What Do Human Parasites Do with a Chloroplast Anyway?

The malaria parasite has a chloroplast, which is a holdover from its algal past. The authors discuss the fascinating biology of this organelle and its promise for treatment in light of a seminal new study

Apicoplast isoprenoid precursor synthesis and the molecular basis of fosmidomycin resistance in Toxoplasma gondii

Expression of a bacterial transporter protein in Toxoplasma gondii results in parasite susceptibility to Formidomycin, a drug targeting isoprenoid precursor synthesis

A metabolic Catch-22 due to evolutionary acquired isoprenoid dependency.

<p>Schematic representation of the putative evolution of the apicoplast and its metabolism. The ancestor of apicomplexans arose from the endosymbiotic merger of a protist host and a single celled red alga. The host likely benefited from the symbiont's ability to photosynthesize. Initially there were two redundant isoprenoid synthesis pathways: a cytoplasmic pathway (likely using the mevalonate pathway as ciliates still do <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001137#pbio.1001137-Eisen1" target="_blank">[47]</a>) and a plastid DOXP pathway. Note that both pathways have multiple enzymatic steps and are shown highly simplified here. The cytoplasmic pathway was lost producing dependency. This forced maintenance of the apicoplast even after loss of photosynthesis (lower panel). High concentrations of exogenously supplied IPP can overcome this dependency and thus rescue clindamycin induced loss of the organelle <a href="http://www.plosbiology.org/article/info:doi/10.1371/journal.pbio.1001137#pbio.1001137-Yeh1" target="_blank">[31]</a> (clindamycin specifically blocks apicoplast protein synthesis). Fos, fosmidomycin; N, nucleus; P, plastid; Statin, the active principle of the cholesterol-lowering drug Lipitor).</p

Dissection of the in vitro developmental program of Hammondia hammondi reveals a link between stress sensitivity and life cycle flexibility in Toxoplasma gondii

Most eukaryotic parasites are obligately heteroxenous, requiring sequential infection of different host species in order to survive. Toxoplasma gondii is a rare exception to this rule, having a uniquely facultative heteroxenous life cycle. To understand the origins of this phenomenon, we compared development and stress responses in T. gondii to those of its its obligately heteroxenous relative, Hammondia hammondi and have identified multiple H. hammondi growth states that are distinct from those in T. gondii. Of these, the most dramatic difference was that H. hammondi was refractory to stressors that robustly induce cyst formation in T. gondii, and this was reflected most dramatically in its unchanging transcriptome after stress exposure. We also found that H. hammondi could be propagated in vitro for up to 8 days post-excystation, and we exploited this to generate the first ever transgenic H. hammondi line. Overall our data show that H. hammondi zoites grow as stringently regulated, unique life stages that are distinct from T. gondii tachyzoites, and implicate stress sensitivity as a potential developmental innovation that increased the flexibility of the T. gondii life cycle

Genome-wide Analysis of Host-Plasmodium yoelii Interactions Reveals Regulators of the Type I Interferon Response

Invading pathogens trigger specific host responses, an understanding of which might identify genes that function in pathogen recognition and elimination. In this study, we performed trans-species expression quantitative trait locus (ts-eQTL) analysis using genotypes of the Plasmodium yoelii malaria parasite and phenotypes of mouse gene expression. We significantly linked 1,054 host genes to parasite genetic loci (LOD score ≥ 3.0). Using LOD score patterns, which produced results that differed from direct expression-level clustering, we grouped host genes that function in related pathways, allowing functional prediction of unknown genes. As a proof of principle, 14 of 15 randomly selected genes predicted to function in type I interferon (IFN-I) responses were experimentally validated using overexpression, small hairpin RNA knockdown, viral infection, and/or infection of knockout mice. This study demonstrates an effective strategy for studying gene function, establishes a functional gene database, and identifies regulators in IFN-I pathways

Strain-specific innate immune signaling pathways determine malaria parasitemia dynamics and host mortality

Intramural Research Program of the Division of Intramural Research at the NIAID; National Institutes of Health (NIH); National Cancer Institute; NIH [R01CA090327, R01CA101795]; China Scholarship Council (CSC)Malaria infection triggers vigorous host immune responses; however, the parasite ligands, host receptors, and the signaling pathways responsible for these reactions remain unknown or controversial. Malaria parasites primarily reside within RBCs, thereby hiding themselves from direct contact and recognition by host immune cells. Host responses to malaria infection are very different from those elicited by bacterial and viral infections and the host receptors recognizing parasite ligands have been elusive. Here we investigated mouse genome-wide transcriptional responses to infections with two strains of Plasmodium yoelii (N67 and N67C) and discovered differences in innate response pathways corresponding to strain-specific disease phenotypes. Using in vitro RNAi-based gene knockdown and KO mice, we demonstrated that a strong type I IFN (IFN-I) response triggered by RNA polymerase III and melanoma differentiation-associated protein 5, not Toll-like receptors (TLRs), binding of parasite DNA/RNA contributed to a decline of parasitemia in N67-infected mice. We showed that conventional dendritic cells were the major sources of early IFN-I, and that surface expression of phosphatidylserine on infected RBCs might promote their phagocytic uptake, leading to the release of parasite ligands and the IFN-I response in N67 infection. In contrast, an elevated inflammatory response mediated by CD14/TLR and p38 signaling played a role in disease severity and early host death in N67C-infected mice. In addition to identifying cytosolic DNA/RNA sensors and signaling pathways previously unrecognized in malaria infection, our study demonstrates the importance of parasite genetic backgrounds in malaria pathology and provides important information for studying human malaria pathogenesis