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1.  Fosmidomycin Uptake into Plasmodium and Babesia-Infected Erythrocytes Is Facilitated by Parasite-Induced New Permeability Pathways 
PLoS ONE  2011;6(5):e19334.
Background
Highly charged compounds typically suffer from low membrane permeability and thus are generally regarded as sub-optimal drug candidates. Nonetheless, the highly charged drug fosmidomycin and its more active methyl-derivative FR900098 have proven parasiticidal activity against erythrocytic stages of the malaria parasite Plasmodium falciparum. Both compounds target the isoprenoid biosynthesis pathway present in bacteria and plastid-bearing organisms, like apicomplexan parasites. Surprisingly, the compounds are inactive against a range of apicomplexans replicating in nucleated cells, including Toxoplasma gondii.
Methodology/Principal Findings
Since non-infected erythrocytes are impermeable for FR90098, we hypothesized that these drugs are taken up only by erythrocytes infected with Plasmodium. We provide evidence that radiolabeled FR900098 accumulates in theses cells as a consequence of parasite-induced new properties of the host cell, which coincide with an increased permeability of the erythrocyte membrane. Babesia divergens, a related parasite that also infects human erythrocytes and is also known to induce an increase in membrane permeability, displays a similar susceptibility and uptake behavior with regard to the drug. In contrast, Toxoplasma gondii-infected cells do apparently not take up the compounds, and the drugs are inactive against the liver stages of Plasmodium berghei, a mouse malaria parasite.
Conclusions/Significance
Our findings provide an explanation for the observed differences in activity of fosmidomycin and FR900098 against different Apicomplexa. These results have important implications for future screens aimed at finding new and safe molecular entities active against P. falciparum and related parasites. Our data provide further evidence that parasite-induced new permeability pathways may be exploited as routes for drug delivery.
doi:10.1371/journal.pone.0019334
PMCID: PMC3087763  PMID: 21573242
2.  γδ T Cell Immune Manipulation during Chronic Phase of Simian HIV Infection Confers Immunological Benefits1 
Vγ2Vδ2 T cells, a major human γδ T cell subset, recognize the phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) produced by mycobacteria and some opportunistic pathogens, and they contribute to innate/adaptive/homeostatic and anticancer immunity. As initial efforts to explore Vγ2Vδ2 T cell-based therapeutics against HIV/AIDS-associated bacterial/protozoal infections and neoplasms, we investigated whether a well-defined HMBPP/IL-2 therapeutic regimen could overcome HIV-mediated immune suppression to massively expand polyfunctional Vγ2Vδ2 T cells, and whether such activation/expansion could impact AIDS pathogenesis in simian HIV (SHIV)-infected Chinese rhesus macaques. While HMBPP/IL-2 coadministration during acute or chronic phase of SHIV infection induced massive activation/expansion of Vγ2Vδ2 T cells, the consequences of such activation/expansions were different between these two treatment settings. HMBPP/IL-2 cotreatment during acute SHIV infection did not prevent the increases in peak and set-point viral loads or the accelerated disease progression seen with IL-2 treatment alone. In contrast, HMBPP/IL-2 cotreatment during chronic infection did not exacerbate disease, and more importantly it could confer immunological benefits. Surprisingly, although viral antigenic loads were not increased upon HMBPP/IL-2 cotreatment during chronic SHIV infection, HMBPP activation of Vγ2Vδ2 T cells boosted HIV Env-specific Ab titers. Such increases in Abs were sustained for >170 days and were immediately preceded by increased production of IFN-γ, TNF-α, IL-4, and IL-10 during peak expansion of Vγ2Vδ2 T cells displaying memory phenotypes, as well as the short-term increased effector function of Vγ2Vδ2 T cells and CD4+ and CD8+ αβ T cells producing antimicrobial cytokines. Thus, HMBPP/Vγ2Vδ2 T cell-based intervention may potentially be useful for combating neoplasms and HMBPP-producing opportunistic pathogens in chronically HIV-infected individuals.
