ReviewMore than just immune evasion: Hijacking complement by Plasmodium falciparum
Introduction
Malaria remains a major global health threat accounting for a yearly death toll of about 700,000 people on a background of about 200 million infections worldwide (WHO Malaria Report 2014). There are five species of Plasmodium that infect humans: P. falciparum, P. knowlesi, P. vivax, P. ovale and P. malariae. P. falciparum is responsible for the majority of human fatalities worldwide. Severe P. falciparum malaria remains an important cause of maternal and childhood morbidity and mortality. An emerging view is that the innate immune response to malaria infection driven by the complement system may be a determinant in the severity of infections (reviewed in Silver et al. (2010)). This review will cover the complex interaction between the human complement system and malaria infection in terms of hosts’ immune responses, parasites survival strategies and implications for the pathogenesis of severe complications of malaria.
Malaria parasites have a complex life cycle involving an insect vector, the female Anopheles mosquito, and a vertebrate host, the human (Fig. 1). Infection in humans is initiated through the bite of an infected female mosquito. The mosquito bite injects Plasmodium parasites, in the form of sporozoites, into the human bloodstream. Sporozoites travel to the liver to invade hepatocytes beginning the liver stage infection. Within 10 days, a single sporozoite multiplies asexually into thousands of merozoites which are released into the blood stream when the infected liver cell ruptures. These merozoites are capable of invading healthy red blood cells initiating the blood stage cycle of human infection. Within 48 h of invading a red blood cell, a single merozoite progresses through the ring and trophozoite forms to replicate and divide via schizogony into 16–32 new daughter merozoites. The infected red blood cell subsequently ruptures to release newly formed merozoites which are capable of re-infecting other healthy red blood cells. The blood stage cycle is responsible for all the clinical symptoms such as fever and chills. Some of the infected red blood cells will leave the asexual cycle to develop into the sexual forms of the parasites, called gametocytes, which freely circulate in the blood stream. When a female Anopheles mosquito bites an infected human, gametocytes are ingested into the mosquito midgut. The rest of the sexual stages occur within the mosquito host, where gametocytes are activated to mature into male and female gametes that undergo fertilisation to produce a diploid zygote. The diploid zygote develops into a mobile ookinete that crosses the midgut wall to embed itself as an oocyst on the exterior of the midgut. Thousands of sporozoites develop within the oocyst, which are subsequently released to migrate to the mosquito salivary glands and ready to be transmitted to the next human via a mosquito bite. Within both the human and mosquito host, the malaria parasite in its various sexual and asexual forms is exposed to the hosts’ immune system.
Section snippets
Activation and regulation
As an important part of the “first line of defence”, complement proteins act rapidly upon entry of pathogens into the human host to facilitate opsonisation of pathogens for phagocytosis, lyse pathogens directly and stimulate the adaptive immune response. This is exemplified by the correlation of deficiencies in certain complement components with susceptibility to recurrent infections caused by e.g. Streptococcus pneumoniae, Haemophilus influenza, Neisseria meningitidis (reviewed in Skattum et
Complement receptor 1 and malaria
CR1 is a type one integral membrane glycoprotein composed of an N-terminal ectodomain of varying polypeptide size, a transmembrane region and a C-terminal cytoplasmic domain (Fig. 3) (Krych-Goldberg and Atkinson, 2001). In humans, this glycoprotein is expressed on all peripheral blood cells with the exception of platelets, natural killer cells and most T cells (Fearon, 1980, Tedder et al., 1983). Apart from peripheral blood, CR1 has also been identified on follicular dendritic cells in the
Complement evasion strategy in the sexual stages of malaria parasites
Gametocytes, the sexual forms of the malaria parasites, also develop within human red blood cells (Fig. 1). When a female mosquito takes a blood meal, gametocytes are ingested. Upon arrival at the midgut, external stimuli trigger the release of gametocytes from their red blood cells to fully mature into female and male gametes. Within 1 h post-blood meal, fertilisation of these gametes produces a zygote that develops into a diploid ookinete. The motile ookinete is now able to exit the midgut
Complement and cerebral malaria
Cerebral malaria represents one of the most severe complications of human malaria infections. It is characterised by unarousable coma with associated parasitemia. It can affect both adults and children with survivors often suffering long-term cognitive and neurological damage. In 1981 Adam et al. investigated the role of immune complexes and complement in cerebral malaria. They found that hypocomplementaemia and elevated levels of the complement activation product C3d were associated with
Mosquito immunity to malaria
To complete its life cycle, malaria parasites have to evade the human immune system and to outsmart the innate defence mechanisms of the mosquito host. Several studies have looked at how Anopheles mosquitoes respond to Plasmodium infection. The discovery of thioester protein 1 (TEP1) revealed that there was a complement-like system present in Anopheles driven by thioester dependent deposition of the TEP1 protein (Levashina et al., 2001). Subsequently Leucine rich repeat (LRR) proteins (i.e.
Conclusions and future perspectives
Upon completion of its life cycle, P. falciparum has successfully evaded the immune defence of its two hosts. The erythroid receptor and complement regulator CR1 is implicated in malaria pathologies at various levels. High CR1 densities aid the efficient clearance of IC, which occur at high number during infection, thus protecting vulnerable host tissues and organs such as kidney and brain from inflammation and damage. High expression levels of CR1 may also support the red cells to better
Acknowledgements
WHT is supported by the Australian Research Council Future Fellowship. CQS is supported by the Deutsche Forschungsgemeinschaft, Germany.
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