Northwestern scientists investigating severe malaria infections in children have uncovered key biological markers that could help guide future treatments, according to a study published in Nature Communications.
Malaria remains a significant global health challenge, particularly in young children in sub-Saharan Africa. While some infections cause mild flu-like symptoms, others lead to life-threatening complications, including brain inflammation and severe anemia, said Rafal Sobota, MD, PhD, ’24 GME, assistant professor in the Ken and Ruth Davee Department of Neurology‘s Division of Neurocritical Care, who was first author of the study.
“I am interested in human genetic predisposition to infectious diseases,” Sobota said. “In this study, we looked for signals — whether they’re transcriptomic or proteomic — that either govern malarial disease or poor prognosis.”
In the study, investigators analyzed cases of Plasmodium falciparum malaria in Mali and compared children with severe forms of the disease — such as cerebral malaria and severe malarial anemia — to those with milder infections.
Using advanced multi-omics approaches — which allow scientists to analyze gene activity, protein levels and metabolites in the blood — scientists identified crucial molecular patterns in the most severe cases.
Among children with severe malaria, investigators found increased activity of three genes —MMP8, IL1R2 and ARG1 — involved in the inflammatory response. These genes were highly active across different severe malaria subtypes, suggesting that dangerous forms of the disease share a common inflammatory response.
Sobota and his collaborators also observed elevated levels of TIMP-1, MMP8 and MMP9, proteins linked to central nervous system damage, suggesting they might be associated with the breakdown of the endothelial barrier between blood and brain tissue, worsening neurological symptoms.
“Because we were able to compare the different subtypes of severe malaria, we found responses that were specific to each single type of malaria,” Sobota said. “We found specific markers that are also important in distinguishing the types of severe malaria from each other.”
The findings highlight specific inflammatory signals that may drive the most dangerous symptoms and suggest potential therapeutic targets, Sobota said.
Building on these findings, Sobota and his collaborators will work to understand the differences among patients with cerebral malaria.
“Historically, cerebral malaria has been studied as a singular phenotype,” Sobota said. “I am interested in identifying subtypes of this disease. If there are different mechanisms driving cerebral malaria, then we might need a more nuanced, targeted approach to identifying therapies.”
The study was supported by National Institutes of Health grants R01HL130750 and R01HL146377; cooperative agreement U19AI065683; and NIH International Research in Infectious Diseases grant R01AI099628.
