p. 1-10Background: 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.
Methods: 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.
Results: 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.
Conclusions: 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.Salvado
