Macrophage-infectivity potentiator of Trypanosoma cruzi (TcMIP) is a new pro-type 1 immuno-stimulating protein for neonatal human cells and vaccines in mice.
Radwanska, Magdalena; De Lemos Esteves, Frédéric; Linsen, Loeset al.
[en] This work identifies the protein "macrophage infectivity potentiator" of Trypanosoma cruzi trypomastigotes, as supporting a new property, namely a pro-type 1 immunostimulatory activity on neonatal cells. In its recombinant form (rTcMIP), this protein triggers the secretion of the chemokines CCL2 and CCL3 by human umbilical cord blood cells from healthy newborns, after 24h in vitro culture. Further stimulation for 72h results in secretion of IFN-γ, provided cultures are supplemented with IL-2 and IL-18. rTcMIP activity is totally abolished by protease treatment and is not associated with its peptidyl-prolyl cis-trans isomerase enzymatic activity. The ability of rTcMIP to act as adjuvant was studied in vivo in neonatal mouse immunization models, using acellular diphtheria-tetanus-pertussis-vaccine (DTPa) or ovalbumin, and compared to the classical alum adjuvant. As compared to the latter, rTcMIP increases the IgG antibody response towards several antigens meanwhile skewing antibody production towards the Th-1 dependent IgG2a isotype. The amplitude of the rTcMIP adjuvant effect varied depending on the antigen and the co-presence of alum. rTcMIP did by contrast not increase the IgE response to OVA combined with alum. The discovery of the rTcMIP immunostimulatory effect on neonatal cells opens new possibilities for potential use as pro-type 1 adjuvant for neonatal vaccines. This, in turn, may facilitate the development of more efficient vaccines that can be given at birth, reducing infection associated morbidity and mortality which are the highest in the first weeks after birth.
Disciplines :
Biochemistry, biophysics & molecular biology
Author, co-author :
Radwanska, Magdalena; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium
De Lemos Esteves, Frédéric ; Université de Liège - ULiège > Centres généraux > CARE Digital Tools | Outils numériques
Linsen, Loes; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium
Coltel, Nicolas; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium
Cencig, Sabrina; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium
Widart, Joëlle ; Université de Liège - ULiège > Département de pharmacie
Massart, Anne-Cécile ; Université de Liège - ULiège > Département de chimie (sciences) > Center for Analytical Research and Technology (CART)
Colson, Séverine ; Université de Liège - ULiège > Centres généraux > Centre d'ingénierie des protéines
Di Paolo, Alexandre; Center for Protein Engineering (CIP), Université de Liège (ULg), Liège, Belgium
Percier, Pauline; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium
Ait Djebbara, Sarra; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium
Guillonneau, François ; Université de Liège - ULiège > Département de chimie (sciences) > Chimie analytique inorganique
Flamand, Véronique; Institute for Medical Immunology (IMI), and ULB Center for Research in Immunology (U-CRI), Gosselies, Belgium
De Pauw, Edwin ; Université de Liège - ULiège > Département de chimie (sciences)
Frère, Jean-Marie ; Université de Liège - ULiège > Département des sciences de la vie > Centre d'Ingénierie des Protéines (CIP)
Carlier, Yves; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium ; Department of Tropical Medicine, School of Public Health and Tropical Medicine, Tulane University, New Orleans, MA, United States
Truyens, Carine; Laboratory of Parasitology, Faculty of Medicine, and ULB Center for Research in Immunology (UCRI), Université Libre de Bruxelles (ULB), Brussels, Belgium
Macrophage-infectivity potentiator of Trypanosoma cruzi (TcMIP) is a new pro-type 1 immuno-stimulating protein for neonatal human cells and vaccines in mice.
