Hostname: page-component-77c89778f8-gvh9x Total loading time: 0 Render date: 2024-07-20T03:53:55.414Z Has data issue: false hasContentIssue false
  • English
  • Français

Co-factor-independent phosphoglycerate mutase of Leishmania donovani modulates macrophage signalling and promotes T-cell repertoires bearing epitopes for both MHC-I and MHC-II

Published online by Cambridge University Press:  15 November 2017

MANISH K. SINGH ,
FAUZIA JAMAL ,
AMIT K. DUBEY ,
PUSHKAR SHIVAM ,
SARITA KUMARI ,
PUSHPANJALI ,
GHUFRAN AHMED ,
MANAS R. DIKHIT ,
S. NARAYAN  and
V. N. R. DAS
...Show all authors
MANISH K. SINGH
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
FAUZIA JAMAL
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
AMIT K. DUBEY
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India National Institute of Pharmaceutical Education and Research, Hajipur 844102, India
PUSHKAR SHIVAM
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
SARITA KUMARI
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
PUSHPANJALI
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
GHUFRAN AHMED
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
MANAS R. DIKHIT
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
S. NARAYAN
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
V. N. R. DAS
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
KRISHNA PANDEY
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
K. K. SINHA
Affiliation:
Post Graduate Department of Botany, Tilka Manjhi Bhagalpur University, Bhagalpur, 812007, India
P. DAS
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
SHUBHANKAR K. SINGH*
Affiliation:
Rajendra Memorial Research Institute of Medical Sciences, Patna 800007, India
*
*Corresponding author: Microbiology Division, RMRIMS (ICMR), Agamkuan, Patna-800007, India. E-mail: sksrmri@yahoo.com, sksingh@icmr.org.in
Get access Rights & Permissions [Opens in a new window]

Summary

Immunoactivation depends upon the antigen potential to modulate T-cell repertoires. The present study has enumerated the effect of 61 kDa recombinant Leishmania donovani co-factor-independent phosphoglycerate mutase (rLd-iPGAM) on mononuclear cells of healthy and treated visceral leishmaniasis subjects as well as on THP-1 cell line. rLd-iPGAM stimulation induced higher expression of interleukin-1β (IL-1β) in the phagocytic cell, its receptor and CD69 on T-cell subsets. These cellular activations resulted in upregulation of host-protective cytokines IL-2, IL-12, IL-17, tumour necrosis factor-α and interferon-γ, and downregulation of IL-4, IL-10 and tumour growth factor-β. This immune polarization was also evidenced by upregulation of nuclear factor-κ light-chain enhancer of activated B cells p50 and regulated expression of suppressor of mother against decapentaplegic protein-4. rLd-iPGAM stimulation also promoted lymphocyte proliferation and boosted the leishmaniacidal activity of macrophages by upregulating reactive oxygen species. It also induced 1·8-fold higher release of nitric oxide (NO) by promoting the transcription of inducible nitric oxide synthase gene. Besides, in silico analysis suggested the presence of major histocompatibility complex class I and II restricted epitopes, which can proficiently trigger CD8+ and CD4+ cells, respectively. This study reports rLd-iPGAM as an effective immunoprophylactic agent, which can be used in future vaccine design.

Keywords

Leishmania donovanico-factor-independent phosphoglycerate mutaseinnate immunityadaptive immunityvisceral leishmaniasis
Type
Research Article
Information
Parasitology , Volume 145 , Issue 3 , March 2018 , pp. 292 - 306
Check for updates
Copyright
Copyright © Cambridge University Press 2017 

