Natural immune response to Plasmodium vivax alpha-helical coiled coil protein motifs and its association with the risk of P. vivax malaria

RESEARCH ARTICLE Natural immune response to Plasmodium vivax alpha-helical coiled coil protein motifs and its association with the risk of P. vivax malaria Nora Céspedes1,2☯, Connie S. N. Li Wai Suen3,4☯, Cristian Koepfli3,4, Camila T. França3,4, Ingrid Felger5, Issa Nebie6, Myriam Arévalo-Herrera1,2, Ivo Mueller3,4,7,8, Giampietro Corradin9, Sócrates Herrera1,10* a1111111111 a1111111111 a1111111111 a1111111111 a1111111111 OPEN ACCESS Citation: Céspedes N, Li Wai Suen CSN, Koepfli C, França CT, Felger I, Nebie I, et al. (2017) Natural immune response to Plasmodium vivax alphahelical coiled coil protein motifs and its association with the risk of P. vivax malaria. PLoS ONE 12(6): e0179863. https://doi.org/10.1371/journal. pone.0179863 Editor: Érika Martins Braga, Universidade Federal de Minas Gerais, BRAZIL Received: March 15, 2017 Accepted: June 5, 2017 Published: June 26, 2017 Copyright: © 2017 Céspedes et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Data Availability Statement: All relevant data are within the paper and its Supporting Information files. Funding: This work was supported by Colciencias (Contract 278-2008, Contract 360-2011 and Contract 719-2013) and a grant from NIAID (ICEMR grant U19AI089702). Also, this work was made possible through Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. The funders had no 1 Malaria Vaccine and Drug Development Center (MVDC), Cali, Colombia, 2 School of Health, University of Valle, Cali, Colombia, 3 Population Health & Immunity Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Australia, 4 Department of Medical Biology, University of Melbourne, Melbourne, Australia, 5 Swiss Tropical and Public Health Institute, Basel, Switzerland, 6 Centre National de Recherche et de Formation sur le Paludisme, Ouagadougou, Burkina Faso, 7 Malaria: Parasites and Hosts Unit, Department of Parasites & Insect Vectors, Institut Pasteur, Paris, France, 8 Barcelona Institute of Global Health (ISGLOBAL), Barcelona, Spain, 9 Biochemistry Department, University of Lausanne, Epalinges, Switzerland, 10 Caucaseco Scientific Research Center, Cali, Colombia ☯ These authors contributed equally to this work. * Abstract Protein α-helical coiled coil structures are known to induce antibodies able to block critical functions in different pathogens. In a previous study, a total of 50 proteins of Plasmodium vivax erythrocytic asexual stages containing α-helical coiled coil structural motifs were identified in silico, and the corresponding peptides were chemically synthesized. A total of 43 peptides were recognized by naturally acquired antibodies in plasma samples from both Papua New Guinea (PNG) and Colombian adult donors. In this study, the association between IgG antibodies to these peptides and clinical immunity was further explored by measuring total IgG antibody levels to 24 peptides in baseline samples from a longitudinal study of children aged 1–3 years (n = 164) followed for 16 months. Samples were reactive to all peptides tested. Eight peptides were recognized by >50% of individuals, whereas only one peptide had < 20% reactivity. Children infected at baseline were seropositive to 23/24 peptides. No significant association was observed between antibody titers and age or molecular force of infection, suggesting that antibody levels had already reached an equilibrium. There was a strong association between antibody levels to all peptides and protection against P. vivax clinical episodes during the 16 months follow-up. These results suggest that the selected coiled coil antigens might be good markers of both exposure and acquired immunity to P. vivax malaria, and further preclinical investigation should be performed to determine their potential as P. vivax vaccine antigens. PLOS ONE | https://doi.org/10.1371/journal.pone.0179863 June 26, 2017 1 / 14 Natural immune response to P. vivax coiled coil motif and association with malaria risk role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: The authors have declared that no competing interests exist. Introduction Plasmodium vivax is the second most important Plasmodium species in terms of epidemiological significance, with an estimate of 13.8 million malaria cases globally in 2015, and about half of the total number of malaria cases occurring outside Africa [1]. Although this parasite has been classically considered benign, several features make it difficult to control and eliminate. First, severe and lethal P. vivax malaria cases have been reported [1–4]; second, chloroquineresistant strains have recently emerged with at least one case confirmed in 10 countries [1]; third, this parasite species produces hypnozoite-forms that upon periodic reactivation induce clinical relapses [5, 6], even in individuals who have left endemic regions; and fourth, gametocytes emerge early during the erythrocytic cycle possibly increasing its transmissibility [7, 8]. Because of the difficulty in controlling P. vivax, in areas where the two species coexist its incidence appears to decrease more slowly than that of Plasmodium falciparum [1]. Due to limitations associated with classical malaria control measures, vaccination against malaria is currently considered a potentially valuable cost-effective complement for malaria control activities that would significantly contribute to its elimination [9]. During the last 2–3 decades, significant efforts have been invested on developing P. falciparum [10], and more recently P. vivax vaccines [11]. However, discovery of new potential vaccine candidates is required. The use of bioinformatics tools has allowed to explore the malaria genome/proteome databases, and to identify parasite proteins containing specific domains with functional importance for the parasite that could be immunologically targeted and therefore represent novel candidate antigens for vaccine development. Protein α-helical coiled coils are stable structures capable of eliciting antibodies able to block functional domains in different microorganisms [12–14]. These motifs have been investigated in influenza virus [13, 15], HIV-1 [12], coronaviruses [14] and malaria parasites [16]. In the case of P. falciparum, 170 α-helical coiled coil motifs have been identified in silico, from proteins predicted to be in different cellular locations such as the cytoplasm, the nucleus, the mitochondria, and the peroxysomes and in addition, some of them have trans- membrane segments. Therefore, synthetic peptides containing these motifs were synthesized, and tested for their reactivity in serum obtained from adult donors from Burkina Faso, Tanzania and Colombia [17]. The most (...truncated)