Host–parasite interactions: an intimate epigenetic relationship

Cheeseman, Kevin; Weitzman, Jonathan B

doi:10.1111/cmi.12471

Cited by 84 publications

(89 citation statements)

References 77 publications

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“…Conceptually, the behavioral changes induced in the host's offspring would enable an increased probability of transmission for the parasites own progeny (Poulin and Thomas, 2008). Most of this research has focused on intracellular protozoan parasites, specifically, Theileria, Toxoplasma, and Plasmodium (Lüder et al, 2009;Hari Dass and Vyas, 2014;Sivakumar et al, 2014;Cheeseman and Weitzman, 2015). The epigenetic programming by the parasite falls into 3 categories: the epigenator, the epigenetic initiator and the epigenetic maintainer (Berger et al, 2009).…”

Section: Genomic Manipulationmentioning

confidence: 99%

“…The epigenetic programming by the parasite falls into 3 categories: the epigenator, the epigenetic initiator and the epigenetic maintainer (Berger et al, 2009). In order to establish stably heritable states of genetic suppression, the pathogen must possess mechanisms that progress logically from the epigenator to the maintainer to have a lasting structural influence on host's DNA (Berger et al, 2009;Cheeseman and Weitzman, 2015).…”

Section: Genomic Manipulationmentioning

confidence: 99%

“…Recently, extensive studies indicate that several intracellular parasite species meet these criteria, implying that in these cases, infection can have a direct impact on gene expression (Lüder et al, 2009;Hari Dass and Vyas, 2014;Sivakumar et al, 2014;Cheeseman and Weitzman, 2015). This in turn has a variety of adaptive consequences for the parasite.…”

Section: Genomic Manipulationmentioning

confidence: 99%

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Lessons in Mind Control: Trends in Research on the Molecular Mechanisms behind Parasite-Host Behavioral Manipulation

Herbison

2017

Front. Ecol. Evol.

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Scientific and public interest in host manipulation by parasites has surged over the past few decades, resulting in an exponential growth of cases where potential behavioral manipulation has been identified. However, these studies dwarf the number of genuine attempts to elucidate the mechanistic processes behind this behavioral manipulation. Ultimately, this imbalance has slowed progress in the study of the mechanisms underlying host manipulation. As it stands, research suggests that the mechanisms of host manipulation fall into three categories: immunological, genomic/proteomic and neuropharmacological, and forth potential category: symbioant-mediated manipulation. After exploration of the literature pertaining to these four pathways, four major trends become evident. First and foremost, there is a severe disconnect between the observed molecular and behavioral shifts in a parasitized host. Indeed, very rarely a study demonstrates that molecular changes observed in a host are the result of active manipulation by the resident parasite, or that these molecular changes directly result in behavioral manipulation that increases the parasite's fitness. Secondly, parasites may often employ multiple pathways in unison to achieve control over their hosts. Despite this, current scientific approaches usually focus on each manipulation pathway in isolation rather than integrating them. Thirdly, the relative amount of host-parasite systems yet to be investigated in terms of molecular manipulation is staggering. Finally, as a result of the aforementioned trends, guiding mechanisms or principles for the multiple types of behavioral manipulation are yet to be found. Researchers should look to identify the manipulative factors required to generate the molecular changes seen in hosts, while also considering the "multi-pronged" approach parasites are taking to manipulate behavior. Assessing gene expression and its products during transitional periods in parasites may be a key methodological approach for tackling these recent trends in the host manipulation literature.

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Section: Genomic Manipulationmentioning

confidence: 99%

Section: Genomic Manipulationmentioning

confidence: 99%

Section: Genomic Manipulationmentioning

confidence: 99%

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Lessons in Mind Control: Trends in Research on the Molecular Mechanisms behind Parasite-Host Behavioral Manipulation

Herbison

2017

Front. Ecol. Evol.

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“…Thus, the discovery of novel drug targets, and new chemotherapies with novel mechanisms of action, are high priorities. Small molecules that act on epigenetic regulatory proteins, such as those responsible for post-translational modifications of histones, are of increasing interest as chemical tools for dissecting fundamental mechanisms of parasite growth and as possible new drug leads (Andrews et al., 2012b, Ay et al., 2015, Cheeseman and Weitzman, 2015). Clinically approved drugs are also attracting interest for repurposing for new uses since this can shorten time to market and reduce costs compared to de novo drug discovery for malaria or Neglected Tropical Diseases (NTDs).…”

Section: Introductionmentioning

confidence: 99%

Effect of clinically approved HDAC inhibitors on Plasmodium, Leishmania and Schistosoma parasite growth

Chua

Arnold

et al. 2017

International Journal for Parasitology: Drugs and Drug Resistan

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Malaria, schistosomiasis and leishmaniases are among the most prevalent tropical parasitic diseases and each requires new innovative treatments. Targeting essential parasite pathways, such as those that regulate gene expression and cell cycle progression, is a key strategy for discovering new drug leads. In this study, four clinically approved anti-cancer drugs (Vorinostat, Belinostat, Panobinostat and Romidepsin) that target histone/lysine deacetylase enzymes were examined for in vitro activity against Plasmodium knowlesi, Schistosoma mansoni, Leishmania amazonensis and L. donovani parasites and two for in vivo activity in a mouse malaria model. All four compounds were potent inhibitors of P. knowlesi malaria parasites (IC50 9–370 nM), with belinostat, panobinostat and vorinostat having 8–45 fold selectivity for the parasite over human neonatal foreskin fibroblast (NFF) or human embryonic kidney (HEK 293) cells, while romidepsin was not selective. Each of the HDAC inhibitor drugs caused hyperacetylation of P. knowlesi histone H4. None of the drugs was active against Leishmania amastigote or promastigote parasites (IC50 > 20 μM) or S. mansoni schistosomula (IC50 > 10 μM), however romidepsin inhibited S. mansoni adult worm parings and egg production (IC50 ∼10 μM). Modest in vivo activity was observed in P. berghei infected mice dosed orally with vorinostat or panobinostat (25 mg/kg twice daily for four days), with a significant reduction in parasitemia observed on days 4–7 and 4–10 after infection (P < 0.05), respectively.

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“…Herein, we hypothesized that tick-pathogen associations evolved to form “ intimate epigenetic relationships ” similar to those described for Theileria spp. and its vertebrate host (Cheeseman and Weitzman, 2015) in which the pathogen induces transcriptional reprogramming in infected ticks. This will ultimately favor pathogen propagation, but will also select for the most suitable ecological adaptations in the tick vector.…”

mentioning

confidence: 99%