Laboratory of Tropical Diseases – Prof. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil; Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, United Kingdom
Laboratory of Tropical Diseases – Prof. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil; Post-Graduation in Medical Pathophysiology, School of Medical Sciences, University of Campinas, Campinas, Brazil
Laboratory of Tropical Diseases – Prof. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
Dario Beraldi
Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, United Kingdom
Kannan Venugopal
Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity & Inflammation, University of Glasgow, Glasgow, United Kingdom
Diogenes Lima
School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil
School of Pharmaceutical Sciences, University of São Paulo, São Paulo, Brazil; Hospital Israelita Albert Einstein, São Paulo, Brazil
Erich V De Paula
Department of Clinical Pathology, School of Medical Sciences, University of Campinas, Campinas, Brazil
Stefanie CP Lopes
Department of Clinical Pathology, School of Medical Sciences, University of Campinas, Campinas, Brazil; Institute Leônidas & Maria Deane, Fiocruz, Manaus, Brazil; Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Brazil
Marcus VG Lacerda
Institute Leônidas & Maria Deane, Fiocruz, Manaus, Brazil; Tropical Medicine Foundation Dr. Heitor Vieira Dourado, Manaus, Brazil
Laboratory of Tropical Diseases – Prof. Luiz Jacintho da Silva, Department of Genetics, Evolution, Microbiology and Immunology, Institute of Biology, University of Campinas, Campinas, Brazil
Plasmodium vivax is the major cause of human malaria in the Americas. How P. vivax infection can lead to poor clinical outcomes, despite low peripheral parasitaemia, remains a matter of intense debate. Estimation of total P. vivax biomass based on circulating markers indicates existence of a predominant parasite population outside of circulation. In this study, we investigate associations between both peripheral and total parasite biomass and host response in vivax malaria. We analysed parasite and host signatures in a cohort of uncomplicated vivax malaria patients from Manaus, Brazil, combining clinical and parasite parameters, multiplexed analysis of host responses, and ex vivo assays. Patterns of clinical features, parasite burden, and host signatures measured in plasma across the patient cohort were highly heterogenous. Further data deconvolution revealed two patient clusters, here termed Vivaxlow and Vivaxhigh. These patient subgroups were defined based on differences in total parasite biomass but not peripheral parasitaemia. Overall Vivaxlow patients clustered with healthy donors and Vivaxhigh patients showed more profound alterations in haematological parameters, endothelial cell (EC) activation, and glycocalyx breakdown and levels of cytokines regulating different haematopoiesis pathways compared to Vivaxlow. Vivaxhigh patients presented more severe thrombocytopenia and lymphopenia, along with enrichment of neutrophils in the peripheral blood and increased neutrophil-to-lymphocyte ratio (NLCR). When patients’ signatures were combined, high association of total parasite biomass with a subset of markers of EC activation, thrombocytopenia, and lymphopenia severity was observed. Finally, machine learning models defined a combination of host parameters measured in the circulation that could predict the extent of parasite infection outside of circulation. Altogether, our data show that total parasite biomass is a better predictor of perturbations in host homeostasis in P. vivax patients than peripheral parasitaemia. This supports the emerging paradigm of a P. vivax tissue reservoir, particularly in the haematopoietic niche of bone marrow and spleen.