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Agallou, M., Margaroni, M. and Karagouni, E. (2011). Cellular vaccination with bone marrow-derived dendritic cells pulsed with a peptide of Leishmania infantum KMP-11 and CpG oligonucleotides induces protection in a murine model of visceral leishmaniasis. Vaccine 29, 5053–5064.CrossRefGoogle Scholar
Altschul, S. F., Madden, T. L., Schäffer, A. A., Zhang, J., Zhang, Z. and Miller, W. (1997). Gapped BLAST and PSI-BLAST: a new generation of protein database search programs. Nucleic Acids Research 25, 3389–3402.Google Scholar
Amit, A., Dikhit, M. R., Mahantesh, V., Chaudhary, R., Singh, A. K., Singh, A., Singh, S. K., Das, V. N. R., Pandey, K., Ali, V., Narayan, S., Sahoo, G. C., Das, P. and Bimal, S. (2016). Immunomodulation mediated through Leishmania donovani protein disulfide isomerase by eliciting CD8+ T-cell in cured visceral leishmaniasis subjects and identification of its possible HLA class-1 restricted T-cell epitopes. Journal of Biomolecular Structure and Dynamics 35, 1–35.Google Scholar
Anselmo, S. S., Giudice, A., Pereira, J. M. B., Guimaraes, L. H., De Jesus, A. R., Tatiana, R. M., Mary, E. W., Edgar, M. C. and Roque, P. A. (2009). Resistance of Leishmania (Viannia) braziliensis to nitric oxide: correlation with antimony therapy and TNF-α production. BMC Infectious Disease 10, 209.Google Scholar
Aseffa, A., Gumy, A., Launois, P., MacDonald, H. B., Louis, J. A. and Fabienne, T. C. (2002). The early IL-4 response to Leishmania major and the resulting Th2 cell maturation steering progressive disease in BALB/c mice are subject to the control of regulatory CD4+CD25+ T cells. The Journal of Immunology 169, 3232–3241.Google Scholar
Bisti, S., Konidou, G., Boelaert, J., Lebastard, M. and Soteriadou, K. (2006). The prevention of the growth of L. major progeny in BALB/c iron-loaded mice: a process coupled to increased oxidative burst, the amplitude and duration of which depend on initial parasite development stage and dose. Microbes and Infection 8, 1464–1472.CrossRefGoogle ScholarPubMed
Carrillo, E., Crusat, M., Nieto, J., Chicharro, C., Thomas, Mdel. C. and Martinez, E. (2008). Immunogenicity of HSP-70, KMP-11 and PFR-2 leishmanial antigens in the experimental model of canine visceral leishmaniasis. Vaccine 26, 1902–1911.Google Scholar
Chakravarty, J., Kumar, S. and Trivedi, S. (2011). A clinical trial to evaluate the safety and immunogenicity of the LEISHF1+MPL-SE vaccine for use in the prevention of visceral leishmaniasis. Vaccine 29, 3531–3537.Google Scholar
Chevalier, N., Rigden, D. J., van Roy, J., Opperdoes, F. R. and Michels, P. A. M. (2000). Trypanosoma brucei contains a 2, 3-bisphosphoglycerate independent phosphoglycerate mutase. European Journal of Biochemistry 267, 1464–1472.CrossRefGoogle ScholarPubMed
Christopher, L. K., El-Safi, S. H., Wynn, T. A., Maria, M. H., Satti, M. M. H., Kordofani, A. M., Hashim, F. A., Ali, M. H., Neva, F. A., Nutman, T. B. and Sacks, D. L. (1993). In vivo cytokine profiles in patients with Kala-azar marked elevation of both interleukin-10 and interferon-gamma. Journal of Clinical Investigation 91, 1644–1648.Google Scholar
Coler, R. N., Goto, Y., Vanitha, L. B. and Steven, G. R. (2007). Leish-111f, a recombinant polyprotein vaccine that protects against visceral leishmaniasis by elicitation of CD4+ T cells. Infection and Immunity 75, 4648–4654.Google Scholar
Coler, R. N., Duthie, M. S., Hofmeyer, K. A., Guderian, J., Jayashankar, L., Vergara, J., Rolf, T., Misquith, A., Laurance, J. D., Raman, V. S., Bailor, H. R., Cauwelaert, N. D., Reed, S. J., Vallur, A., Favila, M., Orr, M. T., Ashman, J., Ghosh, P., Mondal, D. and Reed, S. G. (2015). From mouse to man: safety, immunogenicity and efficacy of a candidate leishmaniasis vaccine LEISH-F3+GLA-SE. Clinical and Translational Immunology 4, e35.CrossRefGoogle Scholar
