GROWTH AND DIFFERENTIATION FACTOR 15: A BIOMARKER OF DISEASE TOLERANCE IN HUMAN MALARIA INFECTION

Abstract

Currently, artesunate is the most effective antimalarial drug for treating severe malaria patients as it clears the parasite relatively quickly. Despite being treated with artesunate, about 15-20% of children admitted with severe malaria die due to unknown causes. It has been suggested that maladaptive inflammation which persist after parasite clearance continue to cause tissue damage, thus increasing the risk of malaria hospital death. Thus, moderating the negative effect of maladaptive inflammation along with artesunate treatment is key in improving malaria survival. Tolerance response, an intrinsic host defense has been shown to protect tissues from inflammatory damage. Therefore, identifying modulators that mediate tolerance response is key in the development of adjunctive therapies against severe malaria. Recently, growth and differentiation factor 15 (GDF15) has been shown to promote tissue tolerance and adaptation during mice sepsis model by maintaining cardiac adaptive physiology. However, it is unknown whether GDF15 plays a similar role in the context of human malaria infection. Further, GDF15 is upregulated in individuals carrying homozygous sickle cell and beta thalassemia variants. However, its variations with sickle cell and alpha thalassemia genotypes remain largely unknown. Its variation among sickle cell and alpha thalassemia variants may raise the possibility of its role in the causal pathway through which they offer malaria protection. I hypothesized that high GDF15 levels at the time of hospital admissions is associated with reduced cardiac injury risk of malaria death. To test this, 572 children were selected purposely from pediatric malaria admissions and outpatient clinics and stratified based on malaria clinical presentation ranging from mild, moderate and severe malaria at Kilifi County Hospital, Kenya. Plasma levels of GDF15 and cardiac troponin I were measured while children were further genotyped for both alpha thalassemia (-α 3.7kb) deletion and vi sickle cell (rs334) mutation. The association between GDF15 and cardiac troponin I levels on the risk of malaria hospital death was tested using linear logistic, multivariable logistic interaction effect and Cox proportional hazard regression analysis. This study shows that GDF15 was negatively associated with age and hemoglobin levels while positively with PfHRP2 levels. GDF15 was elevated and positively associated with increasing malaria severity thus produced in response to extent of systemic cell stress and tissue damage. Further, high GDF15 levels were associated with reduced cardiac injury risk of malaria early death. Though, to a certain systemic stress threshold beyond which its moderating effect is lost. Lastly, there was no significant variation in GDF15 levels with sickle cell and alpha thalassemia genotypes during malaria infection. In conclusion, the study provides evidence that high GDF15 at the time of hospital admission is associated with reduced cardiac injury risk of malaria early death supporting its cardioprotective role under acute infections. Therefore, further investigation on its potential role as potential adjunctive therapy against severe malaria is needed.