Activation of the MyD88 Pathway of Innate Immune Response to Recombinant BCG Malaria Vaccine Candidate: The Role of TLR-4
DOI:
https://doi.org/10.47430/ujmr.1832.015Keywords:
Malaria, vaccine, TLR-4, Immune response, MyD88, immunisation, macrophages, MSPAbstract
Malaria, a highly devastating disease caused by Plasmodium spp. puts half the world’s population at risk and has defied the ever-enhanced treatment, control and elimination strategies, necessitating the search for vaccine alternatives. A recombinant BCG (rBCG) expressing the merozoite surface protein 1C (MSP-1C) of Plasmodium falciparum was developed in our laboratory, which exhibited some immunomodulatory effects through undefined mechanisms likely activated by Toll-like receptor-4 (TLR-4). This study tested the hypothesis that TLR-4 mediates the attachment between rBCG and macrophages eliciting an immune response through the myeloid differentiation primary response 88 (MyD88) pathway. In this study, mice (n = 6 per group) were injected with PBS-T80, parent BCG or rBCG in the presence or absence of a TLR-4 inhibitor; TAK- 242 and western blot analysis carried out on the macrophages obtained to determine the role of TLR-4 in the activation of the MyD88. The results obtained showed a significant increase in the expression of the proteins in favour of the rBCG construct compared to the parent BCG and PBS- T80. These increase was significantly inhibited in the presence of TAK-242 signifying the role of TLR-4 in the activation MyD88 pathway of innate immune responses against recombinant BCG malaria vaccine candidate, presenting for the first time an empirical evidence of the importance of TLR-4/macrophage attachment mechanism and its effects as a fore-runner in the MyD88 pathway of immune response to our rBCG expressing the MSP-1C of P. falciparum.
Downloads
References
Ailian, Z., Yu, Y., Yan, W., Gan, Z., Xiumei, Y., Danyang, W. and Bin, W. (2017). Adjuvant-active aqueous extracts from Artemisia rupestris L. improve immune responses through TLR4 signaling pathway. Vaccine 35:1037-1045.
https://doi.org/10.1016/j.vaccine.2017.01.002
Akira, S. and Takeda, K. (2004). Toll-like receptor signaling. Nature Reviews Immunology 4:499-511.
https://doi.org/10.1038/nri1391
Aung, M. T., Aung, P. P., Jordi, L., Daniel, M. P. and Francois, H. N. (2017). Combating multidrug-resistant Plasmodium falciparum malaria. The FEBS Journal, 284:2569-2578.
https://doi.org/10.1111/febs.14127
Batool, S. M. (2015). Malaria in Pregnant Women. International Journal of Infection, 2(3). e22992.
https://doi.org/10.17795/iji22992
Bisseye, C., Yindom, L. M., Simporé, J., Morgan, W. D., Holder, A. A. and Ismaili, J. (2011). An engineered Plasmodium falciparum C-terminal 19kilodalton merozoite surface protein 1 vaccine candidate induces high levels of interferon-gamma production associated with cellular immune responses to specific peptide sequences in Gambian adults naturally exposed to malaria. Clinical and Experimental Immunology, 166(3):366-373.
https://doi.org/10.1111/j.1365-2249.2011.04467.x
Bridget, B., Giri, S. R., Mathew, J. G., Timothy, W. and Nicholas, M. A. (2017). World malaria report: time to acknowledge Plasmodium knowlesi malaria. Malaria Journal, 16:135.
https://doi.org/10.1186/s12936-017-1787-y
Bryant, C. E., Symmons, M. and Gay, N. J. (2015). Toll-like receptor signalling through macromolecular protein complexes. Molecular Immunology, 63(2):162-165.
https://doi.org/10.1016/j.molimm.2014.06.033
CDC (2009). Centers for Disease Control and Prevention Simian malaria in a U.S. traveller -New York. MMWR Morb. Mortal. Wkly Rep. 58(9):229-232.
CDC (2017a). Steven Glenn. Laboratory and consultation division.
CDC (2017b). Centre for Disease Control, December 20, 2017.