FWB - Fédération Wallonie-Bruxelles [BE] ULB - Université Libre de Bruxelles [BE] F.R.S.-FNRS - Fonds de la Recherche Scientifique [BE]
Funding text :
Financial support was provided by The Fédération Wallonie-Bruxelles (FWB – grant 041/5892), The Fonds de Maturation of ULB (grant AdjuvacII), The Fonds d’Encouragement à la Recherche (ULB), the Fonds Emile Defay (ULB), the Fonds David et Alice Van Buuren (ULB), and the Fond National de la Recherche Scientifique (FNRS, grants J010615F and 29127680). Acknowledgments
Pulendran B S Arunachalam P O’Hagan DT. Emerging concepts in the science of vaccine adjuvants. Nat Rev Drug Discovery (2021) 20:454–75. doi: 10.1038/s41573-021-00163-y
Tom JK Albin TJ Manna S Moser BA Steinhardt RC Esser-Kahn AP. Applications of immunomodulatory immune synergies to adjuvant discovery and vaccine development. Trends Biotechnol (2019) 37:373–88. doi: 10.1016/j.tibtech.2018.10.004
Barman S Soni D Brook B Nanishi E Dowling DJ. Precision vaccine development: Cues from natural immunity. Front Immunol (2021) 12:662218. doi: 10.3389/fimmu.2021.662218
Petrovsky N Aguilar JC. Vaccine adjuvants: Current state and future trends. Immunol Cell Biol (2004) 82:488–96. doi: 10.1111/j.0818-9641.2004.01272.x
Vekemans J Truyens C Torrico F Solano M Torrico MC Rodriguez P et al. Maternal trypanosoma cruzi infection upregulates capacity of uninfected neonate cells to produce pro- and anti-inflammatory cytokines. Infect Immun (2000) 68:5430–4. doi: 10.1128/IAI.68.9.5430-5434.2000
Dauby N Alonso-Vega C Suarez E Flores A Hermann E Córdova M et al. Maternal infection with trypanosoma cruzi and congenital chagas disease induce a trend to a type 1 polarization of infant immune responses to vaccines. PloS Negl Trop Dis (2009) 3:e571. doi: 10.1371/journal.pntd.0000571
Jennewein MF Abu-Raya B Jiang Y Alter G Marchant A. Transfer of maternal immunity and programming of the newborn immune system. Semin Immunopathol (2017) 39:605–13. doi: 10.1007/s00281-017-0653-x
Kemmerling U Osuna A Schijman AG Truyens C. Congenital transmission of trypanosoma cruzi: A review about the interactions between the parasite, the placenta, the maternal and the Fetal/Neonatal immune responses. Front Microbiol (2019) 10:1854. doi: 10.3389/fmicb.2019.01854
Carlier Y Truyens C. Congenital chagas disease as an ecological model of interactions between trypanosoma cruzi parasites, pregnant women, placenta and fetuses. Acta Trop (2015) 151:103–15. doi: 10.1016/j.actatropica.2015.07.016
Zingales B Andrade SG Briones MR Campbell DA Chiari E Fernandes O et al. A new consensus for trypanosoma cruzi intraspecific nomenclature: Second revision meeting recommends TcI to TcVI. MemInstOswaldo Cruz (2009) 104:1051–4. doi: 10.1590/S0074-02762009000700021
el Bouhdidi A Truyens C Rivera MT Bazin H Carlier Y. Trypanosoma cruzi infection in mice induces a polyisotypic hypergammaglobulinaemia and parasite-specific response involving high IgG2a concentrations and highly avid IgG1 antibodies. Parasite Immunol (1994) 16:69–76. doi: 10.1111/j.1365-3024.1994.tb00325.x
Messenger LA Llewellyn MS Bhattacharyya T Franzén O Lewis MD Ramírez JD et al. Multiple mitochondrial introgression events and heteroplasmy in trypanosoma cruzi revealed by maxicircle MLST and next generation sequencing. PloS Negl Trop Dis (2012) 6:e1584. doi: 10.1371/journal.pntd.0001584
Moro A Ruiz-Cabello F Fernández-Cano A Stock RP González A. Secretion by trypanosoma cruzi of a peptidyl-prolyl cis-trans isomerase involved in cell infection. EMBO J (1995) 14:2483–90. doi: 10.1002/j.1460-2075.1995.tb07245.x
FDA. Guidance for industry: Pyrogen and endotoxins testing: Questions and answers, in: US Food drug adm (2019). Available at: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/guidance-industry-pyrogen-and-endotoxins-testing-questions-and-answers (Accessed April 13, 2021).
