A Natural Peptide Antigen within the Plasmodium Ribosomal Protein RPL6 Confers Liver TRM Cell-Mediated Immunity against Malaria in Mice

Ana Maria Valencia-Hernandez; Wei Yi Ng; Nazanin Ghazanfari; Sonia Ghilas; Maria N de Menezes; Lauren E Holz; Cheng Huang; Kieran English; Myo Naung; Peck Szee Tan; Kirsteen M Tullett; Thiago M Steiner; Matthias H Enders; Lynette Beattie; Yu Cheng Chua; Claerwen M Jones; Anton Cozijnsen; Vanessa Mollard; Yeping Cai; David G Bowen; Anthony W Purcell; Nicole L La Gruta; Jose A Villadangos; Tania de Koning-Ward; Alyssa E Barry; Winfried Barchet; Ian A Cockburn; Geoffrey I McFadden; Stephanie Gras; Mireille H Lahoud; Patrick Bertolino; Ralf B Schittenhelm; Irina Caminschi; William R Heath; Daniel Fernandez-Ruiz

doi:10.1016/j.chom.2020.04.010

A Natural Peptide Antigen within the Plasmodium Ribosomal Protein RPL6 Confers Liver T_RM Cell-Mediated Immunity against Malaria in Mice

Cell Host Microbe. 2020 Jun 10;27(6):950-962.e7. doi: 10.1016/j.chom.2020.04.010. Epub 2020 May 11.

Authors

Ana Maria Valencia-Hernandez¹, Wei Yi Ng², Nazanin Ghazanfari³, Sonia Ghilas³, Maria N de Menezes², Lauren E Holz³, Cheng Huang⁴, Kieran English⁵, Myo Naung⁶, Peck Szee Tan⁷, Kirsteen M Tullett⁷, Thiago M Steiner³, Matthias H Enders⁸, Lynette Beattie³, Yu Cheng Chua², Claerwen M Jones⁷, Anton Cozijnsen⁹, Vanessa Mollard⁹, Yeping Cai¹⁰, David G Bowen⁵, Anthony W Purcell⁷, Nicole L La Gruta⁷, Jose A Villadangos¹¹, Tania de Koning-Ward¹², Alyssa E Barry⁶, Winfried Barchet¹³, Ian A Cockburn¹⁰, Geoffrey I McFadden⁹, Stephanie Gras⁷, Mireille H Lahoud⁷, Patrick Bertolino⁵, Ralf B Schittenhelm⁴, Irina Caminschi¹⁴, William R Heath¹⁵, Daniel Fernandez-Ruiz¹⁶

Affiliations

¹ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, NRW, 53127, Germany.
² Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia.
³ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia.
⁴ Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia; Monash Proteomics & Metabolomics Facility, Monash University, Clayton, VIC 3800, Australia.
⁵ Centenary Institute, The University of Sydney and AW Morrow Gastroenterology and Liver Centre, Newtown, NSW 2042, Australia.
⁶ School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia; Burnet Institute, Melbourne, VIC 3000, Australia; Walter and Eliza Hall Institute, Parkville, VIC 3052, Australia.
⁷ Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia.
⁸ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia; Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, NRW, 53127, Germany.
⁹ School of Biosciences, University of Melbourne, Parkville 3010, Australia.
¹⁰ John Curtin School of Medical Research, The Australian National University, Canberra, ACT 2600, Australia.
¹¹ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; Department of Biochemistry and Molecular Biology, University of Melbourne, at the Bio21 Molecular Science and Biotechnology Institute, Parkville, VIC 3010, Australia.
¹² School of Medicine, Deakin University, Waurn Ponds, VIC 3216, Australia.
¹³ Institute of Clinical Chemistry and Clinical Pharmacology, University Hospital of Bonn, Bonn, NRW, 53127, Germany.
¹⁴ Monash Biomedicine Discovery Institute and Department of Biochemistry and Molecular Biology, Monash University, Clayton, VIC 3800, Australia. Electronic address: [email protected].
¹⁵ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: [email protected].
¹⁶ Department of Microbiology and Immunology, University of Melbourne, at the Peter Doherty Institute for Infection and Immunity, Melbourne, VIC 3000, Australia; ARC Centre of Excellence in Advanced Molecular Imaging, University of Melbourne, Parkville, VIC 3010, Australia. Electronic address: [email protected].

PMID: 32396839
DOI: 10.1016/j.chom.2020.04.010

Abstract

Liver-resident memory CD8⁺ T (T_RM) cells remain in and constantly patrol the liver to elicit rapid immunity upon antigen encounter and can mediate efficient protection against liver-stage Plasmodium infection. This finding has prompted the development of immunization strategies where T cells are activated in the spleen and then trapped in the liver to form T_RM cells. Here, we identify PbRPL6_120-127, a H2-K^b-restricted epitope from the putative 60S ribosomal protein L6 (RPL6) of Plasmodium berghei ANKA, as an optimal antigen for endogenous liver T_RM cell generation and protection against malaria. A single dose vaccination targeting RPL6 provided effective and prolonged sterilizing immunity against high dose sporozoite challenges. Expressed throughout the parasite life cycle, across Plasmodium species, and highly conserved, RPL6 exhibits strong translation potential as a vaccine candidate. This is further advocated by the identification of a broadly conserved, immunogenic HLA-A^∗02:01-restricted epitope in P. falciparum RPL6.

Keywords: CD8 T cell; T cell memory; adaptive immmunity; antigen; dendritic cell targeting; epitope discovery; liver; malaria; tissue-resident memory T cell; vaccine.

MeSH terms

Animals
Anopheles
Antigens, Protozoan / immunology*
CD8-Positive T-Lymphocytes / immunology
Cell Line
Dendritic Cells / immunology
Female
Immunity, Cellular / immunology*
Immunization
Immunologic Memory / immunology
Liver / immunology*
Liver / parasitology
Malaria / parasitology
Malaria Vaccines / immunology
Malaria, Falciparum / metabolism
Male
Mice
Mice, Inbred C57BL
Peptides / immunology*
Plasmodium berghei / immunology*
Ribosomal Proteins / immunology*
Sporozoites / immunology

Substances

Antigens, Protozoan
Malaria Vaccines
Peptides
Ribosomal Proteins
ribosomal protein L6