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Cozy niches: certain host cell environments make malaria parasites
resistant to drugs
EMBARGO: June 4, 2015, 11am Pacific / 2pm Eastern
Of the two species of Plasmodium parasites commonly infecting humans, P. vivax grows
exclusively in immature red blood cells called reticulocytes. P. falciparum can infect
reticulocytes, but it grows primarily in mature red blood cells (called erythrocytes) which
make up 99% of red cells in circulation. A study published on June 4th in PLOS Pathogens
shows that the different metabolic states of these human host cells provide different
growth conditions for the respective parasites—and warn that, as a consequence, drugs
that work against one Plasmodium species might fail to be effective against the other.
After their birth in the bone marrow, red blood cells undergo a number of changes to
develop into highly specialized oxygen transporters. They expel their nucleus (with its DNA
content) before they are released into the blood as reticulocytes. As they mature they get
rid of many of their other organelles as well, until they are disk-shaped cells full of
hemoglobin, a red protein (which gives blood its color) designed to carry oxygen.
To address whether the two classes of host red blood cells offer different resources for
parasite survival, and whether these resources could influence antimalarial drug efficacy,
Andy Waters, from the Wellcome Trust Centre for Molecular Parasitology at the University
of Glasgow, UK, and colleagues from Glasgow and Melbourne, Australia, undertook a
comprehensive biochemical analysis of the metabolites present in reticulocytes on one
hand and in mature erythrocytes on the other.
They found that reticulocytes contain elevated levels of many metabolites that could
potentially be scavenged by the invading and growing malaria parasite. They also saw a
marked overlap in metabolic pathways observed in the reticulocyte and those predicted in
the parasite. Such common pathways might be uniquely dispensable to Plasmodium during
its growth in reticulocytes while they are essential—and hence a good drug target—for
growth in erythrocytes.
To test this hypothesis, the researchers used genetic tools to disrupt some of the
overlapping pathways in P. berghei, a species that causes malaria in mice and, similar to
P. vivax, has a strong preference for growth in host reticulocytes. They found that indeed
such mutant P. berghei strains could grow in mouse reticulocytes (utilizing the host’s
metabolic products).
Moreover, when the researchers compared the sensitivity to a drug known to target one of
the overlapping pathways in a test-tube experiment, they found that P. berghei was
considerably less sensitive to the drug than P. falciparum, presumably because the former
was able to scavenge the metabolites from their reticulocyte host environment whereas no
such external sources were available in the erythrocyte host cells invaded by P. falciparum.
Their data, the researchers say, show that reticulocytes provide a highly enriched host cell
environment for Plasmodium parasites. They suggest that “the availability of the
reticulocyte metabolome might reduce or block the efficacy of antimalarial drugs that
target parasite metabolism. Furthermore reticulocyte resident P. falciparum may enjoy
similar protection, giving rise to the possibility that infections could re-emerge.”
Contact:
Andy Waters
e-mail: [email protected]
phone: +44.(0)141.330.8720
Please use this URL to provide readers access to the paper (Link goes live upon
article publication):
http://dx.plos.org/10.1371/journal.ppat.1004882
Related Image for Press Use:
https://www.plos.org/wp-content/uploads/2013/05/Pathogens_Waters_JUN4_IMG.jpg
Image Caption and credit:
Mosquito mid-guts infected with P. berghei oocysts. Left panel shows a mosquito mid-gut
infected with wild-type parasites. Right panel shows a mosquito mid-gut infected with
mutant parasites lacking malate dehydrogenase, which make fewer oocysts but still are
able to transmit the parasite.
Credit: Waters et al., CC-BY
Authors and Affiliations:
Anubhav Srivastava, University of Glasgow, UK
Darren J. Creek, University of Glasgow, UK; Monash University, Australia
Krystal J. Evans, Walter and Eliza Hall Institute of Medical Research, Australia
David De Souza, University of Melbourne, Australia
Louis Schofield, Walter and Eliza Hall Institute of Medical Research, Australia; James Cook University, Australia
Sylke Müller, University of Glasgow, UK
Michael P. Barrett, University of Glasgow, UK
Malcolm J. McConville, University of Melbourne, Australia
Andrew P. Waters, University of Glasgow, UK
Please contact [email protected] if you would like more information.
Funding: This study was supported by Wellcome Trust (http://www.wellcome.ac.uk/) grant 083811/Z/07/Z
(holder APW); National Health and Medical Research Council (http://www.nhmrc.gov.au/) grant 1059530
(holder MJM); European Virtual Institute of Malaria Research (http://www.evimalar.org/) grant FP7-PEOPLE2010-IRSES Project 5 (holder AS) and University of Glasgow Staff Research Scholarship 2009-14 (holder AS)
The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the
manuscript.
Competing Interests: The authors have declared that no competing interests exist.
Citation: Srivastava A, Creek DJ, Evans KJ, De Souza D, Schofield L, Müller S, et al. (2015) Host Reticulocytes
Provide Metabolic Reservoirs That Can Be Exploited by Malaria Parasites. PLoS Pathog 11(6): e1004882.
doi:10.1371/journal.ppat.1004882
About PLOS Pathogens
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fungi, parasites, prions, and viruses, and how these pathogens interact with their host organisms. For more
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