doi:10.4049/jimmunol.0901760
PMCID: PMC2863296  PMID: 19786533
3.  Prolonged (E)-4-Hydroxy-3-Methyl-But-2-Enyl Pyrophosphate-Driven Antimicrobial and Cytotoxic Responses of Pulmonary and Systemic Vγ2Vδ2 T Cells in Macaques1 
Although phosphoantigen-specific Vγ2Vδ2 T cells appear to play a role in antimicrobial and anticancer immunity, mucosal immune responses and effector functions of these γδ T cells during infection or phospholigand treatment remain poorly characterized. In this study, we demonstrate that the microbial phosphoantigen (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP) plus IL-2 treatment of macaques induced a prolonged major expansion of circulating Vγ2Vδ2 T cells that expressed CD8 and produced cytotoxic perforin during their peak expansion. Interestingly, HMBPP-activated Vγ2Vδ2 T cells underwent an extraordinary pulmonary accumulation, which lasted for 3–4 mo, although circulating Vγ2Vδ2 T cells had returned to baseline levels weeks prior. The Vγ2Vδ2 T cells that accumulated in the lung following HMBPP/IL-2 cotreatment displayed an effector memory phenotype, as follows: CCR5+CCR7−CD45RA−CD27+ and were able to re-recognize phosphoantigen and produce copious amounts of IFN-γ up to 15 wk after treatment. Furthermore, the capacity of massively expanded Vγ2Vδ2 T cells to produce cytokines in vivo coincided with an increase in numbers of CD4+ and CD8+ αβ T cells after HMBPP/IL-2 cotreatment as well as substantial perforin expression by CD3+Vγ2− T cells. Thus, the prolonged HMBPP-driven antimicrobial and cytotoxic responses of pulmonary and systemic Vγ2Vδ2 T cells may confer immunotherapeutics against infectious diseases and cancers.
PMCID: PMC2865221  PMID: 18056373
5.  Mycoplasma penetrans Is Capable of Activating Vγ9/Vδ2 T Cells While Other Human Pathogenic Mycoplasmas Fail To Do So  
Infection and Immunity  2004;72(8):4881-4883.
While most mycoplasma species appear to have evolutionarily lost the ability to synthesize isoprenoid precursors, Mycoplasma penetrans has retained the nonmevalonate pathway that proceeds via the immunogenic intermediate (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMB-PP). Consequently, this pathogen is capable of stimulating human Vγ9/Vδ2 T cells.
doi:10.1128/IAI.72.8.4881-4883.2004
PMCID: PMC470652  PMID: 15271953
6.  Fosmidomycin, a Novel Chemotherapeutic Agent for Malaria 
In previous studies, fosmidomycin has been shown to possess activity against Plasmodium falciparum in vitro and in the mouse model. It has a novel mode of action through inhibition of 1-deoxy-d-xylulose 5-phosphate reductoisomerase, an enzyme of the nonmevalonate pathway of isoprenoid biosynthesis, which is absent in humans. In this open-label, uncontrolled trial, the efficacy and safety of fosmidomycin, in an oral dose of 1,200 mg every 8 h for 7 days, were evaluated in the treatment of acute uncomplicated Plasmodium falciparum malaria in 20 adult subjects in Gabon and Thailand. Clinical assessments were performed and thick blood smears were evaluated every 8 h until parasite clearance and resolution of symptoms were achieved; assessments continued at weekly intervals thereafter for the duration of the 28-day followup period. All subjects were clinically and parasitologically cured on day 7 (primary end point). Parasite and fever clearance were rapid, with means of 44 and 41 h, respectively. On day 28, seven out of nine subjects (78%) were cured in Gabon and two out of nine subjects (22%) were cured in Thailand. The drug was well tolerated, although mild gastrointestinal side effects were recorded for five subjects. Analysis of hematological and biochemical parameters showed no clinically significant changes throughout the study. Fosmidomycin is an effective and safe antimalarial drug, although its use as a single agent is restricted by the occurrence of recrudescent infections. However, its role in combination therapy should be explored.
doi:10.1128/AAC.47.2.735-738.2003
PMCID: PMC151759  PMID: 12543685
7.  GcpE Is Involved in the 2-C-Methyl-d-Erythritol 4-Phosphate Pathway of Isoprenoid Biosynthesis in Escherichia coli 
Journal of Bacteriology  2001;183(8):2411-2416.
In a variety of organisms, including plants and several eubacteria, isoprenoids are synthesized by the mevalonate-independent 2-C-methyl-d-erythritol 4-phosphate (MEP) pathway. Although different enzymes of this pathway have been described, the terminal biosynthetic steps of the MEP pathway have not been fully elucidated. In this work, we demonstrate that the gcpE gene of Escherichia coli is involved in this pathway. E. coli cells were genetically engineered to utilize exogenously provided mevalonate for isoprenoid biosynthesis by the mevalonate pathway. These cells were then deleted for the essential gcpE gene and were viable only if the medium was supplemented with mevalonate or the cells were complemented with an episomal copy of gcpE.
doi:10.1128/JB.183.8.2411-2416.2001
PMCID: PMC95155  PMID: 11274098

Results 1-7 (7)