Elsevier

Molecular Immunology

Volume 67, Issue 1, September 2015, Pages 71-84
Molecular Immunology

Review
More than just immune evasion: Hijacking complement by Plasmodium falciparum

https://doi.org/10.1016/j.molimm.2015.03.006Get rights and content

Highlights

  • In our review we discuss the complex interaction between complement and malaria infection in terms of hosts immune responses, parasite survival and pathogenesis of severe forms of malaria.

  • We will focus on the role of complement receptor 1 and its associated polymorphisms in malaria immune complex clearance, as a mediator of parasite rosetting and as an entry receptor for Plasmodium falciparum invasion.

  • Complement evasion strategies of P. falciparum parasites in human and mosquitoes will also be highlighted.

Abstract

Malaria remains one of the world's deadliest diseases. Plasmodium falciparum is responsible for the most severe and lethal form of human malaria. P. falciparum's life cycle involves two obligate hosts: human and mosquito. From initial entry into these hosts, malaria parasites face the onslaught of the first line of host defence, the complement system. In this review, we discuss the complex interaction between complement and malaria infection in terms of hosts immune responses, parasite survival and pathogenesis of severe forms of malaria. We will focus on the role of complement receptor 1 and its associated polymorphisms in malaria immune complex clearance, as a mediator of parasite rosetting and as an entry receptor for P. falciparum invasion. Complement evasion strategies of P. falciparum parasites will also be highlighted. The sexual forms of the malaria parasites recruit the soluble human complement regulator Factor H to evade complement-mediated killing within the mosquito host. A novel evasion strategy is the deployment of parasite organelles to divert complement attack from infective blood stage parasites. Finally we outline the future challenge to understand the implications of these exploitation mechanisms in the interplay between successful infection of the host and pathogenesis observed in severe malaria.

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.

References (141)

  • P. Dasari et al.

    Digestive vacuole of Plasmodium falciparum released during erythrocyte rupture dually activates complement and coagulation

    Blood

    (2012)
  • P.K. Datta et al.

    HIV and complement: hijacking an immune defense

    Biomed. Pharmacother. Biomed. Pharmacother.

    (2006)
  • C. Dunk et al.

    Angiopoietin-1 and angiopoietin-2 activate trophoblast Tie-2 to promote growth and migration during placental development

    Am. J. Pathol.

    (2000)
  • M. Fraiture et al.

    Two mosquito LRR proteins function as complement control factors in the TEP1-mediated killing of Plasmodium

    Cell Host Amp. Microbe

    (2009)
  • C. Frolet et al.

    Boosting NF-kappaB-dependent basal immunity of Anopheles gambiae aborts development of Plasmodium berghei

    Immunity

    (2006)
  • T.-W. Gilberger et al.

    A novel erythrocyte binding antigen-175 paralogue from Plasmodium falciparum defines a new trypsin-resistant receptor on human erythrocytes

    J. Biol. Chem.

    (2003)
  • K. Hayton et al.

    Erythrocyte binding protein PfRH5 polymorphisms determine species-specific pathways of Plasmodium falciparum invasion

    Cell Host Microbe

    (2008)
  • A.H. Herrera et al.

    Analysis of complement receptor type 1 (CR1) expression on erythrocytes and of CR1 allelic markers in Caucasian and African American populations

    Clin. Immunol. Immunopathol.

    (1998)
  • O. Kaneko et al.

    Gene structure and expression of a Plasmodium falciparum 220-kDa protein homologous to the Plasmodium vivax reticulocyte binding proteins

    Mol. Biochem. Parasitol.

    (2002)
  • D.K. Kaul et al.

    Rosetting of Plasmodium falciparum-infected red blood cells with uninfected red blood cells enhances microvascular obstruction under flow conditions

    Blood

    (1991)
  • A. Khattab et al.

    Complement activation in primiparous women from a malaria endemic area is associated with reduced birthweight

    Placenta

    (2013)
  • M. Krych-Goldberg et al.

    Decay accelerating activity of complement receptor type 1 (CD35). Two active sites are required for dissociating C5 convertases

    J. Biol. Chem.

    (1999)
  • E.A. Levashina et al.

    Conserved role of a complement-like protein in phagocytosis revealed by dsRNA knockout in cultured cells of the mosquito, Anopheles gambiae

    Cell

    (2001)
  • C.-A. Lobo et al.

    Glycophorin C is the receptor for the Plasmodium falciparum erythrocyte binding ligand PfEBP-2 (baebl)

    Blood

    (2003)
  • J.M. Moulds et al.

