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  • Review Article
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Innate immunity to malaria

Nature Reviews Immunology volume 4, pages 169–180 (2004)Cite this article

Key Points

  • Innate immune responses have been shown to contribute to the control of malaria infections in mice and there is indirect evidence that they also contribute to the control of infection in humans.

  • There is conflicting evidence on the effect of malaria infection on dendritic cells (DCs), with conventional activation of DCs reported in some model systems and modulation of DC function towards an immunoregulatory phenotype reported in other systems.

  • Natural killer T (NKT) cells have a role in immunity to liver-stage parasites in mice, but there is little evidence so far for a role for these cells in the response to human malaria.

  • γδ T cells are activated in malaria infections in both mice and humans, and contribute to parasite clearance, but this role does not seem to be essential; some studies indicate that they might contribute to immune-mediated pathology.

  • NK cells are frequently the earliest source of interferon-γ during a blood-stage malaria infection and have an essential role in controlling acute parasitaemia in mice. Heterogeneity of the NK-cell response in humans indicates that their activation might be influenced by polymorphic NK-cell receptors.

  • Polymorphisms have been described in many genes encoding components of the innate immune response and there is evidence that such polymorphisms might affect the outcome of infection in humans.

  • Although a robust pro-inflammatory cytokine response emanating from cells of the innate immune system might be important for controlling acute infection, the potential for these responses to contribute to immune-mediated pathology needs to be investigated.

  • Innate immune responses influence the nature and magnitude of the adaptive immune response to malaria. Activators of the innate response might therefore be incorporated into malaria vaccines to provide adjuvant activity.

Abstract

Malaria is a major cause of disease and death in tropical countries. A safe and effective vaccine is essential to achieve significant and sustained reductions in malaria-related morbidity and mortality. Driven by this need, research on the immunology of malaria has tended to focus on adaptive immunity. The potential for innate immune mechanisms to provide rapid protection against malaria has been largely neglected. On the basis of data from animal models, and clinical and epidemiological studies, this review considers the potential for innate immune mechanisms directed against Plasmodium parasites both to contribute to protection from malaria and to modulate adaptive immune responses.

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Figure 1: The life cycle of Plasmodium falciparum in the human host and mosquito vector.
Figure 2: Representative course of infection with Plasmodium chabaudi chabaudi AS.
Figure 3: Linking innate and adaptive immunity to blood-stage malaria.

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Acknowledgements

We gratefully acknowledge the assistance of M. Tam in the preparation of this manuscript. E.M.R. would like to acknowledge the contributions of K. Artavanis-Tsakonas, M. Walther, D. Korbel, D. Davis, K. McQueen and P. Parham to studies on innate immunity in her laboratory. The work is supported by the UK Medical Research Council, The Wellcome Trust, Boehringer Ingelheim Funds, The Burroughs Wellcome Fund and the Canadian Institutes of Health Research.

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Authors and Affiliations

  1. McGill University Health Centre Research Institute and Department of Medicine, Centre for the Study of Host Resistance, McGill University, 1650 Cedar Avenue, Montreal, H3G 1A4, Quebec, Canada

    Mary M. Stevenson

  2. Department of Infectious and Tropical Diseases, London School of Hygiene and Tropical Medicine, Keppel Street, London, WC1E 7HT, UK

    Eleanor M. Riley

Authors
  1. Mary M. Stevenson
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  2. Eleanor M. Riley
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Correspondence to Mary M. Stevenson.

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DATABASES

LocusLink

CD36

CD40

CD80

CD83

CD86

CTLA4

GM-CSF

ICAM1

IFN-γ

IL-2

IL-4

IL-8

IL-10

IL-12

LT-α

Myd88

TGF-β

Tlr2

Tlr4

Tlr6

TNF

FURTHER INFORMATION

World Health Organization web site

Literature and links detailing genetic determinants of susceptibility to malaria

Glossary

γδ T CELLS

Although γδ T-cell receptors are potentially diverse, circulating γδ T cells express a restricted set of these receptors and seem to recognize a relatively restricted set of ligands; this might reflect postnatal expansion of a small number of γδ T-cell clones by a few potent antigens, such as those expressed by mycobacteria or other widely distributed bacteria.

SEVERE COMBINED IMMUNODEFICIENT (SCID) MICE

Mice with this defect in their immune system do not have B or T cells and can, therefore, not mount adaptive immune responses.

NUDE MICE

A mutation in mice that causes both hairlessness and defective formation of the thymus, which results in a lack of mature T cells.

CYTOPHILIC ANTIBODY

Opsonizing antibody subclasses in mice (IgG2a and IgG2b) and in humans (IgG1 and IgG3), which mediate phagocytosis by macrophages.

UNMETHYLATED CpG MOTIFS

Sequences in bacterial DNA recognized by the mammalian immune system, which consist of unmethylated CpG dinucleotides in certain base contexts.

MIXED LYMPHOCYTE REACTION

(MLR). When peripheral-blood mononuclear cells or splenocytes from MHC-disparate donors are mixed together in the same culture, T helper cells from each donor recognize allogeneic MHC molecules on antigen-presenting cells from the other donor, and the T helper cells are induced to proliferate and release cytokines.

NKT CELLS

A heterogeneous population of lymphocytes with phenotypic and functional characteristics of both classical T cells and natural killer (NK) cells. Classical mouse NKT cells express the NK1.1 cell-surface marker, are T-cell receptor (TCR) Vα14+, recognize lipid-containing antigen in the context of the non-classical MHC class I molecule CD1d and are selectively activated by the synthetic ligand α-galactosylceramide. Various unconventional T cells have also now been described that express a diverse array of TCRs and are not CD1d restricted.

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Stevenson, M., Riley, E. Innate immunity to malaria. Nat Rev Immunol 4, 169–180 (2004). https://doi.org/10.1038/nri1311

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