Sci Transl Med. 2019 Jun 5;11(495):eaav3963. doi: 10.1126/scitranslmed.aav3963. | PubMed

Kathleen W Dantzler^1,2, Siyuan Ma³, Priscilla Ngotho², Will J R Stone^4,5, Dingyin Tao^6,7, Sanna Rijpma⁴, Mariana De Niz², Sandra K Nilsson Bark¹, Matthijs M Jore⁴, Tonke K Raaijmakers⁴, Angela M Early⁸, Ceereena Ubaida-Mohien⁹, Leandro Lemgruber², Joseph J Campo¹⁰, Andy A Teng¹⁰, Timothy Q Le¹⁰, Cassidy L Walker¹⁰, Patricia Hermand¹¹, Philippe Deterre¹¹, D Huw Davies¹², Phil Felgner¹², Isabelle Morlais¹³, Dyann F Wirth¹, Daniel E Neafsey⁸, Rhoel R Dinglasan^6,14, Miriam Laufer¹⁵, Curtis Huttenhower³, Karl Seydel^16,17, Terrie Taylor^16,17, Teun Bousema^18,5, Matthias Marti^19,2

1. Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
2. Wellcome Centre for Molecular Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK.
3. Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, MA, USA.
4. Radboud Institute for Health Sciences, Radboud University Medical Center, Netherlands.
5. Immunology and Infection Department, London School of Hygiene and Tropical Medicine, London, UK.
6. W. Harry Feinstone Department of Molecular Microbiology and Immunology and the Malaria Research Institute, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
7. National Center for Advancing Translational Sciences, National Institutes of Health, Rockville, MD, USA.
8. Broad Institute of Harvard and MIT, Cambridge, MA, USA.
9. National Institute on Aging, National Institutes of Health, Baltimore, MD, USA.
10. Antigen Discovery Inc., Irvine, CA, USA.
11. Sorbonne Universités, UPMC Univ Paris 06, INSERM, Centre d'Immunologie et des Maladies Infectieuses (CIMI-Paris), UMR 1135, ERL CNRS 8255, F-75013 Paris, France.
12. Division of Infectious Diseases, Department of Medicine, University of California, Irvine, CA, USA.
13. UMR MIVEGEC UM1-CNRS 5290-IRD 224, Institut de Recherche pour le Développement, Montpellier Cedex, France.
14. Emerging Pathogens Institute, Department of Infectious Diseases and Immunology, University of Florida College of Veterinary Medicine, Gainesville, FL, USA.
15. Division of Malaria Research, Institute for Global Health, University of Maryland School of Medicine, Baltimore, MD, USA.
16. Department of Osteopathic Medical Specialties, College of Osteopathic Medicine, Michigan State University, East Lansing, MI, USA.
17. Blantyre Malaria Project, University of Malawi College of Medicine, Blantyre, Malawi.
18. Radboud Institute for Health Sciences, Radboud University Medical Center, Netherlands. teun.bousema@radboudumc.nl matthias.marti@glasgow.ac.uk.
19. Department of Immunology and Infectious Disease, Harvard T.H. Chan School of Public Health, Boston, MA, USA. teun.bousema@radboudumc.nl matthias.marti@glasgow.ac.uk.

Abstract

The recent decline in global malaria burden has stimulated efforts toward Plasmodium falciparum elimination. Understanding the biology of malaria transmission stages may provide opportunities to reduce or prevent onward transmission to mosquitoes. Immature P. falciparum transmission stages, termed stages I to IV gametocytes, sequester in human bone marrow before release into the circulation as mature stage V gametocytes. This process likely involves interactions between host receptors and potentially immunogenic adhesins on the infected red blood cell (iRBC) surface. Here, we developed a flow cytometry assay to examine immune recognition of live gametocytes of different developmental stages by naturally exposed Malawians. We identified strong antibody recognition of the earliest immature gametocyte-iRBCs (giRBCs) but not mature stage V giRBCs. Candidate surface antigens (n = 30), most of them shared between asexual- and gametocyte-iRBCs, were identified by mass spectrometry and mouse immunizations, as well as correlations between responses by protein microarray and flow cytometry. Naturally acquired responses to a subset of candidate antigens were associated with reduced asexual and gametocyte density, and plasma samples from malaria-infected individuals were able to induce immune clearance of giRBCs in vitro. Infected RBC surface expression of select candidate antigens was validated using specific antibodies, and genetic analysis revealed a subset with minimal variation across strains. Our data demonstrate that humoral immune responses to immature giRBCs and shared iRBC antigens are naturally acquired after malaria exposure. These humoral immune responses may have consequences for malaria transmission potential by clearing developing gametocytes, which could be leveraged for malaria intervention.

Presented by Kathleen Dantzler