Scientists have discovered a possible way to fight cerebral malaria - by giving patients carbon monoxide (CO) (05/2007)
Cerebral malaria (CM) is a severe form of malaria that affects the brain and is fatal in about 30-50% of the cases. But scientists in Portugal, in an article about to be published in Nature Medicine, report of a gene – Hmox1 – that protects against the disease by releasing CO into the host blood stream counteracting CM inflammatory processes (CO is known for its inflammatory properties). Maria M Mota, one of the leaders of the study, believes that their study in mice will be relevant for the treatment of human cerebral malaria and, supporting this idea, the protein produced by Hmox1 has already been reported in cerebral malaria patients. This also means that if these results can be reproduced in humans, inhalation of CO could potentially be used to treat 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 undoubtedly 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 provoked by a parasite called Plasmodium, which is transmitted through the bite of female mosquitoes, and is characterised by fever and 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 the different sensitivities to ECM.
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 what Pamplona and colleagues noticed was the existence of a direct correlation between HO-1/CO production and ECM protection in both strains of mice.
Further supporting this observation it was seen that ECM protected mice, when genetically manipulated to loose HO-1, lost their protection while mice that normally developed ECM, when induced to produce HO-1, were protected against the disease. Administration of CO also protected against ECM suggesting that HO-1 effect was mediated through this gas and later this effect was shown to be 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 components of the blood 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, which will then accumulate in the infected tissues. What Pamplona, Mota and colleagues found was that CO bonded haemoglobin stopping its oxidation and avoiding in this way the formation of free heme.
The final step was to try and link heme accumulation to ECM and, in fact, it was discovered that heme was capable of disrupt 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 suggests that, if human experiments confirm Pamplona Soares, Mota and colleagues’ results, malaria patients can 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.
1 Nature Medicine advanced online publication (14 May 2007)
“Heme oxygenase-1 and carbon monoxide suppress the pathogenesis of experimental cerebral malaria”
Authors of the original paper
Link to the journal – http://www.nature.com/nm/index.html