The genome of Cryptosporidium hominis

Xu, Ping; Widmer, Giovanni; Wang, Ying‐Ping; Ozaki, Luiz Shozo; Alves, João M. P.; Serrano, Myrna G.; Puiu, Daniela; Manque, Patrício; Akiyoshi, Donna E.; Mackey, Aaron J.; Pearson, William R.; Dear, Paul H.; Bankier, Alan T.; Peterson, Darrell L.; Abrahamsen, Mitchell S.; Kapur, Vivek; Tzipori, Saul; Buck, Gregory A.

doi:10.1038/nature02977

Cited by 503 publications

(435 citation statements)

References 29 publications

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“…MQO is one of the few mitochondrial enzymes retained by Cryptosporidium spp. [9,65,66], suggesting that it may have a role in mitochondrial development or integrity. Moreover, MQO, together with FH, is one of only two TCA enzymes essential in the asexual stages of P. falciparum [36].…”

Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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Pages 15apicomplexan mitochondrion in energy generation has remained unclear, given the glucosereplete intracellular nature of the environmental niches of these parasites and the apparent reduction of mitochondrial metabolic pathways [4][5][6][7]. For example, apicomplexan mitochondria lack 'type I' NADH dehydrogenase (NDH, complex I of the ETC) and many apparently lack the enzymes and transporters required for fatty acid b-oxidation [8,9]. Furthermore, the pyruvate dehydrogenase complex (PDH) responsible for conversion of pyruvate into acetyl-CoA -an obligate fuel for the TCA cycle -is only present in the apicoplast [10]. Consequently, there was no obvious entry point to allow catalysis of glycolytic pyruvate by the TCA cycle [10][11][12][13][14]. Despite this, there is overwhelming evidence that apicomplexans rely on a functional and canonical TCA cycle (as reviewed [4,5,15]), and apicomplexan genome annotations indicate the presence of all enzymes of the TCA cycle. Only one clade of apicomplexans, Cryptosporidium spp., show evidence of outright loss of the TCA cycle, but these taxa retain only a highly reduced mitochondrion, the mitosome, and have also lost their apicoplast [5,8,16].This review highlights how metabolomics technologies coupled to genetic manipulation have helped in unraveling apicomplexan parasite plasticity in carbon source utilization through different life stages, revealing a complex and sometimes counter-intuitive pattern of metabolic gains, losses, and reassignments. These changes have presumably been tailored to allow these parasites to thrive within their various host niches, but may constitute some much-needed Achilles' heels in the fight against these devastating diseases. Plasmodium falciparum and the Glycolytic DeceitGlycolysis has long appeared to be the main source of ATP and NAD(P)H in the erythrocytic stages of the malaria parasites, [5,[17][18][19][20][21]. Indeed, glucose uptake in P. falciparum-infected red blood cells (RBCs) has been observed to increase 75-100-fold compared to uninfected RBC [22][23][24][25]. Up to 93% of glucose is converted directly to lactate in asexual stages [26][ 4 _ T D $ D I F F ] and is ultimately excreted into the surrounding host cell. Perturbation of glucose uptake is detrimental to parasite growth [27,28], suggesting that glycolysis is an important part of the parasite's strategy for rapid proliferation. In a manner analogous to the Warburg effect observed in highly-proliferative cancer lines and other rapidly-growing cells (e.g., yeast and bloodstream Trypanosoma spp.), Plasmodium (in erythrocytic stages) has opted for fast generation of ATP through substrate-level phosphorylation and secretion of lactate as an end-product (aerobic fermentative glycolysis), as opposed to the 'slow but efficient' mitochondrial oxidative phosphorylation and complete oxidation [29]. Reasons for this dependence on glycolytic fermentation remain unclear -after all, blood stages of Plasmodium certainly have access to oxygen -but it may be a way of avoiding excessiv...

