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Proteomic Analysis Uncovers Markers Associated with Malaria Complications

NEW YORK (GenomeWeb News) — A proteomic analysis of blood from children with malaria has uncovered certain protein biomarkers linked to the development of complications due to infection, researchers from Nigeria, Sweden, and the UK reported in PLOS Pathogens yesterday.

The international team examined the levels of more than 1,000 proteins in the plasma of children with and without malaria as well as children with malaria-related complications such as cerebral malaria and severe malaria anemia.

The levels of more than 40 proteins, including a number of inflammatory response proteins, differed between children with malaria and controls, while higher levels of muscle-related proteins were associated with cerebral malaria.

"These findings will hopefully lead to an increased understanding of the disease and may contribute to the development of clinical algorithms that could predict which children are more at risk [of developing] severe malaria," said Peter Nilsson from the KTH-Royal Institute of Technology in Sweden and his colleagues wrote in their paper.

Malaria is a life-threatening disease that caused an estimated 627,000 deaths in 2012, according to the World Health Organization. In Nigeria, the researchers added, about a third of childhood deaths are attributable to Plasmodium falciparum, one of the parasites that causes malaria.

Searching for markers to differentiate complicated and uncomplicated malaria, the researchers selected 304 proteins to be included on a targeted affinity proteomic array along with 711 other proteins randomly chosen from the Human Protein Atlas.

In a discovery cohort of 256 childhood malaria patients — including more than 175 patients with complicated malaria — and controls from Nigeria, along with a verification cohort of 332 people, Nilsson and his colleagues identified 41 proteins that could distinguish children with malaria from healthy community controls.

These proteins, gleaned from both the targeted and random sets of proteins, include a number of inflammation-related proteins such as von Willebrand factor and C-reactive protein.

Additionally, Nilsson and his colleagues uncovered 13 proteins whose levels could differentiate complicated from uncomplicated malaria. For instance, individuals with severe malaria anemia, the researchers noted, had higher levels of oxidative-stress-related proteins.

The researchers also noted two proteins that were increased in the plasma of children with cerebral malaria — carbonic anhydrase III (CA3) and creatine kinase (CK) — that are usually associated with muscle tissue. This, they added, suggests that there could be a link between muscle damage and cerebral malaria. Also elevated in patients with cerebral malaria were endothelial activation and platelet adhesion markers.

Through multivariate analyses, the researchers developed panels of proteins that could differentiate malaria complications from uncomplicated disease. A three-protein signature — made of iIGFBP1, von Willebrand factor, and hemoglobin subunit — was the best at differentiating severe malaria anemia from uncomplicated malaria, they noted, and a 23-protein signature was best at distinguishing between cerebral malaria and uncomplicated malaria.

A nine-protein classifier that included CA3 and CK was best for cerebral malaria and severe malaria anemia.

Nilsson and his colleagues verified their findings in a separate set of 363 samples.

The researchers also further explored which isoforms of CA3 and CK were present in patients' blood. By using additional antibodies and immunohistochemical staining, the researchers found that the muscle-specific forms were present, which they said indicates that smooth muscle cells of the microvasculature could be injured.

Because of this, Nilsson and his colleagues suggested that muscle damage markers and endothelial cell activation/platelet adhesion markers together in the plasma are specific to cerebral malaria pathogenesis.

"Our data therefore indicate that children with uncomplicated malaria that develop cerebral malaria are likely to have vascular lesions and muscle damage, which can be readily monitored in plasma," they added.