Chaohui, D., Li, S., Lihuai, Y., Guoqiang, Z., Shenglong, W. and Wenbin, B. (2016). Effects of porcine MyD88 knockdown on the expression of TLR4 pathway related genes and proinflammatory cytokines. Bioscience Reports.
Dan, W., Kun, T., Junjie, X., Shuyun, X., Yaowen, J., Quan, C. and Sirong, H. (2016). TAK-242 attenuates acute cigarette smoke-induced pulmonary inflammation in mouse via the TLR4/NF- κB signaling pathway. Biochemical and Biophysical Research Communications, 472(3):508-515
https://doi.org/10.1016/j.bbrc.2016.03.001
David, E. S., Catriona, T. P. and Adrian, P. M. (2015). IL-10 production in macrophages is regulated by a TLRdriven CREB- mediated mechanism that is linked to genes involved in cell metabolism. The Journal of Immunology 195(3):1218-1232.
https://doi.org/10.4049/jimmunol.1500146
Dhaniah, M., Rapeah, S. and Norazmi, M. N. (2014). Immunomodulatory effects of recombinant BCG expressing MSP-1C of Plasmodium falciparum on LPS- or LPS+IFN-γ-stimulated J774A.1 cells. Human Vaccinine and Immunotherapeutics, 10(7):1880-1891.
https://doi.org/10.4161/hv.28695
Djuardi, Y., Sartono, E., Wibowo, H., Supali, T. and Yazdanbakhsh, M. (2010). A longitudinal study of bcg vaccination in early childhood: the development of innate and adaptive immune responses. PLoS ONE, 5(11); e14066.
https://doi.org/10.1371/journal.pone.0014066
Dunne, A., Carpenter, S., Brikos, C., Gray, P., Strelow, A., Wesche, H., Morrice, N. and O'Neill, L. A. J. (2010). IRAK1 and IRAK4 promote phosphorylation ubiquitination and degradation of MyD88 adaptor-like (Mal). The Journal of Biological Chemistry, 285(24):18276-18282.
https://doi.org/10.1074/jbc.M109.098137
Fairhurst, R. M. and Dondorp, A. M. (2016). Artemisinin-resistant Plasmodium falciparum malaria. Microbiology Spectrum, 4(3).
https://doi.org/10.1128/microbiolspec.EI10-0013-2016
Feachem, R. and Sabot, O. (2008). A new global malaria eradication strategy. Lancet, 371:1633-1635.
https://doi.org/10.1016/S0140-6736(08)60424-9
Franklin, B. S., Rodrigues, S. O., Antonelli, L. R., Oliveira, R. V., Goncalves, A. M., Sales-Junior, P. A., Valente, E. P., Alvarez-Leite, J. I., Ropert, C., Golenbock, D. T. and Gazzinelli, R. T. (2007). MyD88-dependent activation of dendritic cells and CD4(+) T lymphocytes mediates symptoms but is not required for the immunological control of parasites during rodent malaria. Microbes and Infection, 9(7):881-890.
https://doi.org/10.1016/j.micinf.2007.03.007
Gill, R., Tsung, A. and Billiar, T. R. (2010). Linking oxidative stress to inflammation: Toll-like receptors. Free Radical Biology and Medicine, 48(9):1121-1132.
https://doi.org/10.1016/j.freeradbiomed.2010.01.006
Gowda, D. C. (2007). TLR-mediated cell signaling by malaria GPIs. Trends in Parasitology, 23(12):596-604.
https://doi.org/10.1016/j.pt.2007.09.003
Gun, S. Y., Claser, C., Tan, K. S. and Renia, L. (2014). Interferons and interferon regulatory factors in malaria. Mediators of Inflammation, 243713.
https://doi.org/10.1155/2014/243713
Hajebrahimi, B., Bagheri, M., Hassanshahi, G., Nazari, M., Bidaki, R., Khodadadi, H., Arababadi, M. K. and Kennedy, D. (2014). The adapter proteins of TLRs, TRIF and MYD88, are upregulated in depressed individual. International Journal of Psychiatry in Clinical Practices, 18(1):41-44
https://doi.org/10.3109/13651501.2013.859708
Hanson, M. S., Bansal, G. P., Langermann, S. Stover, C. K. and Orme, I. (1995). Efficacy and safety of live recombinant BCG vaccines. Developments in biological standardization. 84:229-236.
