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A study published in PLOS Pathogens suggests the different metabolic states of reticulocytes and erythrocytes provide different growth conditions for the malaria parasites Plasmodium vivax and Plasmodium falciparum.
As P vivax grows exclusively in reticulocytes, and P falciparum grows primarily in erythrocytes, the research suggests drugs that work against one species might fail to be effective against the other.
Andrew Waters, PhD, of the University of Glasgow in the UK, and his colleagues set out to determine whether the 2 classes of host red blood cells offer different resources for parasite survival and whether these resources could influence antimalarial drug efficacy.
To do that, the team analyzed the metabolites present in reticulocytes and erythrocytes. They found that reticulocytes contain elevated levels of many metabolites that could potentially be scavenged by the invading and growing malaria parasite.
And there was a marked overlap in metabolic pathways observed in the reticulocyte and those predicted in the parasite. The researchers thought these common pathways might be uniquely dispensable to Plasmodium during its growth in reticulocytes but essential—and therefore a good drug target—for growth in erythrocytes.
To test this hypothesis, the team disrupted 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 reticulocytes.
They found the mutant P berghei strains could grow in mouse reticulocytes (utilizing the host’s metabolic products).
The researchers also compared the sensitivity of P berghei and P falciparum to a drug known to target one of the overlapping pathways, the pyrimidine biosynthesis inhibitor 5-fluoroorotate (5FOA).
They found that P berghei was considerably less sensitive to 5FOA than P falciparum. The IC50 value of 5FOA in vitro was almost 90-fold higher in P berghei than in P falciparum.
This was presumably because P berghei was able to scavenge the metabolites from their reticulocyte host environment, but no such external sources were available in the erythrocyte host cells invaded by P falciparum.
The researchers said their results indicate that reticulocytes provide a highly enriched host cell environment for Plasmodium parasites, and the availability of the reticulocyte metabolome might reduce or block the efficacy of antimalarial drugs that target parasite metabolism. 
Image by Peter H. Seeberger
A study published in PLOS Pathogens suggests the different metabolic states of reticulocytes and erythrocytes provide different growth conditions for the malaria parasites Plasmodium vivax and Plasmodium falciparum.
As P vivax grows exclusively in reticulocytes, and P falciparum grows primarily in erythrocytes, the research suggests drugs that work against one species might fail to be effective against the other.
Andrew Waters, PhD, of the University of Glasgow in the UK, and his colleagues set out to determine whether the 2 classes of host red blood cells offer different resources for parasite survival and whether these resources could influence antimalarial drug efficacy.
To do that, the team analyzed the metabolites present in reticulocytes and erythrocytes. They found that reticulocytes contain elevated levels of many metabolites that could potentially be scavenged by the invading and growing malaria parasite.
And there was a marked overlap in metabolic pathways observed in the reticulocyte and those predicted in the parasite. The researchers thought these common pathways might be uniquely dispensable to Plasmodium during its growth in reticulocytes but essential—and therefore a good drug target—for growth in erythrocytes.
To test this hypothesis, the team disrupted 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 reticulocytes.
They found the mutant P berghei strains could grow in mouse reticulocytes (utilizing the host’s metabolic products).
The researchers also compared the sensitivity of P berghei and P falciparum to a drug known to target one of the overlapping pathways, the pyrimidine biosynthesis inhibitor 5-fluoroorotate (5FOA).
They found that P berghei was considerably less sensitive to 5FOA than P falciparum. The IC50 value of 5FOA in vitro was almost 90-fold higher in P berghei than in P falciparum.
This was presumably because P berghei was able to scavenge the metabolites from their reticulocyte host environment, but no such external sources were available in the erythrocyte host cells invaded by P falciparum.
The researchers said their results indicate that reticulocytes provide a highly enriched host cell environment for Plasmodium parasites, and the availability of the reticulocyte metabolome might reduce or block the efficacy of antimalarial drugs that target parasite metabolism.
Image by Peter H. Seeberger
A study published in PLOS Pathogens suggests the different metabolic states of reticulocytes and erythrocytes provide different growth conditions for the malaria parasites Plasmodium vivax and Plasmodium falciparum.
As P vivax grows exclusively in reticulocytes, and P falciparum grows primarily in erythrocytes, the research suggests drugs that work against one species might fail to be effective against the other.
Andrew Waters, PhD, of the University of Glasgow in the UK, and his colleagues set out to determine whether the 2 classes of host red blood cells offer different resources for parasite survival and whether these resources could influence antimalarial drug efficacy.
To do that, the team analyzed the metabolites present in reticulocytes and erythrocytes. They found that reticulocytes contain elevated levels of many metabolites that could potentially be scavenged by the invading and growing malaria parasite.
And there was a marked overlap in metabolic pathways observed in the reticulocyte and those predicted in the parasite. The researchers thought these common pathways might be uniquely dispensable to Plasmodium during its growth in reticulocytes but essential—and therefore a good drug target—for growth in erythrocytes.
To test this hypothesis, the team disrupted 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 reticulocytes.
They found the mutant P berghei strains could grow in mouse reticulocytes (utilizing the host’s metabolic products).
The researchers also compared the sensitivity of P berghei and P falciparum to a drug known to target one of the overlapping pathways, the pyrimidine biosynthesis inhibitor 5-fluoroorotate (5FOA).
They found that P berghei was considerably less sensitive to 5FOA than P falciparum. The IC50 value of 5FOA in vitro was almost 90-fold higher in P berghei than in P falciparum.
This was presumably because P berghei was able to scavenge the metabolites from their reticulocyte host environment, but no such external sources were available in the erythrocyte host cells invaded by P falciparum.
The researchers said their results indicate that reticulocytes provide a highly enriched host cell environment for Plasmodium parasites, and the availability of the reticulocyte metabolome might reduce or block the efficacy of antimalarial drugs that target parasite metabolism.