Abstract
BackgroundAsymptomatic Plasmodium infections are characterized by the absence of clinical disease and the ability to restrict parasite replication. Increasing levels of regulatory T cells (Tregs) in Plasmodium falciparum infections have been associated with the risk of developing clinical disease, suggesting that individuals with asymptomatic infections may have reduced Treg frequency. However, the relationship between Tregs, cellular activation and parasite control in asymptomatic malaria remains unclear.MethodsIn a cross-sectional study, the levels of Tregs and other T cell activation phenotypes were compared using flow cytometry in symptomatic, asymptomatic and uninfected children before and after stimulation with infected red blood cell lysates (iRBCs). In addition, the association between these T cell phenotypes and parasitaemia were investigated.ResultsIn children with asymptomatic infections, levels of Tregs and activated T cells were comparable to those in healthy controls but significantly lower than those in symptomatic children. After iRBC stimulation, levels of Tregs remained lower for asymptomatic versus symptomatic children. In contrast, levels of activated T cells were higher for asymptomatic children. Strikingly, the pre-stimulation levels of two T cell activation phenotypes (CD8+CD69+ and CD8+CD25+CD69+) and the post-stimulation levels of two regulatory phenotypes (CD4+CD25+Foxp3+ and CD8+CD25+Foxp3+) were significantly positively correlated with and explained 68% of the individual variation in parasitaemia. A machine-learning model based on levels of these four phenotypes accurately distinguished between asymptomatic and symptomatic children (sensitivity = 86%, specificity = 94%), suggesting that these phenotypes govern the observed variation in disease status.ConclusionCompared to symptomatic P. falciparum infections, in children asymptomatic infections are characterized by lower levels of Tregs and activated T cells, which are associated with lower parasitaemia. The results indicate that T cell regulatory and activation phenotypes govern both parasitaemia and disease status in paediatric malaria in the studied sub-Saharan African population.
Highlights
Asymptomatic Plasmodium infections are characterized by the absence of clinical disease and the ability to restrict parasite replication
Characteristics of the study population Venous blood samples were obtained from 57 children including 18 with asymptomatic P. falciparum infections, 22 with symptomatic malaria, and 17 with no P. falciparum parasites detected in blood by microscopy or rapid diagnostic test (Table 1)
The results suggest that expression levels of the considered regulatory and activation markers determine most of the individual variation in parasitaemia and predict disease status in asymptomatic and symptomatic P. falciparum infections
Summary
Asymptomatic Plasmodium infections are characterized by the absence of clinical disease and the ability to restrict parasite replication. Increasing levels of regulatory T cells (Tregs) in Plasmodium falciparum infections have been associated with the risk of developing clinical disease, suggesting that individuals with asymptomatic infections may have reduced Treg frequency. Understanding the regulatory and protective immune responses during asymptomatic and clinical infections remain necessary to comprehend mechanisms that enable the control of infections as well as the persistence and survival of the parasite. During Plasmodium falciparum infections, it is believed that the effector function of immune cells will be compromised due to immune regulation [7] This may be induced by the specific expansion of certain T or B cell sub-sets and modulation of certain antigen presenting cells, such as the dendritic cells [8]. The association between such cellular activation and regulatory markers and parasite control during asymptomatic infections is inadequately understood
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