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  • Review Article
  • Published:

Looking under the skin: the first steps in malarial infection and immunity

Nature Reviews Microbiology volume 11, pages 701–712 (2013)Cite this article

Subjects

A Corrigendum to this article was published on 08 October 2013

This article has been updated

Key Points

  • Malaria is the most deadly parasitic infection of humans, killing up to 1 million people per year. No vaccine is currently available, and the development of drug-resistant Plasmodium spp. is of increasing concern.

  • The first phase of infection, the pre-erythrocytic (PE) phase, is clinically asymptomatic. Only after parasite replication in the liver and infection of large numbers of erythrocytes do symptoms arise.

  • The PE phase comprises sporozoites (the infectious stage) and the liver stages. Once injected by a mosquito, the sporozoites can remain in the skin, be transported in lymph vessels to draining lymph nodes or travel through the bloodstream to the liver. In the liver, sporozoites undergo an elaborate replication and developmental programme and transform into the merozoites that are released from the liver to infect erythrocytes.

  • The PE phase of infection is a formidable window of opportunity for therapeutic interventions owing to the small number of parasites present. Thus, targeting this 'bottleneck' of Plasmodium spp. infection with vaccines is an attractive strategy.

  • Live attenuated parasites mimicking the PE phase of infection can be used as vaccines. Attenuation is achieved by radiation, genetic alterations or drug-mediated developmental arrest.

Abstract

Malaria, which is caused by Plasmodium spp., starts with an asymptomatic phase, during which sporozoites, the parasite form that is injected into the skin by a mosquito, develop into merozoites, the form that infects erythrocytes. This pre-erythrocytic phase is still the most enigmatic in the parasite life cycle, but has long been recognized as an attractive vaccination target. In this Review, we present what has been learned in recent years about the natural history of the pre-erythrocytic stages, mainly using intravital imaging in rodents. We also consider how this new knowledge is in turn changing our understanding of the immune response mounted by the host against the pre-erythrocytic forms.

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Figure 1: The Plasmodium spp. life cycle.
Figure 2: The pre-erythrocytic phase in rodents.
Figure 3: Host cell traversal by sporozoites.
Figure 4: Liver-stage maturation and live attenuated parasite-based vaccine strategies.

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Change history

  • 08 October 2013

    In Box 3 of the above article (page 709) the sentence “Recently, it was found that five intravenous injections of >105 cryopreserved RAS protected all six tested patients against a challenge by bites of five mosquitoes 3 weeks after the last immunization dose, whereas four intravenous immunizations protected only three of nine patients139” should have read “Recently, it was found that five intravenous injections of >105 cryopreserved RAS protected all six tested patients against a challenge by bites of five mosquitoes 3 weeks after the last immunization dose, whereas four intravenous immunizations protected only six of nine patients139.” The authors apologize to readers for any misunderstanding caused. This has now been corrected online.

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Authors and Affiliations

  1. Institut Pasteur, Unité de Biologie et Génétique du Paludisme, 28 Rue du Dr Roux, 75724 Paris Cedex 15, France.,

    Robert Ménard, Joana Tavares & Rogerio Amino

  2. Department of Pathogens and Immunity, John Curtin School of Medical Research, Australian National University, Canberra, ACT 0200, Australia

    Ian Cockburn

  3. School of Animal, Plant and Environmental Sciences, Faculty of Science, and Wits Research Institute for Malaria, Faculty of Health Sciences, University of the Witwatersrand, Private Bag 3, Wits, Johannesburg, 2050, South Africa

    Miles Markus

  4. Johns Hopkins Malaria Research Institute, Bloomberg School of Public Health, Johns Hopkins University, 615 North Wolfe Street, Baltimore, 21210, Maryland, USA

    Fidel Zavala

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  1. Robert Ménard
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  2. Joana Tavares
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PowerPoint slides

Glossary

Sterilizing immunity

Immunity resulting in parasite clearance from the host.

Schizonts

Multinucleate, intracellular parasite stages originating from a single organism that reproduces by schizogony. Schizonts contain many individual merozoites when mature.

Hypnozoites

Dormant, non-dividing, intrahepatocytic forms of certain Plasmodium species, including Plasmodium vivax and Plasmodium ovale, which infect humans.

Recurrences

New phases of parasite multiplication inside erythrocytes. These recurrences originate from intra-erythrocytic parasite forms (recrudescence) or hypnozoites (relapse).

Gliding

A substrate-dependent type of unicellular motility defined by the lack of cell deformation during movement.

Parasitophorous vacuole

The vacuole inside which the parasite resides on host cell entry and throughout intracellular development.

Stellate cells

Pericytes that are located between a hepatocyte and a sinusoidal endothelial cell; also called Ito cells.

Kupffer cell

A resident macrophage in the liver; these cells mostly double-line the endothelial cell wall inside the sinusoid lumen.

Apicoplast

A relict, non-photosynthetic plastid-like organelle of red-algal origin, inherited from secondary endosymbiosis.

Immunoprivileged sites

Sites in the mammalian body that are characterized by the lack of major histocompatibility complex expression, the absence of phagocytic and antigen-presenting cells, and a potent immunosuppressant microenvironment.

Subunit vaccination

Vaccination using material that is distinct from live parasites (typically, recombinant proteins or virus-vectored antigens).

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Ménard, R., Tavares, J., Cockburn, I. et al. Looking under the skin: the first steps in malarial infection and immunity. Nat Rev Microbiol 11, 701–712 (2013). https://doi.org/10.1038/nrmicro3111

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