Brito LA Singh M. Acceptable levels of endotoxin in vaccine formulations during preclinical research. J Pharm Sci (2011) 100:34–7. doi: 10.1002/jps.22267
Liu Z Yuan X Luo Y He Y Jiang Y Chen ZK et al. Evaluating the effects of immunosuppressants on human immunity using cytokine profiles of whole blood. Cytokine (2009) 45:141–7. doi: 10.1016/j.cyto.2008.12.003
Ünal CM Steinert M. Microbial peptidyl-prolyl cis/trans isomerases (PPIases): Virulence factors and potential alternative drug targets. Microbiol Mol Biol Rev MMBR (2014) 78:544–71. doi: 10.1128/MMBR.00015-14
Snapper CM Paul WE. Interferon-gamma and b cell stimulatory factor-1 reciprocally regulate ig isotype production. Science (1987) 236:944–7. doi: 10.1126/science.3107127
Fike AJ Kumova OK Carey AJ. Dissecting the defects in the neonatal CD8+ T-cell response. J Leukoc Biol (2019) 106:1051–61. doi: 10.1002/JLB.5RU0319-105R
Levy O. Innate immunity of the newborn: Basic mechanisms and clinical correlates. Nat Rev Immunol (2007) 7:379–90. doi: 10.1038/nri2075
Elahi S Ertelt JM Kinder JM Jiang TT Zhang X Xin L et al. Immunosuppressive CD71+ erythroid cells compromise neonatal host defence against infection. Nature (2013) 504:158–62. doi: 10.1038/nature12675
Lopez JM Antiparra R Lippens G Zimic M Sheen P Maruenda H. Backbone chemical shift assignment of macrophage infectivity potentiator virulence factor of trypanosoma cruzi. Biomol NMR Assign (2019) 13:21–5. doi: 10.1007/s12104-018-9844-1
Pereira PJB Vega MC González-Rey E Fernández-Carazo R Macedo-Ribeiro S Gomis-Rüth FX et al. Trypanosoma cruzi macrophage infectivity potentiator has a rotamase core and a highly exposed alpha-helix. EMBO Rep (2002) 3:88–94. doi: 10.1093/embo-reports/kvf009
Humbert MV Almonacid Mendoza HL Jackson AC Hung M-C Bielecka MK Heckels JE et al. Vaccine potential of bacterial macrophage infectivity potentiator (MIP)-like peptidyl prolyl cis/trans isomerase (PPIase) proteins. Expert Rev Vaccines (2015) 14:1633–49. doi: 10.1586/14760584.2015.1095638
Kak G Raza M Tiwari BK. Interferon-gamma (IFN-γ): Exploring its implications in infectious diseases. Biomol Concepts (2018) 9:64–79. doi: 10.1515/bmc-2018-0007
Balasubramani A Mukasa R Hatton RD Weaver CT. Regulation of the ifng locus in the context of T-lineage specification and plasticity. Immunol Rev (2010) 238:216–32. doi: 10.1111/j.1600-065X.2010.00961.x
DuPage M Bluestone JA. Harnessing the plasticity of CD4(+) T cells to treat immune-mediated disease. Nat Rev Immunol (2016) 16:149–63. doi: 10.1038/nri.2015.18
Schaller TH Batich KA Suryadevara CM Desai R Sampson JH. Chemokines as adjuvants for immunotherapy: Implications for immune activation with CCL3. Expert Rev Clin Immunol (2017) 13:1049–60. doi: 10.1080/1744666X.2017.1384313
Maghazachi AA. Role of chemokines in the biology of natural killer cells. Curr Top Microbiol Immunol (2010) 341:37–58. doi: 10.1007/82_2010_20
Griffith JW Sokol CL Luster AD. Chemokines and chemokine receptors: Positioning cells for host defense and immunity. Annu Rev Immunol (2014) 32:659–702. doi: 10.1146/annurev-immunol-032713-120145
Zimmermann P Curtis N. Factors that influence the immune response to vaccination. Clin Microbiol Rev (2019) 32:e00084–18. doi: 10.1128/CMR.00084-18
O’Hagan DT Friedland LR Hanon E Didierlaurent AM. Towards an evidence based approach for the development of adjuvanted vaccines. Curr Opin Immunol (2017) 47:93–102. doi: 10.1016/j.coi.2017.07.010
