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Complexity of immunological processes in the pathogenesis of malaria

Nature Reviews Immunology volume 6, page 424 (2006)Cite this article

In their letter, Geoff Butcher and Janice Taverne speculate on the potential dangers of glycosylphosphatidylinositol (GPI)-based vaccines. The topic of GPI-based vaccines was only a minor component of our Review1, which focused on the immune mechanisms elicited during infection with the malaria parasite Plasmodium falciparum that might cause disease. We did include a brief discussion about the possibility of developing GPI-based vaccines, and followed this by a brief summary of the opposing views, which are reiterated in the letter from Butcher and Taverne. We noted that safety concerns apply to all malaria vaccines under development, including GPI-based vaccines. Therefore, we do not believe that we ignored safety concerns about GPI-based vaccines. In addition, although Butcher and Taverne assert that the host, rather than the parasite, produces the toxins that initiate disease, we believe that the parasite produces the toxins that initiate disease. Because malaria GPI is highly conserved, ubiquitous and produced in excess of the amount required for anchoring, we questioned whether it is the target of immune responses that efficiently control parasitaemia, and discussed this in our Review1.

Rather than focus on GPI-based vaccines, our Review1 of malarial pathogenesis builds on and extends previous discussions of the topic by suggesting a role for complex cellular infiltrates, rather than simple systemic cytokine excess, as the fundamental immunological event in disease pathogenesis. Sequestered parasites secrete products (including toxins) that initiate cellular recruitment and activation, contributing to cerebral and placental malaria, and to anaemia. These processes are subject to complex homeostatic regulation. We discussed a range of parasite molecules with potential toxic, inflammatory and counter-regulatory activity (see TABLE 2 of our Review1). Engagement of host pattern-recognition receptors by these molecules induces expression of numerous host genes, of which tumour-necrosis factor (TNF) is but one. TNF might therefore simply be a marker of pattern-recognition receptor activation, which is historically useful as a read-out for in vitro assays, but might not have a key causal role in cerebral malaria and anaemia. Indeed, TNF might be beneficial during malaria, and toxins clearly induce pathogenic gene expression independently of this molecule2. Our view therefore differs substantially from the systemic inflammation model that was originally proposed by Maegraith3, rather than by Clark4 as suggested by Butcher and Taverne.

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Authors and Affiliations

  1. The Walter and Eliza Hall Institute of Medical Research, 1G Royal Parade, Parkville, 3050, Victoria, Australia

    Louis Schofield

  2. Department of Pathology, University of Sydney, Camperdown, 2042, New South Wales, Australia

    Georges E. Grau

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  1. Louis Schofield
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  2. Georges E. Grau
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Schofield, L., Grau, G. Complexity of immunological processes in the pathogenesis of malaria. Nat Rev Immunol 6, 424 (2006). https://doi.org/10.1038/nri1858-c2

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