Abstract
Cerebral malaria (CM) is a serious and often fatal complication of Plasmodium falciparum infections; however, the precise mechanisms leading to CM is poorly understood. Mouse malaria models have provided insight into the key events in pathogenesis of CM. T-cell immune response is known to play an important role in malaria infection, and members of the T-cell immunoglobulin- and mucin-domain-containing molecule (Tim) family have roles in T-cell-mediated immune responses. Tim-1 and Tim-3 are expressed on terminally differentiated Th2 and Th1 cells, respectively, and participate in the regulation of Th immune response. Until now, the role of Tim family proteins in Plasmodium infection remains unclear. In the present study, the mRNA levels of Tim-1, Tim-3, and some key Th1 and Th2 cytokines in the spleen of Kunming outbred mice infected with Plasmodium berghei ANKA (PbANKA) were determined using real-time polymerase chain reaction (qRT-PCR). Compared with uninfected controls, Tim-1 expression was significantly decreased in infected mice with CM at day 10 postinfection (p.i.) but significantly increased in infected mice with non-CM at day 22 p.i.; in contrast, Tim-3 expression was significantly increased in infected mice both with CM at day 10 p.i. and with non-CM at day 22 p.i. The expressions of IFN-γ, TNF-α, IL-10, and IL-12 were significantly increased but IL-4 was significantly decreased in infected mice with CM at days 10 p.i., whereas the expressions of IFN-γ, TNF-α, IL-4, IL-10, and TGF-β were significantly increased but IL-12 was significantly decreased in infected mice with non-CM at days 22 p.i. Furthermore, the expression of Tim-1 and Tim-3 could reflect Th2 and Th1 immune response in the spleen of PbANKA-infected mice, respectively. Our data suggest that PbANKA infection could inhibit the differentiation of T lymphocytes toward Th2 cells, promote the Th1 cell differentiation, and induce Th1-biased immune response in the early infective stage, whereas the infection could promote Th2 cell differentiation and induce Th2-biased immune response in the late infective stage. Our data indicate that both Tim-1 and Tim-3 may play a role in the process of PbANKA infection, which may represent a potential therapeutic target.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
References
Amante FH, Haque A, Stanley AC, Rivera FDEL, Randall L, Wilson YA, Yeo G, Pieper C, Crabb BS, de Koning-Ward TF, Lundie RJ, Good MF, Pinzon-Charry A, Pearson MS, Duke MG, McManus DP, Loukas A, Hill GR, Engwerda CR (2010) Immune-mediated mechanisms of parasite tissue sequestration during experimental cerebral malaria. J Immunol 185:3632–3642
de Kossodo S, Grau GE (1993) Profiles of cytokine production in relation with susceptibility to cerebral malaria. J Immunol 151:4811–4820
Engwerda C, Belnoue E, Grüner AC, Rénia L (2005) Experimental models of cerebral malaria. Curr Top Microbiol Immunol 297:103–143
Geng H, Zhang GM, Li D, Zhang H, Yuan Y, Zhu HG, Xiao H, Han LF, Feng ZH (2006) Soluble form of T cell Ig mucin 3 is an inhibitory molecule in T cell-mediated immune response. J Immunol 176:1411–1420
Gómez ND, Safeukui I, Adelani AA, Tewari R, Reddy JK, Rao S, Holder A, Buffet P, Mohandas N, Haldar K (2011) Deletion of a malaria invasion gene reduces death and anemia, in model hosts. PLoS One 6:e25477
Good MF, Xu H, Wykes M, Engwerda CR (2005) Development and regulation of cell-mediated immune responses to the blood stages of malaria: implications for vaccine research. Annu Rev Immunol 23:69–99
Grau GE, Fajardo LF, Piguet PF, Allet B, Lambert PH, Vassalli P (1987) Tumor necrosis factor (cachectin) as an essential mediator in murine cerebral malaria. Science 237:1210–1212
Helegbe GK, Yanagi T, Senba M, Huy NT, Shuaibu MN, Yamazaki A, Kikuchi M, Yasunami M, Hirayama K (2011) Histopathological studies in two strains of semi-immune mice infected with Plasmodium berghei ANKA after chronic exposure. Parasitol Res 108:807–814
Hunt NH, Grau GE (2003) Cytokines: accelerators and brakes in the pathogenesis of cerebral malaria. Trends Immunol 24:491–499
Jacobs P, Radzioch D, Stevenson MM (1996) A Th1-associated increase in tumor necrosis factor alpha expression in the spleen correlates with resistance to blood-stage malaria in mice. Infect Immun 64:535–541
Jash A, Kwon HK, Sahoo A, Lee CG, So JS, Kim J, Oh YK, Kim YB, Im SH (2011) Topical application of porcine placenta extract inhibits the progression of experimental contact hypersensitivity. J Ethnopharmacol 133:654–662
Jennings VM, Actor JK, Lal AA, Hunter RL (1997) Cytokine profile suggesting that murine cerebral malaria is encephalitis. Infect Immun 65:4883–4887
John CC, Bangirana P, Byarugaba J, Opoka RO, Idro R, Jurek AM, Wu B, Boivin MJ (2008) Cerebral malaria in children is associated with long-term cognitive impairment. Pediatrics 122:e92–e99
