Protection from Severe Malaria Explained

Photo: Blood cells with haemoglobin

In red blood cells with mutated
hemoglobin variants, the trafficking
system disassembles into short
pieces (yellow). Targeted transport
of proteins to the surface does
not occur;© Heidelberg University

A degradation product of the altered haemoglobin provides protection from severe malaria. Within the red blood cells infected by the malaria parasite, it blocks the establishment of a trafficking system used by the parasite’s special adhesive proteins – adhesins – to access the exterior of the blood cells. As a result, the infected blood cells do not adhere to the vessel walls, as is usually the case for this type of malaria. This means that no dangerous circulatory disorders or neurological complications occur.

In the 1940s, researchers already discovered that sickle-cell anaemia with its characteristic blood mutation was particularly prevalent in certain population groups in Africa. They also survived malaria tropica, whose course is usually especially virulent. With malaria tropica, the malaria parasites (Plasmodia) enter the person after a bite of an infected Anopheles mosquito. The mosquito first multiplies in the person’s liver cells and then infects the red blood cells (erythrocytes).

In humans with mutated haemoglobin, these complications occur in a weakened form or not at all. “At the cell surface of infected erythrocytes with mutated haemoglobin, there are significantly fewer adhesins of the parasite than in normal red blood cells,” explained Lanzer. “For this reason, we had a closer look at the trafficking system within the host cell.” To this end, the team compared the blood cells with normal haemoglobin and two haemoglobin variants (haemoglobin S and haemoglobin C), which occur in around one-fifth of the African population in malaria-infected areas.

In so doing, the scientists used high-resolution microscopy techniques such as cry electron tomography to discover a new transport mechanism. The parasite uses a certain protein (actin) from the cytoskeleton (cellular skeleton) of the erythrocytes for its own trafficking network. “It forms a completely new structure that has nothing in common with the rest of the cytoskeleton,” explained Doctor Marek Cyrklaff. “The vesicles with the adhesins reach the cell surface of the red blood cells directly via these actin filaments.”

In contrast to erythrocytes with the two haemoglobin variants, here only short pieces of actin filaments are found. Targeted transport to the surface is not possible. “The entire transport system of the malaria parasite is degenerated in these blood cells,” Cyrklaff added. Laboratory tests showed that the haemoglobins themselves were not responsible for this, but rather a degradation product, ferryl haemoglobin. This is an irreversibly damaged, chemically altered haemoglobin that is no longer able to bind oxygen. The haemoglobins S and C are considerably more unstable than normal haemoglobin. As a result, blood cells with these variants contain ten times more ferryl haemoglobin than other erythrocytes. This high concentration destabilizes the binding of the actin structure and it disintegrates.

“With these results, we have now described a molecular mechanism for the first time that explains this haemoglobin variant’s protective effect against malaria,” Lanzer said.; Source: Heidelberg University Hospital