P Trichobilharzia regenti: host immune response in the pathogenesis of neuroinfection in mice. Exp Parasitol. 2011;128(4):328-335.

Horák P, Dvořák J, Kolářová L, Trefil L Trichobilharzia regenti, a pathogen of the avian and mammalian central nervous systems. Parasitology. 1999;119(6):577-581.

Bulantová J, Macháček T, Panská L, et al. Trichobilharzia regenti (Schistosomatidae): 3D imaging techniques in characterization of larval migration through the CNS of vertebrates. Micron. 2016;83:62-71.

Macháček T, Panská L, Dvořáková H, Horák P. Nitric oxide and cytokine production by glial cells exposed in vitro to neuropathogenic schistosome Trichobilharzia regenti. Parasit Vectors. 2016;9(1):1-10.

Frey A, Di Canzio J, Zurakowski D. A statistically defined endpoint titer determination method for immunoassays. J Immunol Methods. 1998;221(1-2):35-41.

Foligne B, Zoumpopoulou G, Dewulf J, et al. A key role of dendritic cells in probiotic functionality. PLoS ONE. 2007;2(3):e313.

Fernandez EM, Valenti V, Rockel C, et al. Anti-inflammatory capacity of selected lactobacilli in experimental colitis is driven by NOD2-mediated recognition of a specific peptidoglycan-derived muropeptide. Gut. 2011;60(8):1050-1059.

Hrdý J, Zanvit P, Novotná O, Kocourková I, Žižka J, Prokešová L. Cytokine expression in cord blood cells of children of healthy and allergic mothers. Folia Microbiol (Praha). 2010;55(5):515-519.

Redpath SA, van der Werf N, MacDonald AS, Maizels RM, Taylora MD Schistosoma mansoni larvae do not expand or activate Foxp3+ regulatory T Cells during their migratory phase. Infect Immun. 2015;83(10):3881-3889.

Prendergast CT, Sanin DE, Cook PC, Mountford AP. CD4+ T cell hyporesponsiveness after repeated exposure to Schistosoma mansoni larvae is dependent upon interleukin-10. Infect Immun. 2015;83(4):1418-1430.

Sanin DE, Prendergast CT, Bourke CD, Mountford AP. Helminth infection and commensal microbiota drive early IL-10 production in the skin by CD4+ T cells that are functionally suppressive. PLOS Pathog. 2015;11(5):e1004841.

Winkel BMF, Dalenberg MR, de Korne CM, et al. Early induction of human regulatory dermal antigen presenting cells by skin-penetrating Schistosoma mansoni cercariae. Front Immunol. 2018;9:2510.

Finkelman FD, Katona IM, Mosmann TR, Coffman RL. IFN-gamma regulates the isotypes of Ig secreted during in vivo humoral immune responses. J Immunol. 1988;140(4):1022-1027.

Snapper CM, Finkelman FD, Paul WE. Regulation of IgG1 and IgE production by interleukin 4. Immunol Rev. 1988;102(1):51-75.

Nembrini C, Marsland BJ, Kopf M. IL-17-producing T cells in lung immunity and inflammation. J Allergy Clin Immunol. 2009;123(5):986-994.

Soloviova K, Fox EC, Dalton JP, Caffrey CR, Davies SJ. A secreted schistosome cathepsin B1 cysteine protease and acute schistosome infection induce a transient T helper 17 response. PLoS Negl Trop Dis. 2019;13(1):e0007070.

Allen JE, Sutherland TE, Rückerl D. IL-17 and neutrophils: unexpected players in the type 2 immune response. Curr Opin Immunol. 2015;34:99-106.

Gu Y, Yang J, Ouyang X, et al. Interleukin 10 suppresses Th17 cytokines secreted by macrophages and T cells. Eur J Immunol. 2008;38(7):1807-1813.

Sombetzki M, Koslowski N, Rabes A, et al. Host defense versus immunosuppression: unisexual infection with male or female Schistosoma mansoni differentially impacts the immune response against invading cercariae. Front Immunol. 2018;9:861.

Fischer FR, Luo Y, Luo M, Santambrogio L, Dorf ME. RANTES-induced chemokine cascade in dendritic cells. J Immunol. 2001;167(3):1637-1643.

Bonecchi R, Bianchi G, Bordignon PP, et al. Differential expression of chemokine receptors and chemotactic responsiveness of type 1 T helper cells (Th1s) and Th2s. J Exp Med. 1998;187(1):129-134.

Khan IA, MacLean JA, Lee FS, et al. IP-10 is critical for effector T cell trafficking and host survival in Toxoplasma gondii infection. Immunity. 2000;12(5):483-494.

Vasquez RE, Xin L, Soong L. Effects of CXCL10 on dendritic cell and CD4+ T-cell functions during Leishmania amazonensis infection. Infect Immun. 2008;76(1):161-169.

Yoneyama H, Narumi S, Zhang Y, et al. Pivotal role of dendritic cell-derived CXCL10 in the retention of T helper cell 1 lymphocytes in secondary lymph nodes. J Exp Med. 2002;195(10):1257-1266.

Cano A, Mattana A, Henriquez FL, Alexander J, Roberts CW. Acanthamoeba proteases contribute to macrophage activation through PAR1, but not PAR2. Parasite Immunol. 2019;41(2):e12612.

Bonnart C, Feuillet G, Vasseur V, Cenac N, Vergnolle N, Blanchard N. Protease-activated receptor 2 contributes to Toxoplasma gondii -mediated gut inflammation. Parasite Immunol. 2017;39(11):e12489.

Dvořáková H, Leontovyč R, Macháček T, et al. Isoforms of cathepsin B1 in neurotropic schistosomula of Trichobilharzia regenti differ in substrate preferences and a highly expressed catalytically inactive paralog binds cystatin. Front Cell Infect Microbiol. 2020;10:66.

Netea MG, Joosten LAB, Latz E, et al. Trained immunity: a program of innate immune memory in health and disease. Science. 2016;352(6284):427.

Quinn SM, Cunningham K, Raverdeau M, et al. Anti-inflammatory trained immunity mediated by helminth products attenuates the induction of T cell-mediated autoimmune disease. Front Immunol. 2019;10:1109.

MrgprA3 neurons drive cutaneous immunity against helminths through selective control of myeloid-derived IL-33

Winners vs. losers: Schistosoma mansoni intestinal and liver eggs exhibit striking differences in gene expression and immunogenicity

The neurotropic schistosome vs experimental autoimmune encephalomyelitis: are there any winners?

Suppression of the growth and metastasis of mouse melanoma by Taenia crassiceps and Mesocestoides corti tapeworms

The Impact of Escherichia coli Probiotic Strain O83:K24:H31 on the Maturation of Dendritic Cells and Immunoregulatory Functions In Vitro and In Vivo

Mechanisms of the host immune response and helminth-induced pathology during Trichobilharzia regenti (Schistosomatidae) neuroinvasion in mice

In Vitro Characterization of Gut Microbiota-Derived Commensal Strains: Selection of Parabacteroides distasonis Strains Alleviating TNBS-Induced Colitis in Mice

Nitric oxide debilitates the neuropathogenic schistosome Trichobilharzia regenti in mice, partly by inhibiting its vital peptidases