Jones LA, Roberts F, Nickdel MB, Brombacher F, McKenzie AN, Henriquez FL, Alexander J, Roberts CW (2010) IL-33 receptor (T1/ST2) signaling is necessary to prevent the development of encephalitis in mice infected with Toxoplasma gondii. Eur J Immunol 40:426–436
Ma N, Madigan MC, Chan-Ling T, Hunt NH (1997) Compromised blood–nerve barrier, astrogliosis, and myelin disruption in optic nerves during fatal murine cerebral malaria. Glia 19:135–151
Malaguarnera L, Musumeci S (2002) The immune response to Plasmodium falciparum malaria. Lancet Infect Dis 2:472–478
McIntire JJ, Umetsu DT, DeKruyff RH (2004) TIM-1, a novel allergy and asthma susceptibility gene. Springer Semin Immun 25:335–348
Nuchnoi P, Ohashi J, Kimura R, Hananantachai H, Naka I, Krudsood S, Looareesuwan S, Tokunaga K, Patarapotikul J (2008) Significant association between TIM1 promoter polymorphisms and protection against cerebral malaria in Thailand. Ann Hum Genet 72(Pt 3):327–336
Omer FM, Kurtzhals JA, Riley EM (2000) Maintaining the immunological balance in parasitic infections: a role for TGF-beta? Parasitol Today 16:18–23
Othoro C, Lal AA, Nahlen B, Koech D, Orago AS, Udhayakumar V (1999) A low interleukin-10 tumor necrosis factor-alpha ratio is associated with malaria anemia in children residing in a holoendemic malaria region in western Kenya. J Infect Dis 179:279–282
Patnaik JK, Das BS, Mishra SK, Mohanty S, Satpathy SK, Mohanty D (1994) Vascular clogging, mononuclear cell margination, and enhanced vascular permeability in the pathogenesis of human cerebral malaria. Am J Trop Med Hyg 51:642–647
Polder TW, Jerusalem CR, Eling WM (1991) Morphological characteristics of intracerebral arterioles in clinical (Plasmodium falciparum) and experimental (Plasmodium berghei) cerebral malaria. J Neurol Sci 101:35–46
Porta J, Carota A, Pizzolato GP, Wildi E, Widmer MC, Margairaz C, Grau GE (1993) Immunopathological changes in human cerebral malaria. Clin Neuropathol 12:142–146
Rennert PD (2003) Novel roles for TIM-1 in immunity and infection. Immunol Lett 141:28–35
Sánchez-Fueyo A, Tian J, Picarella D, Domenig C, Zheng XX, Sabatos CA, Manlongat N, Bender O, Kamradt T, Kuchroo VK, Gutiérrez-Ramos JC, Coyle AJ, Strom TB (2003) Tim-3 inhibits T helper type 1-mediated auto- and alloimmune responses and promotes immunological tolerance. Nat Immunol 4:1093–1101
Sarthou JL, Angel G, Aribot G, Rogier C, Dieye A, Toure Balde A, Diatta B, Seignot P, Roussilhon C (1997) Prognostic value of anti-Plasmodium falciparum-specific immunoglobulin G3, cytokines, and their soluble receptors in West African patients with severe malaria. Infect Immun 65:3271–3276
Serghides L, Kim H, Lu Z, Kain DC, Miller C, Francis RC, Liles WC, Zapol WM, Kain KC (2011) Inhaled nitric oxide reduces endothelial activation and parasite accumulation in the brain, and enhances survival in experimental cerebral malaria. PLoS One 6:e27714
Shang H, Wei H, Yue B, Xu P, Huang H (2009) Microsatellite analysis in two populations of Kunming mice. Lab Anim 43:34–40
Shear HL, Srinivasan R, Nolan T, Ng C (1989) Role of IFN-gamma in lethal and nonlethal malaria in susceptible and resistant murine hosts. J Immunol 143:2038–2044
Shibui A, Hozumi N, Shiraishi C, Sato Y, Iida H, Sugano S, Watanabe J (2009) CD4(+) T cell response in early erythrocytic stage malaria: Plasmodium berghei infection in BALB/c and C57BL/6 mice. Parasitol Res 105:281–286
Siddiqui AJ, Bhardwaj J, Puri SK (2012) mRNA expression of cytokines and its impact on outcomes after infection with lethal and nonlethal Plasmodium vinckei parasites. Parasitol Res 110:1517–1524
Su EW, Lin JY, Kane LP (2008) TIM-1 and TIM-3 proteins in immune regulation. Cytokine 44:9–13
WHO (2011) World malaria report 2011
Xu G, Cheng L, Lu L, Zhu Y, Xu R, Yao X, Li H (2008) Expression of T-cell immunoglobulin- and mucin-domain-containing molecule-1 (TIM-1) is increased in a mouse model of asthma and relationship to GATA-3. Life Sci 82:663–669
Zhao J, Endoh I, Hsu K, Tedla N, Endoh Y, Geczy CL (2011) S100A8 modulates mast cell function and suppresses eosinophil migration in acute asthma. Antioxid Redox Sign 14:1589–1600
Zhu C, Anderson AC, Kuchroo VK (2011) TIM-3 and its regulatory role in immune responses. Curr Top Microbiol 350:1–15
Acknowledgments
Research reported in this publication was supported in part by the Fogarty International Center of the National Institutes of Health under Award Number R01TW008151, the Divisions of Intramural Research at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, and the “111 Project” sponsored by the State Bureau of Foreign Experts and Ministry of Education of China (B12003 and B06016). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
Author information
Authors and Affiliations
Corresponding authors
Rights and permissions
About this article
Cite this article
Huang, B., Liu, M., Huang, S. et al. Expression of Tim-1 and Tim-3 in Plasmodium berghei ANKA infection. Parasitol Res 112, 2713–2719 (2013). https://doi.org/10.1007/s00436-013-3442-z
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00436-013-3442-z