Why does malaria kill?
Malaria kills, because the single-cell parasite, P. falciparum, at some point in its complex life cycle invades human red cells, so it can be sucked in by a mosquito and find a new human host. For the parasite, this strategy is no fun, as it much prefers living inside the liver cells, but you need to be fruitful and multiply, that’s the game, so it is bound to get out of these cozy places and make its living inside our red cells, which are singularly unattractive hosts for inhabitation.
The parasite multiplies inside these cells consuming 4/5 of the hemoglobin in them, so that new merozoites invade new blood cells. The disease symptoms are mainly due to the destruction of the infected erythrocytes and conversion of hemoglobin, the oxygen carrier in the body, to a toxin hemozoin, which (when released into blood as the erythrocyte disintegrates) triggers massive immune response that kills. But why is the parasite consuming all this hemoglobin? This is indeed very strange, when you think of it: the erythrocytes consist of thousands of proteins that are more nutritious than hemoglobin. The merozoites do not need to consume so much of hemoglobin. What they consume, they waste (>80%). Moreover, when you break down hemoglobin, you make heme (alpha-hematin), which is toxic both to the host cell and the parasite. So the parasite needs to deal with this toxin spending its own resources. To this end, the parasite turns alpha-hematin to beta-hematin that crystallizes as 200 nm hemozoin nanoparticles. Chloroquine and quinine interfere with this crystallization: that alone is sufficient to kill the parasite. Hemozoin makes breath-takingly beautiful, optically dichroic magnetic, needle-like crystals, and its synthesis is an ingenious method of dealing with the problem of extra iron. Chemically, it is a thing of great beauty. A malarial patient produces this beautiful nano-art, dying in the process.
Yet it is not in the parasite's interest to kill the host. Furthermore, given the fact that sickling hemoglobin is difficult to digest by the aspartic acid protease in the vacuoles (more resembling of the lysosomes) that the parasite uses, a lot of people in malaria-prone regions get some degree of protection by a hemoglobin mutation, which is not good for spreading of the parasite. Heavy reliance on hemoglobin digestion and hemozoin production are not only queer, as it all looks pointless, it is a major weakness.
...During their asexual reproduction cycle in human red cells, Plasmodium falciparum parasites consume most of the host cell hemoglobin, far more than they require for protein biosynthesis. They also induce a large increase in the permeability of the host cell plasma membrane to allow for an increased traffic of nutrients and waste products. Why do the parasites digest hemoglobin in such excess? And how can infected red cells retain their integrity for the duration of the asexual cycle when comparably permeabilized uninfected cells hemolyse earlier?
...The parasite ingests and digests about 70% of the host cell hemoglobin (Hb) but uses only up to 16% of the released amino acids for protein biosynthesis. The reason why parasites expend so much energy ingesting and digesting excess hemoglobin and detoxifying the cell from toxic ferriprotoporphyrin IX remains puzzling. Another unresolved puzzle concerns the mechanism by which parasitized red cells are able to retain their osmotic stability for the approximately 48-hour reproductive cycle of the parasite despite the rapid dissipation of the Na+ and K+ gradients. A recent study by demonstrated that if permeation pathways were induced in uninfected cells as they are in infected cells, the uninfected cells would hemolyse by approximately 44 hours. Their estimates make the lysis resistance blood cells with large internal parasites even harder to comprehend. http://bloodjournal.hematologylibrary.org/cgi/content/abstract/101/10/4189
So, why is the parasite doing it? The answer is indeed unknown, but it might be the prevention of osmotic lysis. The parasite has to consume the host cell in order to multiply, but if the osmotic pressure, for whatever reason, changes as the protein molecules are broken into pieces (that can permeated the cell wall), the host cell either explodes or implodes, and the parasite dies with it. So it needs to keep the erythrocytes intact in order to eat them alive. The idea is that hemoglobin is consumed for no other reason than to stabilize this osmotic pressure. It is not food, it is destroyed in order to avoid the rapture of the host cell - to live and let live!
...The evolutionary pressures that set the observed values of permeability for K+ and H+ suggest that the need to ensure high nutrient and waste traffic took priority over the energy investments required for host cell ingestion and digestion and to prevent ferriprotoporphyrin IX-induced damage. These are necessary to ensure the osmotic stability of the host cells throughout the asexual reproduction cycle of the parasite.
This idea is both recent and untested, but malaria might be lethal, because it is trying to protect the host cells from premature death during the multiplication stage of the parasite. For that the parasite destroys hemoglobin to keep its host cells alive. Alas, it does not comprehend the larger picture, in which saving the individual host cell at all costs (which it pursues to its own selfish ends) is death of the organism. It is the case of well-meant, but myopic good intentions. Surely, such intentions kill. We all know that. So there is a moral lesson in it...
