Superinfection in malaria: Plasmodium shows its iron will

Abstract

After the bite of a malaria-infected mosquito, the Plasmodium sporozoite infects liver cells and produces thousands of merozoites, which then infect red blood cells, causing malaria. In malaria-endemic areas, several hundred infected mosquitoes can bite an individual each year, increasing the risk of superinfection. However, in infants that are yet to acquire immunity, superinfections are infrequent. We have recently shown that blood-stage parasitaemia, above a minimum threshold, impairs the growth of a subsequent sporozoite infection of liver cells. Blood-stage parasites stimulate the production of the host iron-regulatory factor hepcidin, which redistributes iron away from hepatocytes, reducing the development of the iron-dependent liver stage. This could explain why Plasmodium superinfection is not often found in young nonimmune children. Here, we discuss the impact that such protection from superinfection might have in epidemiological settings or in programmes for controlling malaria, as well as how the induction of hepcidin and redistribution of iron might influence anaemia and the outcome of non-Plasmodium co-infections.

Figure 1

Plasmodium life cycle. (A) During a blood meal, an anopheline mosquito injects Plasmodium sporozoites into the host dermis. (B) After reaching a blood vessel, sporozoites travel to the liver where—after traversing several hepatocytes—they invade a final one. (C) After asexual replication and development inside the hepatocyte, merozoites are released into the bloodstream. (D) Merozoites infect red blood cells during cycles of asexual replication. (E) Occasionally, replication cycles originate female and male gametocytes. (F) Through another blood meal, a mosquito ingests gametocytes into its midgut. (G) Fertilization of gametes occurs in the mosquito midgut with the formation of ookinetes and later the oocysts. (H) Sporozoites released from the oocyst migrate to the salivary gland of the mosquito and are released during the next blood meal.

Figure 2

Parasite-dependent protective effect over age and time. Young children often have high levels of blood-stage parasitaemia. When these children are re-infected with sporozoites, little replication or development of parasites happens in the liver, inhibiting superinfection. The blood parasitaemia of an infection decreases with increasing age. Infected individuals become susceptible to further infections only once parasite densities fall below a critical threshold, raising the probability of superinfection.

Figure 3

Malaria, hepcidin and anaemia. (A) In a healthy individual, loss of red blood cells (RBCs)—for example, by haemorrhage—leads to a hypoxia-induced increase in erythropoietin (EPO) production and a higher erythropoietic drive. Through mechanisms that are not fully understood, hepcidin synthesis by the liver is also reduced, increasing iron availability for incorporation into haemoglobin, and enabling recovery from anaemia. (B) Malaria infection also leads to a loss of RBCs, but causes an increase in hepcidin. Iron is sequestered in macrophages and is therefore not available for an efficient bone marrow response. In addition, the haemozoin released by replicating parasites and cytokines produced during the inflammatory response to infection further inhibits erythropoiesis.

Figure 4

Rodent models used to study the role of hepcidin and iron in primary Plasmodium infections and superinfection. (A) During blood-stage infection, hepcidin upregulation inhibits liver infection, suppressing Plasmodium superinfection. (B) Reduction of hepcidin back to levels in non-infected mice, by using chloroquine to treat blood-stage parasitaemia, allows secondary sporozoite infection to progress to blood infection. (C) Increased hepcidin levels in the absence of blood-stage infection—by using transgenic mice that overexpress hepcidin or through the inoculation of hepcidin peptide or hepcidin-expressing adenovirus into wild-type mice—impair sporozoite liver infection.

Sílvia Portugal

Hal Drakesmith

Maria M Mota