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How oxygen radicals can protect against severe malaria

17.11.2016
Scientists from the Heidelberg University Hospital and the German Center for Infection Research (DZIF) have succeeded in elucidating and specifically activating protective mechanisms against malaria. Oxygen radicals in red blood cells apparently play a key role in this: the scientists were able to curb the development of severe malaria in mice that had a higher proportion of these aggressive molecules.

Through bites by infected anopheles mosquitos, the malaria parasites (plasmodia) enter the human body. Photo Credit: James Gathany – CDC Severe malaria, elicited by the Plasmodium falciparum parasite, causes dangerous circulatory disorders and neurological complications. Through bites by infected anopheles mosquitos, the malaria parasites (plasmodia) enter the human body where they initially reproduce in the liver cells and then enter red blood cells. They reproduce again in the red blood cells, and finally destroy them. The typical phases of fever and anaemia occur when these red blood cells burst. The neurological complications of severe malaria, such as paralysis, cramps, severe brain damage are caused be special adhesive proteins produced by the pathogens, which ensure that red blood cells adhere to vessel walls and cannot be removed.  The parasite establishes a transport system in the blood cell specifically for this purpose. The consequence: smaller blood vessels become clogged and inflamed, and parts of the nervous system are insufficiently supplied with oxygen.

The role of haemoglobins in severe malaria

“The parasites’ ability to adhere the red blood cells to the vessel walls is a key mechanism in sever malaria,” explains Prof Michael Lanzer, DZIF scientist at the Heidelberg University Hospital. In 2011, Lanzer’s research group had already fundamentally elucidated this mechanism. It was based on the observation that patients with sickle cell anaemia, which frequently occurs in Africa, did not develop severe malaria. For the researchers, this suggested that the hereditary haemogoblin changes characteristic for this disease could play a role. In their investigations, the Heidelberg researchers showed that so-called ferrylhaemoglobin, a breakdown product of haemoglobin, disrupts the transport system for the special adhesive proteins and consequently also the adhesion of red blood cells to cell walls. Ferrylhämoglobin is irreversibly damaged, chemically altered haemoglobin that is no longer able to bind oxygen. In sickle cell anaemia it is produced in larger amounts, because the existing haemoglobin variants are more unstable.

Oxygen radicals can trigger the protective mechanism


“Naturally, we were interested in whether this protective mechanism can be triggered artificially,” explains Lanzer. In their current study, the researchers show that aggressive oxygen molecules, also known as oxygen radicals, play a critical role in these processes.  They treated mice with menadione, a food supplement which leads to oxygen radical development, before infecting them. The consequence: the development of severe malaria was mitigated. “It seems that an excess of oxygen radicals in the infected cells also damages the more stable haemoglobin, consequently resulting in the development of ferrylhaemoglobin, the breakdown product which triggers the described protective mechanism against malaria,” Lanzer explains. Hence, menadione’s mechanism of action is similar to that of sickle cell haemoglobin. 

Consequences for medical research

This new finding has consequences for the development of prevention strategies. “Based on this, it may be possible to develop an active agent that changes erythrocytes in such a way that the transport of adhesive proteins to the vessel walls does not occur, hence avoiding the subsequent adhesion of erythrocytes with the known fatal causes,” Lanzer hopes. The first studies on this were also funded by the Bill and Melinda Gates Foundation. 


Publication
Cyrklaff M et al
Oxidative insult can induce malaria-protective trait of sickle and foetal erythrocytes
Nature Communications 7:13401 (2016). Doi: 10.1038/NCOMMS13401

You can find more on the mechanism here:
Cyrklaff M et al: Hemoglobins S and C interfere with Actin Remodeling in Plasmodium falciparum-Infected Erythrocytes:
In: Science 2011. DOI: 10.1126/science.1213775

Contact

Prof Michael Lanzer
Heidelberg University Hospital and
German Center for Infection Research
T: +49 6221 56 7844
E-mail: Opens window for sending emailmichael.lanzer@med.uni-heidelberg.de

Dr Marek Cyrklaff
Heidelberg University Hospital
T: +49 6221 56 6537
E-mail: Opens window for sending emailmarek.cyrklaff@med.uni-heidelberg.de

DZIF Press Office
Karola Neubert and Janna Schmidt
T +49 531 6181 1170/1154
Opens window for sending emailpresse@dzif.de

 

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