Kolanowski, S. T. H. M., Dieker, M. C., Lissenberg-Thunnissen, S. N., van, Schijndel, G. M. W., van, Ham, S. M. and Brinke, A. T. (2014). TLR4mediated pro- inflammatory dendritic cell differentiation in humans requires the combined action of MyD88 and TRIF. Innate Immunity, 20(4):423-430.
https://doi.org/10.1177/1753425913498626
Komai-Koma, M., Li, D., Wang, E., Vaughan, D. and Xu, D. (2014). Anti- toll-like receptor 2 and 4 antibodies suppress inflammatory response in mice. Immunology, 143(3):354-362.
https://doi.org/10.1111/imm.12312
Landstrom, M. (2010). The TAK1- TRAF6 signaling pathway. The International Journal of Biochemistry and Cell Biology, 42(5):585-589.
https://doi.org/10.1016/j.biocel.2009.12.023
Lee, M. S. and Kim, Y. J. (2007). Signaling pathways downstream of patternrecognition receptors and their cross talk Annual Review of Biochemistry, 76:447-480.
https://doi.org/10.1146/annurev.biochem.76.060605.122847
Lin, S.-C., Lo, Y.-C. and Wu, H. (2010). Helical assembly in the MyD88: IRAK4 :IRAK2 complex in TLR/IL-1R signaling. Nature, 465(7300):885-890.
https://doi.org/10.1038/nature09121
Lord, K. A., Hoffman-Liebermann, B., Liebermann, D. A. (1990). Nucleotide sequence and expression of a cDNA encoding MyD88, a novel myeloid differentiation primary response gene induced by IL-6 Oncogene, 5:10951097.
https://doi.org/10.1093/nar/18.9.2823
Mandavi, K. and Rajiv, K. S. (2011). Relative efficacy of uptake and presentation of Mycobacterium bovis BCG antigens by type I mouse lung epithelial cells and peritoneal macrophages. Infection and Immunity, 79(8):3159-3167.
https://doi.org/10.1128/IAI.05406-11
Medzhitov, R. and Janeway, C. Jr. (2002). innate immune recognition. Annual Review of Immunology, 20:197-216.
https://doi.org/10.1146/annurev.immunol.20.083001.084359
Min, S., Ye, R., Zizi, H., Mingjie, Z., Guanqun, H., Wenjing, T., Dengfa, Z. and Shengyuan, Y. (2018). Inhibition of tolllike receptor 4 alleviates hyperalgesia induced by acute dural inflammation in experimental migraine. Molecular Pain, 14:(1-10).
https://doi.org/10.1177/1744806918754612
Mukherjee, S., Mukherjee, S., Bhattacharya, S. and Sinha, B. S .P. (2017). Surface proteins of Setaria cervi induce inflammation in macrophage through toll-like receptor 4 (TLR4)-mediated signaling pathway. Parasite Immunology, 39: e12389.
https://doi.org/10.1111/pim.12389
Norazmi, M. N. and Dale, J. W. (1997). Cloning and expression of a candidate malarial epitope in bacille Calmette Guerin. Biotechnology Letters, 19(11):11351137.
https://doi.org/10.1023/A:1018405013737
Nurul, A. A. and Norazmi, M. N. (2011). Immunogenicity and in vitro protective efficacy of recombinant Mycobacterium bovis bacille Calmette Guerin (rBCG) expressing the 19 kDa merozoite surface protein-1 (MSP-1(19)) antigen of Plasmodium falciparum. Parasitology Research, 108(4):887-897.
https://doi.org/10.1007/s00436-010-2130-5
O'Donnell, R. A., de, Koning-Ward, T. F., Burt, R. A., Bockarie, M., Reeder, J. C., Cowman, A. F. and Crabb, B. S. (2001). Antibodies against merozoite surface protein (MSP)-1(19) are a major component of the invasion inhibitory response in individuals immune to malaria. Journal of Experimental Medicine, 193(12):1403-1412.