Why does malaria kill?
The parasite multiplies inside these cells consuming 4/5 of the hemoglobin in them, so that new merozoites invade new blood cells. The disease symptoms are mainly due to the destruction of the infected erythrocytes and conversion of hemoglobin, the oxygen carrier in the body, to a toxin hemozoin, which (when released into blood as the erythrocyte disintegrates) triggers massive immune response that kills. But why is the parasite consuming all this hemoglobin? This is indeed very strange, when you think of it: the erythrocytes consist of thousands of proteins that are more nutritious than hemoglobin. The merozoites do not need to consume so much of hemoglobin. What they consume, they waste (>80%). Moreover, when you break down hemoglobin, you make heme (alpha-hematin), which is toxic both to the host cell and the parasite. So the parasite needs to deal with this toxin spending its own resources. To this end, the parasite turns alpha-hematin to beta-hematin that crystallizes as 200 nm hemozoin nanoparticles. Chloroquine and quinine interfere with this crystallization: that alone is sufficient to kill the parasite. Hemozoin makes breath-takingly beautiful, optically dichroic magnetic, needle-like crystals, and its synthesis is an ingenious method of dealing with the problem of extra iron. Chemically, it is a thing of great beauty. A malarial patient produces this beautiful nano-art, dying in the process.
Yet it is not in the parasite's interest to kill the host. Furthermore, given the fact that sickling hemoglobin is difficult to digest by the aspartic acid protease in the vacuoles (more resembling of the lysosomes) that the parasite uses, a lot of people in malaria-prone regions get some degree of protection by a hemoglobin mutation, which is not good for spreading of the parasite. Heavy reliance on hemoglobin digestion and hemozoin production are not only queer, as it all looks pointless, it is a major weakness.
...During their asexual reproduction cycle in human red cells, Plasmodium falciparum parasites consume most of the host cell hemoglobin, far more than they require for protein biosynthesis. They also induce a large increase in the permeability of the host cell plasma membrane to allow for an increased traffic of nutrients and waste products. Why do the parasites digest hemoglobin in such excess? And how can infected red cells retain their integrity for the duration of the asexual cycle when comparably permeabilized uninfected cells hemolyse earlier?
...The parasite ingests and digests about 70% of the host cell hemoglobin (Hb) but uses only up to 16% of the released amino acids for protein biosynthesis. The reason why parasites expend so much energy ingesting and digesting excess hemoglobin and detoxifying the cell from toxic ferriprotoporphyrin IX remains puzzling. Another unresolved puzzle concerns the mechanism by which parasitized red cells are able to retain their osmotic stability for the approximately 48-hour reproductive cycle of the parasite despite the rapid dissipation of the Na+ and K+ gradients. A recent study by demonstrated that if permeation pathways were induced in uninfected cells as they are in infected cells, the uninfected cells would hemolyse by approximately 44 hours. Their estimates make the lysis resistance blood cells with large internal parasites even harder to comprehend. http://bloodjournal.hematologylibrary.org/cgi/content/abstract/101/10/4189
So, why is the parasite doing it? The answer is indeed unknown, but it might be the prevention of osmotic lysis. The parasite has to consume the host cell in order to multiply, but if the osmotic pressure, for whatever reason, changes as the protein molecules are broken into pieces (that can permeated the cell wall), the host cell either explodes or implodes, and the parasite dies with it. So it needs to keep the erythrocytes intact in order to eat them alive. The idea is that hemoglobin is consumed for no other reason than to stabilize this osmotic pressure. It is not food, it is destroyed in order to avoid the rapture of the host cell - to live and let live!
...The evolutionary pressures that set the observed values of permeability for K+ and H+ suggest that the need to ensure high nutrient and waste traffic took priority over the energy investments required for host cell ingestion and digestion and to prevent ferriprotoporphyrin IX-induced damage. These are necessary to ensure the osmotic stability of the host cells throughout the asexual reproduction cycle of the parasite.
This idea is both recent and untested, but malaria might be lethal, because it is trying to protect the host cells from premature death during the multiplication stage of the parasite. For that the parasite destroys hemoglobin to keep its host cells alive. Alas, it does not comprehend the larger picture, in which saving the individual host cell at all costs (which it pursues to its own selfish ends) is death of the organism. It is the case of well-meant, but myopic good intentions. Surely, such intentions kill. We all know that. So there is a moral lesson in it...
Why does malaria kill?