    Molecular identification of Knops blood group polymorphisms found in long homologous region D of complement receptor 1

    Blood

    (2001)
  • H.J. Park et al.

    Using mutagenesis and structural biology to map the binding site for the Plasmodium falciparum merozoite protein PfRh4 on the human immune adherence receptor

    J. Biol. Chem.

    (2014)
  • T.N. Ramos et al.

    The C5 convertase is not required for activation of the terminal complement pathway in murine experimental cerebral malaria

    J. Biol. Chem.

    (2012)
  • C. Adam et al.

    Cryoglobulins, circulating immune complexes, and complement activation in cerebral malaria

    Infect. Immun.

    (1981)
  • J.H. Adams et al.

    A family of erythrocyte binding proteins of malaria parasites

    Proc. Natl. Acad. Sci. U. S. A.

    (1992)
  • U. Amara et al.

    Molecular intercommunication between the complement and coagulation systems

    J. Immunol.

    (2010)
  • R.H.G. Baxter et al.

    A heterodimeric complex of the LRR proteins LRIM1 and APL1C regulates complement-like immunity in Anopheles gambiae

    Proc. Natl. Acad. Sci. U. S. A.

    (2010)
  • J. Bernet et al.

    Viral mimicry of the complement system

    J. Biosci.

    (2003)
  • D.J. Birmingham et al.

    CR1 and CR1-like: the primate immune adherence receptors

    Immunol. Rev.

    (2001)
  • B.S. Blaum et al.

    Structural basis for sialic acid-mediated self-recognition by complement factor H

    Nat. Chem. Biol.

    (2015)
  • G.A. Butcher et al.

    Letter: mechanism of host specificity in malarial infection

    Nature

    (1973)
  • Q. Chen et al.

    The semiconserved head structure of Plasmodium falciparum erythrocyte membrane protein 1 mediates binding to multiple independent host receptors

    J. Exp. Med.

    (2000)
  • I.A. Cockburn et al.

    A human complement receptor 1 polymorphism that reduces Plasmodium falciparum rosetting confers protection against severe malaria

    Proc. Natl. Acad. Sci. U. S. A.

    (2004)
  • A. Conroy et al.

    C5a enhances dysregulated inflammatory and angiogenic responses to malaria in vitro: potential implications for placental malaria

    PLoS ONE

    (2009)
  • D.T. Covas et al.

    Knops blood group haplotypes among distinct Brazilian populations

    Transfusion (Paris)

    (2007)
  • C. Crosnier et al.

    Basigin is a receptor essential for erythrocyte invasion by Plasmodium falciparum

    Nature

    (2011)
  • M.M. Darley et al.

    Deletion of carboxypeptidase N delays onset of experimental cerebral malaria

    Parasite Immunol.

    (2012)
  • P. Dasari et al.

    Malarial anemia: digestive vacuole of Plasmodium falciparum mediates complement deposition on bystander cells to provoke hemophagocytosis

    Med. Microbiol. Immunol. (Berl.)

    (2014)
  • J.R. Dunkelberger et al.

    Complement and its role in innate and adaptive immune responses

    Cell Res.

    (2010)
  • M.T. Duraisingh et al.

    Phenotypic variation of Plasmodium falciparum merozoite proteins directs receptor targeting for invasion of human erythrocytes

    EMBO J.

    (2003)
  • T.R. Dykman et al.

    Polymorphism of the human C3b/C4b receptor. Identification of a third allele and analysis of receptor phenotypes in families and patients with systemic lupus erythematosus

    J. Exp. Med.

    (1984)
  • D.T. Fearon

    Identification of the membrane glycoprotein that is the C3b receptor of the human erythrocyte, polymorphonuclear leukocyte, B lymphocyte, and monocyte

    J. Exp. Med.

    (1980)
  • V.P. Ferreira et al.

    Critical role of the C-terminal domains of factor H in regulating complement activation at cell surfaces

    J. Immunol.

    (2006)
  • F.J.I. Fowkes et al.

    Host erythrocyte polymorphisms and exposure to Plasmodium falciparum in Papua New Guinea

    Malar. J.

    (2008)
  • M. Gandhi et al.

    Role of CR1 Knops polymorphism in the pathophysiology of malaria: Indian scenario

    J. Vector Borne Dis.

    (2009)
  • E. Geva et al.

    Human placental vascular development: vasculogenic and angiogenic (branching and nonbranching) transformation is regulated by vascular endothelial growth factor-A, angiopoietin-1, and angiopoietin-2

    J. Clin. Endocrinol. Metab.

    (2002)
  • Cited by (0)

    View full text