Dikhit, M. R., Kumar, S., Sahoo, B. R., Mansuri, R., Amit, A. and Ansari, M. Y. (2015). Computational elucidation of potential antigenic CTL epitopes in Ebola virus . Infection, Genetics and Evolution 36, 369–375.CrossRefGoogle ScholarPubMed
Djalma, S. L., Diego, L. C., Vanessa, C., Larissa, D. C., Alexandre, L. N. S., Tiago, W. P. M., Fredy, R. S. G., Maria, B., Karina, R. B., Richard, A. F., Marcelo, T. B. and Dario, S. Z. (2013). Inflammasome-derived IL-1β production induces nitric oxide-mediated resistance to Leishmania . Nature Medicine 19, 909–915.Google Scholar
Gannt, K. R., Goldman, T. L., McCormick, M. L., Miller, M. A. and Jeronimo, S. M. (2001). Oxidative responses of human and murine macrophage during phagocytosis of Leishmania chagasi . The Journal of Immunonology 167, 893–901.Google Scholar
Garg, R., Gupta, S. K., Tripathi, P., Naik, S. and Sundar, S. (2005). Immunostimulatory cellular responses of cured leishmania infected patients and hamsters against the integral membrane proteins and non-membranous soluble protein of recent clinical isolate of Leishmania donovani . Clinical and Experimental Immunology 140, 149–156.Google Scholar
Ghalib, H. W., Whittle, J. A., Kubin, M., Hashim, F. A., el-Hassan, A. M., Grabstein, K. H., Trinchieri, G. and Reed, S. G. (1995). IL-12 enhances Th1-type responses in human Leishmania donovani infections. The Journal of Immunology 154, 4623–4629.Google Scholar
Ghosh, A., Zhang, W. W. and Matlashewski, G. (2001). Immunization with A2 protein results in a mixed Th1/Th2 and a humoral response which protects mice against Leishmania donovani infections. Vaccine 20, 59–66.Google Scholar
Goto, Y., Bogatzki, L. Y., Bertholet, S., Coler, R. N. and Reed, S. G. (2007). Protective immunization against visceral leishmaniasis using Leishmania sterol 24-c methyltransferase formulated in adjuvant. Vaccine 25, 7450–7458.Google Scholar
Howard, J. G. and Liew, F. Y. (1984). Mechanisms of acquired immunity in leishmaniasis. Philosophical Transactions of Royal Society of London, Series B: Biological Science 307, 87–98.Google ScholarPubMed
Huber, M., Heink, S., Pagenstecher, A., Reinhard, K., Ritter, J., Visekruna, A., Guralnik, A., Bollig, N., Jeltsch, K., Heinemann, C., Wittmann, E., Buch, T., Prazeres da Costa., O., Brüstle, A., Brenner, D., Mak, T. W., Mittrücker, H. W., Tackenberg, B., Kamradt, T. and Lohoff, M. (2013). IL-17A secretion by CD8+ T cells supports Th17-mediated autoimmune encephalomyelitis. Journal of Clinical Investigation 123, 247–260.Google Scholar
Kamhawi, S., Oliveira, F. and Valenzuela, J. G. (2014). Using humans to make a human leishmaniasis vaccine. Science Translational Medicine 6, fs218.CrossRefGoogle ScholarPubMed
Kar, R. K., Ansari, M. Y., Suryadevara, P., Sahoo, B. R., Sahoo, G. C. and Dikhit, M. R. (2013). Computational elucidation of structural basis for ligand binding with Leishmania donovani adenosine kinase. BioMed Research International 2013, 1–14. doi: 10.1155/2013/609289.Google Scholar
Kira, R. G., Schultz-Cherry, S., Rodriguez, N., Jeronimo, S. M. B., Nascimento, E. T., Goldman, T. L., Recker, T. J., Miller, M. A. and Wilson, M. E. (2003). Activation of TGF-β by Leishmania chagasi: importance for parasite survival in macrophages. The Journal of Immunology 170, 2613–2620.Google Scholar
Kumar, R. and Engwerda, C. (2014). Vaccine to prevent leishmaniasis. Clinical and Translational Immunology 2014, e13.Google Scholar
