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Innate sensing of malaria parasites

Key Points

  • Repeated cycles of Plasmodium invasion, replication and release from red blood cells result in the exponential growth of the parasite population, coinciding with a febrile paroxysms and other signs of malaria.

  • The mechanisms underlying the pathogenesis of malaria involve an overwhelming activation of innate immune cells by Plasmodium components and the systemic release of inflammatory mediators.

  • Plasmodium-derived glycosylphosphatidylinositol anchors, haemozoin and nucleic acids are sensed by distinct pattern recognition receptors (PRRs) in specific cellular compartments of macrophages and dendritic cells resulting in the release of inflammatory mediators.

  • Haemozoin acts as a vehicle to transport plasmodial DNA into phagolysosomes and, thereafter, to the host cell cytoplasm where it can be sensed by TLR9 and cytosolic innate immune receptors, respectively.

  • Interferon-γ priming promotes Toll-like receptor hyperresponsiveness and inflammasome assembly, forming the basis of systemic inflammation that is induced by Plasmodium components or microbial superinfection during malaria.

  • Further investigation of the role of PRRs in malaria may help to identify more potent and better-tolerated adjuvants for the development of a truly effective anti-malaria vaccine.

Abstract

Innate immune receptors have a key role in immune surveillance by sensing microorganisms and initiating protective immune responses. However, the innate immune system is a classic 'double-edged sword' that can overreact to pathogens, which can have deleterious effects and lead to clinical manifestations. Recent studies have unveiled the complexity of innate immune receptors that function as sensors of Plasmodium spp. in the vertebrate host. This Review highlights the cellular and molecular mechanisms by which Plasmodium infection is sensed by different families of innate immune receptors. We also discuss how these events mediate both host resistance to infection and the pathogenesis of malaria.

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Figure 1: Plasmodium life cycle and the pathogenesis of malaria.
Figure 2: Innate sensors of Plasmodium PAMPs and malaria DAMPs.
Figure 3: Pattern recognition receptors and the pathophysiology of malaria.

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Acknowledgements

The authors thank M. Trombly for critically reviewing this manuscript. The authors are also grateful to all of the members and collaborators of the R.T.G., K.A.F. and D.T.G. laboratories for their invaluable contributions to the work that is reviewed here. R.T.G. is a recipient of a Scholar Fellowship from Coordenação de Aperfeiçoamento de Pessoal de Ensino Superior (CAPES), Brazil, and the David Rockefeller Center for Latin American Studies at Harvard School of Public Health, USA. The R.T.G. laboratory in Brazil is funded by the National Institute of Science and Technology for Vaccines, Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq) and Fundação de Amparo a Pesquisa de Minas Gerai (Fapemig). D.T.G. is a recipient of a Visiting Scientists Fellowship from CNPq. K.A.F., D.T.G. and R.T.G. are funded by the US National Institutes of Health.

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Glossary

Apicomplexa

A large group of protozoa that includes the Plasmodium genus. They possess an apical complex structure that is involved in penetrating host cells.

Sporozoites

The Plasmodium stage that develops in the salivary glands of the mosquito and infects humans during the blood meal. When they are in the bloodstream, the sporozoites are transported to the liver where they invade hepatocytes for the first round of replication in the vertebrate host.

Merozoites

The pathogenic Plasmodium stage that infects red blood cells (RBCs) and rapidly reproduces asexually, forming schizonts that contain multiple parasites. RBCs are destroyed by the end of this process, which releases many merozoites that will infect other host cells.

Schizogeny

The replicative process of malaria parasites, either in hepatocytes or red blood cells, that involves nuclear division without cytoplasmic segmentation, followed by a cell budding to form the progeny called merozoites.

Pathogen-associated molecular patterns

(PAMPs). Molecular structures that are normally abundant in certain pathogens and are detected by innate immune receptors known as pattern recognition receptors. PAMPs are often used as vaccine adjuvants.

Malaria-associated syndromes

A collection of signs and symptoms that are characteristic of a specific manifestation of malaria, such as anaemia, respiratory distress or cerebral malaria.

Paroxysms

In malaria, paroxysms refer to sudden attacks of disease that are characterized by high fever, chills and various other symptoms. This sudden worsening of malaria symptoms is cyclic and coincides with the synchronous rupture of Plasmodium-infected red blood cells.

Glycosylphosphatidylinositol anchors

(GPI anchors). Glycolipid structures that link surface proteins to the surface membrane of eukaryotic cells. In protozoa, most surface proteins are linked via GPIs, and free GPIs are also expressed at the surface.

Haemozoin

The crystalline product resulting from the digestion of haemoglobin during different intraerythrocytic Plasmodium stages.

Toll-like receptors

(TLRs). A family of pattern recognition receptors that sense pathogen-associated molecular patterns and initiate pro-inflammatory responses during microbial infection.

Inflammasomes

Molecular platforms formed by members of the NOD-like receptors family, which activate caspase 1 to cleave pro-IL-1β and pro-IL-18 and release the active form of these cytokines.

Cytosolic sensors

Different families of pattern recognition receptors located in the cytoplasm that are often activated by DNA and RNA, and that induce the production of type I interferons.

Microvesicles

Vesicles derived from platelets, red blood cells, endothelial cells and leukocytes that serve as a communication system between host cells, and display important pro-inflammatory activity.

Adjuvant

An agent that is mixed with an antigen to increase the immune response to that antigen following immunization.

Reticulocyte

Immature red blood cells (RBCs) that correspond to 1% of total circulating RBCs in humans.

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Gazzinelli, R., Kalantari, P., Fitzgerald, K. et al. Innate sensing of malaria parasites. Nat Rev Immunol 14, 744–757 (2014). https://doi.org/10.1038/nri3742

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