https://doi.org/10.1084/jem.193.12.1403
Peng, J., Zheng, H., Wang, X. and Cheng, Z. (2017). Upregulation of TLR4 via PKC activation contributes to impaired wound healing in high-glucose-treated kidney proximal tubular cells. PLoS ONE, 12(5): e0178147.
https://doi.org/10.1371/journal.pone.0178147
Peter, D. C., Susan, K. P. and Louis, H. M. (2010). Advances and challenges in malaria vaccine development. Journal of Clinical Investigation, 120(12):4168-4178.
https://doi.org/10.1172/JCI44423
Rapeah, S. and Norazmi, M. N. (2006). Immunogenicity of a recombinant Mycobacterium bovis bacille CalmetteGuèrin expressing malarial and tuberculosis epitopes. Vaccine, 24(17):3646-3653.
https://doi.org/10.1016/j.vaccine.2006.01.053
Rasheed, A., Areej, A., A. and Sardar, S. (2017). Palmitate induces interleukin-8 expression in human monocytic cells via TLR4/MyD88 dependent pathway. Journal of Immunology, 198(1):63.
https://doi.org/10.4049/jimmunol.198.Supp.63.16
Ray, A. and Dittel, B. N. (2010). Isolation of mouse peritoneal cavity cells. Journal of Visualized Experiments (35):1488.
https://doi.org/10.3791/1488-v
Rodrigues, L. C., Mangtani, P. and Abubakar, I. (2011). How does the level of BCG vaccine protection against tuberculosis fall over time? BMJ, 343:5974.
https://doi.org/10.1136/bmj.d5974
Rosadini, C. V. and Kagan, J. C. (2017). Early innate immune responses to bacterial LPS. Current Opinion in Immunology, 44:14-19.
https://doi.org/10.1016/j.coi.2016.10.005
Ryu, J. K., Kim, S. J., Rah, S. H., Kang, J. I., Jung, H. E., Lee, D., Lee, H. K., Lee, J. O., Park, B. S., Yoon, T. Y. and Kim, H. M. (2017). Reconstruction of LPS transfer cascade reveals structural determinants within LBP, CD14 and TLR4-MD2 for efficient LPS recognition and transfer. Immunity, 46(1):38-50.
https://doi.org/10.1016/j.immuni.2016.11.007
Si-Hao, D., Dong-Fang, Q., Chuan-Xiang, C., Si, C., Chao, L., , Zhoumeng, L., , Huijun, W. and Wei-Bing, X. (2017). Toll-Like receptor 4 mediates methamphetamine-induced neuroinflammation through caspase-11 signaling pathway in astrocytes. Frontiers in Molecular Neuroscience, 10: 409.
https://doi.org/10.3389/fnmol.2017.00409
Stover, C. K., de, la, Cruz, V. F., Fuerst, T. R., Burlein, J. E., Benson, L. A., Bennett, L. T., Bansal, G. P., Young, J. F., Lee, M. H., Hatfull, G. F., Snapper, S. B., Barletta, R. G., Jacobs, Jr., W. R., and., Bloom, B. R. (1991). New use of BCG for recombinant vaccines. Nature, 351:456.
https://doi.org/10.1038/351456a0
Sumanta, M. Ling-Yu, C., Thomas J. P., Shuang H., Bruce L. Z. and Zhixing, K. P. (2009). Lipopolysaccharide-driven Th2 cytokine production in macrophages is regulated by both MyD88 and TRAM. The Journal of Biological Chemistry, 284(43):29391-29398.
https://doi.org/10.1074/jbc.M109.005272
Suprabhat, M., Subhajit, K. and Santi, P., S., B. (2016). TLR2 and TLR4 mediated host immune responses in major infectious diseases: a review. The Brazilian Journal of Infectious Diseases, 20(2):193-204.
https://doi.org/10.1016/j.bjid.2015.10.011
Takashima, K., Matsunaga, N., Yoshimatsu, M., Hazeki, K., Kaisho, T., Uekata, M., Hazeki, O., Akira, S., Iizawa, Y., Ii, M. (2009). Analysis of binding site for the novel small-molecule TLR4 signal transduction inhibitor TAK-242 and its therapeutic effect on mouse sepsis model. British Journal of Pharmacology, 157(7):1250-62.
