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Protozoan persister-like cells and drug treatment failure

Nature Reviews Microbiology volume 17, pages 607–620 (2019)Cite this article

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Abstract

Antimicrobial treatment failure threatens our ability to control infections. In addition to antimicrobial resistance, treatment failures are increasingly understood to derive from cells that survive drug treatment without selection of genetically heritable mutations. Parasitic protozoa, such as Plasmodium species that cause malaria, Toxoplasma gondii and kinetoplastid protozoa, including Trypanosoma cruzi and Leishmania spp., cause millions of deaths globally. These organisms can evolve drug resistance and they also exhibit phenotypic diversity, including the formation of quiescent or dormant forms that contribute to the establishment of long-term infections that are refractory to drug treatment, which we refer to as ‘persister-like cells’. In this Review, we discuss protozoan persister-like cells that have been linked to persistent infections and discuss their impact on therapeutic outcomes following drug treatment.

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Fig. 1: Persister-like cell types of Plasmodium spp.
Fig. 2: Toxoplasma gondii tachyzoites and bradyzoites.
Fig. 3: Dormant amastigote forms of Trypanosoma cruzi.
Fig. 4: Leishmania life cycle showing impact of persisters.
Fig. 5: Metabolic changes in protozoan persisters.

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Acknowledgements

M.P.B. is funded by a Wellcome Trust core grant to the Wellcome Centre for Integrative Parasitology (104111/Z/14/Z). R.L.T. is supported by a US National Institutes of Health grant (R01 AI124692).

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Authors and Affiliations

  1. Wellcome Centre for Integrative Parasitology, Institute of Infection, Immunity and Inflammation, University of Glasgow, Glasgow, UK

    Michael P. Barrett

  2. Center for Tropical and Emerging Global Diseases, University of Georgia, Athens, GA, USA

    Dennis E. Kyle & Rick L. Tarleton

  3. Department of Molecular Microbiology, Washington University School of Medicine, St Louis, MO, USA

    L. David Sibley & Joshua B. Radke

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M.P.B. researched data for article and provided substantial contribution to discussion of the content. M.P.B., D.E.K., L.D.S., J.B.R. and R.L.T wrote the article and reviewed/edited the manuscript before submission.

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Glossary

Persisters

A subpopulation of slow-growing or growth-arrested cells that have a decreased susceptibility to killing by normally effective cytotoxic agents. Persisters survive treatment with drugs because of their altered metabolism during a temporary state of quiescence and are genetically identical to other, drug-susceptible cells in the population. Persisters may arise stochastically or in response to environmental cues such as nutrient starvation.

Hypnozoite

A small dormant form of Plasmodium vivax and Plasmodium ovale (and Plasmodium cynomolgi in monkeys) that persists in host hepatocytes following infection of sporozoites.

Artemisinin

An antimalarial drug derived from the sweet wormwood plant, Artemisia annua. The structure comprises a sesquiterpene lactone containing an endoperoxide responsible for activity.

Tachyzoite

A rapidly growing intracellular form of Toxoplasma that divides asexually and undergoes successive rounds of lytic growth in a wide range of nucleated cells before being controlled by an efficient immune response. Cause of acute infection and disease manifestation in humans.

Bradyzoite

A persistent form of Toxoplasma found in tissue cysts, which are intracellular and commonly found in skeletal muscle and neurons in the brain. Cysts are not cleared by active immunity or drug therapy. Reactivation can lead to serious disease, especially in those with compromised immune function.

Amastigote

In Trypanosoma cruzi, an intracellular, replicative cell within the mammalian host cell cytoplasm (T. cruzi amastigotes reside in the cytoplasm of various host cell types but show preferential persistence in muscle and adipose tissues). In Leishmania, an intracellular form of Leishmania with a truncated flagellum that replicate in mammalian cells, including macrophages and dendritic cells, within the acidic phagolysosome compartment of these cells.

Sporozoite

In Plasmodium parasites, a form forming in mosquitoes, where it migrates to salivary glands and is injected during a blood meal. It migrates to the liver and invades hepatocytes. In Toxoplasma, an infectious form found in oocysts, the product of the sexual phase, which is shed into the environment and contaminates food and water, leading to transmission. The sporozoite persists in a semidormant state within the oocysts, surviving for many months in the environment.

Schizont

A multinucleated form of the Plasmodium parasite that forms through multiple nuclear divisions preceding cellular division to release merozoite forms. Can occur either in erythrocytes or before the erythrocytic cycle in hepatocytes.

Merozoites

Forms of Plasmodium parasites that emerge from liver cells after differentiation and invade red cells, where the asexual life cycle progression ultimately creates many more merozoites, which burst from infected red cells and invade new ones.

Trophozoite

A form in the Plasmodium parasite life cycle following the ring stage that consumes host haemoglobin before entering schizogony.

Haemolytic anaemia

Anaemia ensuing from lysis of red blood cells, for example due to oxidative stresses induced by primaquine in individuals that are deficient in glucose 6-phosphate dehydrogenase.

Trypomastigotes

In Trypanosoma cruzi, non-replicative, flagellated, extracellular cells that can invade host cells or be transmitted to reduviid vectors during a blood meal.

Promastigote

A form of Leishmania, with an anterior flagellum, that replicates within the midgut of the sandfly vector, which transmits these parasites. Several distinctive other forms exist in the sandfly vector too.

Ergosterol

Major sterol of the Leishmania plasma membrane, also found in fungi. Binds to amphotericin B.

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Barrett, M.P., Kyle, D.E., Sibley, L.D. et al. Protozoan persister-like cells and drug treatment failure. Nat Rev Microbiol 17, 607–620 (2019). https://doi.org/10.1038/s41579-019-0238-x

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