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Networking the host immune response in Plasmodium vivax malaria

Vitor RR Mendonça12, Artur TL Queiroz1, Fabrício M Lopes34, Bruno B Andrade5* and Manoel Barral-Netto126

Author Affiliations

1 Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, Brazil

2 Faculdade de Medicina, Universidade Federal da Bahia, Salvador, Brazil

3 Instituto de Matemática e Estatística, Universidade de São Paulo, São Paulo, Brazil

4 Coordenação de Informática, Universidade Tecnológica Federal do Paraná, Cornélio Procópio, Brazil

5 Immunobiology Section, Laboratory of Parasitic Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, 20893, Bethesda, MD, USA

6 Instituto de Investigação em Imunologia, Instituto Nacional de Ciência e Tecnologia, São Paulo, Brazil

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Malaria Journal 2013, 12:69  doi:10.1186/1475-2875-12-69

Published: 21 February 2013



Plasmodium vivax malaria clinical outcomes are a consequence of the interaction of multiple parasite, environmental and host factors. The host molecular and genetic determinants driving susceptibility to disease severity in this infection are largely unknown. Here, a network analysis of large-scale data from a significant number of individuals with different clinical presentations of P. vivax malaria was performed in an attempt to identify patterns of association between various candidate biomarkers and the clinical outcomes.


A retrospective analysis of 530 individuals from the Brazilian Amazon, including P. vivax-infected individuals who developed different clinical outcomes (148 asymptomatic malaria, 187 symptomatic malaria, 13 severe non-lethal malaria, and six severe lethal malaria) as well as 176 non-infected controls, was performed. Plasma levels of liver transaminases, bilirubins, creatinine, fibrinogen, C-reactive protein, superoxide dismutase (SOD)-1, haem oxygenase (HO)-1 and a panel composed by multiple cytokines and chemokines were measured and compared between the different clinical groups using network analysis.


Non-infected individuals displayed several statistically significant interactions in the networks, including associations between the levels of IL-10 and IL-4 with the chemokine CXCL9. Individuals with asymptomatic malaria displayed multiple significant interactions involving IL-4. Subjects with mild or severe non-lethal malaria displayed substantial loss of interactions in the networks and TNF had significant associations more frequently with other parameters. Cases of lethal P. vivax malaria infection were associated with significant interactions between TNF ALT, HO-1 and SOD-1.


The findings imply that clinical immunity to P. vivax malaria is associated with multiple significant interactions in the network, mostly involving IL-4, while lethality is linked to a systematic reduction of complexity of these interactions and to an increase in connections between markers linked to haemolysis-induced damage.

Malaria; Plasmodium vivax; Biomarkers; Network analysis