Kumar, R., Pai, K. and Sundar, S. (2001). Reactive oxygen intermediates, nitric and IFN-gamma in Indian visceral leishmanisis. Clinical and Experimental Immunology 124, 262–265.Google Scholar
Kumar, P., Pai, K., Pandey, H. P. and Sundar, S. (2002). NADH-oxidase, NADPH-oxidase and myeloperoxidase activity of visceral leishmaniasis patient. Journal of Medical Microbiology 51, 832–836.Google Scholar
Laemmli, U. K. (1970). Cleavage of structural proteins during the assembly of the head of bacteriophage T 4. Nature 227, 680–685.Google Scholar
Liew, F. Y. (1991a). Role of cytokines in killing of intracellular pathogens. Immunology Letter 30, 193–197.CrossRefGoogle ScholarPubMed
Liew, F. Y. (1991b). The effector mechanism and vaccination against cutaneous leishmaniasis. Behring Institute Mitteilungen 1991, 239–243.Google Scholar
Murray, H. W. (1981). Susceptibility of Leishmania to oxygen intermediates and killing by normal macrophages. Journal of Experimental Medicine 153, 1302–1315.Google Scholar
Murray, H. W., Miralles, G. D., Mark, Y. S. and McDermott, D. F. (1993). Role and effect of IL-2 in experimental visceral leishmaniasis. The Journal of Immunonology 151, 929–938.Google Scholar
Murray, H. W., Christine, W., Jianguo, L. and Xiaojing, M. (2006). Responses to Leishmania donovani in mice deficient in interleukin- 12 (IL-12), IL-12/IL-23, or IL-18. Infection and Immunity 74, 4370–4374.Google Scholar
Naederer, T., Ellis, M. A., Sernee, M. F., De Souza, D. P., Curtis, J., Handman, E. and McConville, M. J. (2006). Virulence of Leishmania major in macrophage and mice requires the glucogenic enzyme fructose-1,6-bisphosphotase. Proceeding of the National Academy of Sciences of the United States of America 103, 5502–5507.CrossRefGoogle Scholar
Nascimento, M. S., Carregaro, V., Junior, D. S. L., Costa, D. L., Ryffel, B., Duthie, M. S., Jesus, A., Almedia, R. P. D. and Silva, J. S. D. (2011). Interleukin 17A acts synergistically with interferon γ to promote protection against Leishmania infantum infection. Journal of Infectious Disease 211, 1015–1026.Google Scholar
Nateghi, R. M., Keshavarz, H., Edalat, R., Sarrafnejad, A. and Shahrestani, T. (2010). CD8+ t cells as a source of IFN-γ production in human cutaneous leishmaniasis. PLoS Neglected Tropical Diseases 4, e845. doi: 10.1371/journal.pntd.0000845.Google Scholar
Nielsen, M. and Lund, O. (2009). NN-align. An artificial neural network-based alignment algorithm for MHC class II peptide binding prediction. BioMed Central Bioinformatics 10, 296.Google Scholar
Nowicki, M. W., Kuaprasert, B., McNae, I. W., Morgan, H. P., Harding, M. M., Michels, P. A. M., Fothergill-Gilmore, L. A. and Walkinshaw, M. D. (2009). Crystal structures of Leishmania maxicana phosphoglycerate mutase suggest a one metal mechanism and a new enzyme subclass. Journal of Molecular Biology 394, 535–543.Google Scholar
Pandya, S. K., Verma, R. K., Khare, P., Tiwari, B., Srinivasarao, D. A., Dube, A., Goyal, N. and Mishra, A. (2016). Supplementation of host response by targeting nitric oxide to the macrophage cytosol is efficacious in the hamster model of visceral leishmaniasis and adds to efficacy of amphotericin B. International Journal of Parasitology: Drugs and Drug Resistance 6, 125–132.Google Scholar
Parker, K. C., Bednarek, M. A. and Coligan, J. E. (1994). BIMAS: scheme for ranking potential HLA-A2 binding peptides based on independent binding of individual peptide side-chains. Journal of Immunology 152, 163–175.Google Scholar
