Cerebral malaria (CM) is a severe form of malaria that affects the brain and is fatal in about 30-50% of the cases. But researchers in Portugal report a gene – Hmox1 – that protects against the disease by releasing CO into the host blood stream counteracting CM inflammatory processes (CO is known to have anti-inflammatory properties) and inhibiting the development of the infection in the brain.
Maria M Mota, one of the leaders of the study believes that their results in mice will be relevant to treat human cerebral malaria and, supporting this idea, the protein produced by Hmox1 has already been reported in cerebral malaria patients. And with 300-500 millions of people infected every year, a vaccine that so far has eluded scientists and a disease that is rapidly becoming resistant to the medication available, new therapies are urgently needed.
Malaria is one of the most devastating diseases, only second in impact to tuberculosis, and causing 1 in 5 of all childhood deaths in Africa. Half a million infected cases, largely in developing countries, result in a million deaths a year. The disease is transmitted through the bite of female mosquitoes and is characterised by fever and a general poor condition that, if the patient is healthy, can be effectively treated. But a vaccine continues to elude scientists and the emergence of insectide-resistant mosquitoes and parasites resistant to the malaria drugs available has led to an increase of malaria cases in recent years. Considering that 40% of the world population lives in affected areas, this increase can have catastrophic health and economical consequences, especially in developing countries, but not only there. In fact, and probably due to climate change, malaria mosquitoes have already appeared in places as “remote” as New York.
In conclusion, new effective therapies need to be developed and one possibility is to target the components of the host that interact with the parasite. In fact, although counterintuitive, this approach - as long as it does not interfere with the body normal functions- has the advantage of not loose efficiency due to parasite adaptations, as it is the case with current therapies.
And it was with this possibility in mind that Ana Pamplona, Miguel P Soares, Maria M Mota and colleagues at the Institute of Molecular Medicine and Gulbenkian Institute in Lisbon, Portugal and the University of Debrecen in Hungary studied two different strains of mice, both capable of being infected with Plasmodium and develop malaria but only one capable of develop a cerebral malaria-like disease (called experimental cerebral malaria or ECM). Using this difference as basis for their study the researchers tried to understand what laid behind ECM protection.
And it was found that protection was associated to the activation of the gene Hmxo1, which produces an enzyme (enzymes are proteins capable of triggering chemical reactions in the body) called heme oxygenase-1 (HO-1). HO-1, like the name states, oxidizes heme, an iron-containing molecule that exists inside red blood cells helping the transport of oxygen in the blood.
In fact, during malaria infection a large numbers of red blood cells are destroyed after being infected (anaemia is one of the major problems of the disease) and the molecule heme is released in large quantities into the blood stream of the host becoming a serious problem since this molecule is extremely toxic. To protect themselves animals in this situation produce HO-1, which transform heme into iron, carbon monoxide (CO) that is not toxic when generated this way and another non-toxic molecule called biliverdin. And Pamplona and colleagues noticed that there was a direct correlation between HO-1/CO production and ECM protection in the two strains of mice.
To test this correlation, next, ECM protected mice were genetically manipulated to loose HO-1 and this resulted in loss of protection further supporting the link HO-1/CO - ECM protection. On the other hand, mice that normally developed ECM when induced to produce HO-1 were protected against the disease. Administration of CO had the same protective effect suggesting that HO-1 effect was mediated through this gas.
Further tests showed that HO-1/CO protective effect was connected with blood brain barrier (BBB) integrity.
BBB is a protective layer existent between the brain tissues and the blood vessels whose role is to restrict the passage of substances and cells from the blood to avoid harm to this organ. During brain infection this barrier is disrupted leading to invasion by molecules and cells that although there mostly to combat infection can, nevertheless, provoke damage to the tissues. BBB disruption and brain invasion by blood components are hallmarks of (E)CM (meaning both ECM and its human counterpart CM) and researchers discovered that HO-1/CO was not only able to prevent this BBB disruption (and the concomitant invasion) but also micro vascular damage and brain haemorrhage, two other major characteristics of (E)CM.
But what was the exact mechanism of CO protection? CO did not affect the parasite levels or the red blood cells destruction showing that its protective effect was done in some other way. When infected red blood cells are destroyed, haemoglobin (the molecule in the red blood cell that carries oxygen) is released and rapidly oxidised just to become very unstable and release the (toxic) heme groups mentioned before that will accumulate in the infected tissues. What Pamplona, Mota and colleagues found was that CO bound haemoglobin stopping its oxidation and avoiding in this way the formation of free heme.
The next step was to try and link heme accumulation to ECM and in fact it was discovered that heme was capable of disrupting the BBB permitting the entrance of inflammatory mediators capable of provoke (E)CM symptoms.
In conclusion, Pamplona and colleagues in Portugal show that HO-1 and CO can inhibit the development of cerebral malaria symptoms, such as BBB disruption, brain haemorrhage and micro vascular congestion by preventing the formation of free heme. Their work describes a new “protective” gene against malaria suggesting that others might exist in humans and opening the door to a range of new therapies that have the added bonus of not be easily affected by the malaria parasite extraordinary capacity to adapt.
The research also shows that, if human experiments confirm Pamplona Soares, Mota and colleagues’ results, malaria patients might be cheaply and easily treated against CM development with small quantities of inhaled CO what would be a major step in the control of the disease and its fatalities.