https://doi.org/10.1111/j.1476-5381.2009.00297.x
Tal, G., Mandelberg, A., Dalal, I., Cesar, K., Somekh, E., Tal, A., Oron, A., Itskovich, S., Ballin, A., Houri, S., Beigelman, A., Lider, O., Rechavi, G. and Amariglio, N. (2004). Association between common toll-like receptor 4 mutations and severe respiratory syncytial virus disease. The Journal of Infectious Diseases, 189(11):20572063.
https://doi.org/10.1086/420830
Timo, S., Ilkka, J. and Sampsa, M. (2000). IFN- α and IL-12 induce IL-18 receptor gene expression in human NK and T Cells. The Journal of Immunology, 165(4):1933-1938.
https://doi.org/10.4049/jimmunol.165.4.1933
Wang, X., Lu, Y., Sun, Y., He, W., Liang, J. and Li, L. (2017). TAK-242 protects against apoptosis in coronary microembolization-induced myocardial injury in rats by suppressing TLR-4/NFκB signaling pathway. Cellular Physiology and Biochemistry;41(4):1675-1683.
https://doi.org/10.1159/000471248
Wei, X., Xun, W., Xiaoying, L., Li, X., Lingjie,Z. and Zhengong, Y. (2004). Interferoninducible MyD88 protein inhibits hepatitis B virus replication. Virology; 319(2):306-314.
https://doi.org/10.1016/j.virol.2003.11.005
WHO (2012) Factsheet on the world malaria report.
WHO (2013). World malaria report 2013 shows major progress in fight against malaria, calls for sustained financing, Tech.Rep., 2013.
Xuefen, L., Jingjing, K., Qingting, W., Yingying, Y. and Ping, J. (2015). Effect of TLR4/MyD88 signaling pathway on expression of IL-1 and TNF-α in synovial fibroblasts from temporomandibular joint exposed to lipopolysaccharide, Mediators of Inflammation, Article ID 329405.
https://doi.org/10.1155/2015/329405
Yao, L., Kan, E. M., Lu, J., Hao, A., Dheen, S. T., Kaur, C. and Ling, E. A. (2013). Tolllike receptor 4 mediates microglial activation and production of inflammatory mediators in neonatal rat brain following hypoxia: role of TLR4 in hypoxic microglia. Journal of Neuroinflammation, 10:23.
https://doi.org/10.1186/1742-2094-10-23
Yonglin, Z., Yahui, Z., Ming, Z., Junjie, Z., Xudong, M., Tingqin, H., Honggang, P.,Jiaxi, L. and Jinning, S. (2016). Inhibition of TLR4 signalling-induced inflammation attenuates secondary injury after diffuse axonal injury in rats. Mediators of Inflammation,Article ID 4706915.
https://doi.org/10.1155/2016/4706915
Zakaria, N. M., Suppian R, Nor N. M. and Mat N.F. (2018) Role of toll like-receptor 2 in inflammatory activity of macrophage infected with a recombinant BCG expressing the C-terminus of merozoite surface protein-1 of Plasmodium falciparum. Asian Pac J Trop Biomed;8:333-339
https://doi.org/10.4103/2221-1691.237075
Zarember, K. A. and Godowski, P. J. (2002). Tissue expression of human toll-like receptors and differential regulation of Toll-like receptor mRNAs in leukocytes in response to microbes, their products and cytokines. Journal of Immunology, 168(2):554-561.
https://doi.org/10.4049/jimmunol.168.2.554
Zhang, X., Goncalves, R. and Mosser, D. M. (2008). Isolation and Characterization of Murine Macrophages. Current Protocols in Immunology, chapter, Unit-14.1.
https://doi.org/10.1002/0471142735.im1401s83
Zhou, Z., Zhu, X., Chen, J., Yang, S., Sun, R. and Yang, G. (2014). The interaction between Toll-like receptor 4 signaling pathway and hypoxia-inducible factor 1a in lung is chemiaereperfusion injury.Journal of Surgical Research, 188(1):290-297.
Downloads
Published
How to Cite
Issue
Section
License
Copyright (c) 2023 UMYU Journal of Microbiology Research (UJMR)
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.