Pitta, M. G. R., Romano, P. A., Cabantous, S., Henri, S., Hammad, A., Kouriba, B., Argiro, L., El Kheir, M., Bucheton, B., Mary, C., El-Safi, S. H. and Dessein, A. (2009). IL-17 and IL-22 are associated with protection against human kala azar caused by Leishmania donovani . Journal of Clinical Investigation 119, 2379–2387.Google Scholar
Qila, S., Woodward, J. and Suzuki, Y. (2013). IL-2 Produced by CD8+ immune T cells can augment their IFN-γ production independently from their proliferation in the secondary response to an intracellular pathogen. Journal of Immunology 190, 2199–2207.Google Scholar
Rafati, S., Zahedifard, F. and Nazgouee, F. (2006). Prime-boost vaccination using cysteine proteinasestype I and II of leishmania infantum confers protective immunity in murine visceral leishmaniasis. Vaccine 24, 2169–2175.Google Scholar
Rammensee, H., Bachmann, J., Emmerich, N. P., Bachor, O. A. and Stevanovic, S. (1999). SYFPEITHI: database for MHC ligands and peptide motifs. Immunogenetics 50, 213–219.Google Scholar
Rebecca, J., Faleiro, R. K., Louise, M. H. and Christian, R. E. (2014). Immune regulation during chronic visceral leishmaniasis. PLoS Neglected Tropical Disease 8(7), e2914. doi: 10.1371/journal.pntd.0002914.Google Scholar
Reche, P. A., Glutting, J-P., Zhang, H. and Reinherz, E. L. (2004). Enhancement to the RANKPEP resource for the prediction of peptide binding to MHC molecules using profiles. Immunogenetics 56, 405–419.Google Scholar
Roelen, B. A., Cohen, O. S., Raychowdhury, M. K., Chadee, D. N., Zhang, Y. and Kyriakis, J. M. (2003). Phosphorylation of threonine 276 in Smad4 is involved in transforming growth factor-beta-induced nuclear accumulation. American Journal of Physiology, Cell Physiology 285, C823–C830.Google Scholar
Schuler, M. M., Nastke, M. D. and Stevanović, S. (2007). SYFPEITHI: database for searching and T-cell epitope prediction. Immunoinformatics 409, 75–93.Google Scholar
Singh, S. K., Bimal, S., Narayan, S., Jee, C., Bimal, D., Das, P. and Bimal, R. (2011). Leishmania donovani: assessment of leishmanicidal effects of herbal extracts obtained from plants in the visceral leishmaniasis endemic area of Bihar, India. Experimental Parasitology 127, 552–558.Google Scholar
Singh, P. K., Kushwaha, S., Rana, A. K. and Bhattacharya, S. M. (2014). Cofactor independent phosphoglycerate mutase of Brugia malayi induces a mixed Th1/Th2 type immune response and inhibits larval development in the host. BioMed Research International 2014, 1–19.Google Scholar
Skeiky, Y. A., Kennedy, M., Kaufman, D., Borges, M. M., Guderian, J. A. and Scholler, J. K. (1998). LeIF: a recombinant Leishmania protein that induces an IL-12-mediated Th1 cytokine profile. Journal of Immunology 161, 6171–6179.Google Scholar
Srivastav, S., Saha, A., Barua, J., Ukil, A. and Das, P. K. (2015). IRAK-M regulates the inhibition of TLR-mediated macrophage immune response during late in vitro Leishmania donovani infection. European Journal of Immunology 45, 2787–2797.Google Scholar
Stager, S., Smith, D. F. and Kaye, P. M. (2000). Immunization with a recombinant stage-regulated surface protein from Leishmania donovani induces protection against visceral leishmaniasis. Journal of Immunology 165, 7064–7071.CrossRefGoogle ScholarPubMed
Swain, S. L., Weinberg, A. D., English, M. and Huston, G. (1990). IL-4 directs the development of Th2-like helper effectors. Journal of Immunology 145, 3796–3806.Google Scholar
Towbin, H., Staehelin, T. and Gordon, J. (1979). Electrophoretic transfer of proteins from polyacrylamide gel to nitrocellulose sheet: procedure and some application. Proceeding of National Academy of Science 27, 4350–4354.CrossRefGoogle Scholar
Supplementary material: File

Singh et al supplementary material

Tables S1-S3

Download Singh et al supplementary material(File)
File 23 KB