Egli A Santer D Barakat K Zand M Levin A Vollmer M et al. Vaccine adjuvants–understanding molecular mechanisms to improve vaccines. Swiss Med Wkly (2014) 144:w13940. doi: 10.4414/smw.2014.13940
Kollmann TR Kampmann B Mazmanian SK Marchant A Levy O. Protecting the newborn and young infant from infectious diseases: Lessons from immune ontogeny. Immunity (2017) 46:350–63. doi: 10.1016/j.immuni.2017.03.009
Feng F Wen Z Chen J Yuan Y Wang C Sun C. Strategies to develop a mucosa-targeting vaccine against emerging infectious diseases. Viruses (2022) 14:520. doi: 10.3390/v14030520
Dowling DJ van Haren SD Scheid A Bergelson I Kim D Mancuso CJ et al. TLR7/8 adjuvant overcomes newborn hyporesponsiveness to pneumococcal conjugate vaccine at birth. JCI Insight (2017) 2:e91020. doi: 10.1172/jci.insight.91020
Long Y Sun J Song T-Z Liu T Tang F Zhang X et al. CoVac501, a self-adjuvanting peptide vaccine conjugated with TLR7 agonists, against SARS-CoV-2 induces protective immunity. Cell Discovery (2022) 8:9. doi: 10.1038/s41421-021-00370-2
Zom GGP Khan S Filippov DV Ossendorp F. TLR ligand-peptide conjugate vaccines: Toward clinical application. Adv Immunol (2012) 114:177–201. doi: 10.1016/B978-0-12-396548-6.00007-X
Dowling DJ Levy O. Ontogeny of early life immunity. Trends Immunol (2014) 35:299–310. doi: 10.1016/j.it.2014.04.007
Zhou P Wu H Chen S Bai Q Chen X Chen L et al. MOMP and MIP DNA-loaded bacterial ghosts reduce the severity of lung lesions in mice after chlamydia psittaci respiratory tract infection. Immunobiology (2019) 224:739–46. doi: 10.1016/j.imbio.2019.09.002
Bas S Neff L Vuillet M Spenato U Seya T Matsumoto M et al. The proinflammatory cytokine response to chlamydia trachomatis elementary bodies in human macrophages is partly mediated by a lipoprotein, the macrophage infectivity potentiator, through TLR2/TLR1/TLR6 and CD14. J Immunol Baltim Md 1950 (2008) 180:1158–68. doi: 10.4049/jimmunol.180.2.1158
Humbert MV Christodoulides M. Immunization with recombinant truncated neisseria meningitidis-macrophage infectivity potentiator (rT-Nm-MIP) protein induces murine antibodies that are cross-reactive and bactericidal for neisseria gonorrhoeae. Vaccine (2018) 36:3926–36. doi: 10.1016/j.vaccine.2018.05.069
Rasch J Ünal CM Klages A Karsli Ü Heinsohn N Brouwer RMHJ et al. Peptidyl-Prolyl-cis/trans-Isomerases mip and PpiB of legionella pneumophila contribute to surface translocation, growth at suboptimal temperature, and infection. Infect Immun (2019) 87(1):e00939–17. doi: 10.1128/IAI.00939-17
Christodoulides M. Update on the neisseria macrophage infectivity potentiator-like PPIase protein. Front Cell Infect Microbiol (2022) 12:861489. doi: 10.3389/fcimb.2022.861489
Somarelli JA Lee SY Skolnick J Herrera RJ. Structure-based classification of 45 FK506-binding proteins. Proteins (2008) 72:197–208. doi: 10.1002/prot.21908
Bielecka MK Devos N Gilbert M Hung M-C Weynants V Heckels JE et al. Recombinant protein truncation strategy for inducing bactericidal antibodies to the macrophage infectivity potentiator protein of neisseria meningitidis and circumventing potential cross-reactivity with human FK506-binding proteins. Infect Immun (2015) 83:730–42. doi: 10.1128/IAI.01815-14
Kollmann TR Marchant A Way SS. Vaccination strategies to enhance immunity in neonates. Science (2020) 368:612–5. doi: 10.1126/science.aaz9447
Schijns V Fernández-Tejada A Barjaktarović Ž Bouzalas I Brimnes J Chernysh S et al. Modulation of immune responses using adjuvants to facilitate therapeutic vaccination. Immunol Rev (2020) 296:169–90. doi: 10.1111/imr.12889