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Section: Mitochondrial Metabolism Across the Alveolatamentioning

confidence: 99%

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Jacot

Waller

Soldati‐Favre

et al. 2016

Trends in Parasitology

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“…The complete genomes of six apicomplexans are currently available ( Fig. 2; Carlton et al 2002;Gardner et al 2002Gardner et al , 2005Abrahamsen et al 2004;Xu et al 2004;Pain et al 2005). Furthermore, large expressed sequence tag (EST) collections have been generated for an additional nine species (Ajioka et al 1998;Howe 2001;Li et al 2003a;Cui et al 2005), which can be used to construct so-called ''partial genomes '' (Peregrin-Alvarez and Parkinson 2007;Wasmuth et al 2008).…”

mentioning

confidence: 99%

The origins of apicomplexan sequence innovation

Wasmuth¹,

Daub²,

Peregrín-Alvarez³

et al. 2009

Genome Res.

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The Apicomplexa are a group of phylogenetically related parasitic protists that include Plasmodium, Cryptosporidium, and Toxoplasma. Together they are a major global burden on human health and economics. To meet this challenge, several international consortia have generated vast amounts of sequence data for many of these parasites. Here, we exploit these data to perform a systematic analysis of protein family and domain incidence across the phylum. A total of 87,736 protein sequences were collected from 15 apicomplexan species. These were compared with three protein databases, including the partial genome database, PartiGeneDB, which increases the breadth of taxonomic coverage. From these searches we constructed taxonomic profiles that reveal the extent of apicomplexan sequence diversity. Sequences without a significant match outside the phylum were denoted as apicomplexan specialized. These were collated into 9134 discrete protein families and placed in the context of the apicomplexan phylogeny, identifying the putative origin of each family. Most apicomplexan families were associated with an individual genus or species. Interestingly, many genera-specific innovations were associated with specialized host cell invasion and/or parasite survival processes. Contrastingly, those families reflecting more ancestral relationships were enriched in generalized housekeeping functions such as translation and transcription, which have diverged within the apicomplexan lineage. Protein domain searches revealed 192 domains not previously reported in apicomplexans together with a number of novel domain combinations. We highlight domains that may be important to parasite survival.

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“…Despite this, efforts to develop new and more effective treatments for this disease have been hindered by (1) lack of suitable targets and (2) lack of target validation and transfection tools. The completion of the Cryptosporidium genome (Abrahamsen et al, 2004;Xu et al, 2004), which resulted in a range of potential drug targets being identified, has overcome the first hindrance and IMPDH is now a well recognised and important drug target Johnson et al, 2013;Maurya et al, 2009;Sharling et al, 2010;Umejiego et al, 2008).…”

Section: Discussionmentioning

confidence: 99%

Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides

Jefferies

Yang

Woh

et al. 2015

Experimental Parasitology

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• Yielded a relatively high functional hit rate (~17% i.e. 2/12 Phylomer ® peptides tested).• Successfully shown that TAT can deliver therapeutic Phylomer cargoes inside cells.• Opens up new therapeutic opportunities. Cryptosporidiosis, a gastroenteric disease characterised mainly by diarrheal illnesses in humans and mammals is caused by infection with the protozoan parasite Cryptosporidium. Treatment options for cryptosporidiosis are limited, with the current therapeutic nitazoxanide, only partly efficacious in immunocompetent individuals. The parasite lacks de novo purine synthesis, and is exclusively dependant on purine salvage from its host. Inhibition of the inosine 5' monophosphate dehydrogenase (IMPDH), a purine salvage enzyme that is essential for DNA synthesis, thereby offers a potential drug target against this parasite. In the present study, a yeast-two-hybrid system was used to identify Phylomer peptides within a library constructed from the genomes of 25 phylogenetically diverse bacteria that targeted the IMPDH of Cryptosporidium parvum (IMPcp) and Cryptosporidium hominis (IMPch). We identified 38 unique interacting Phylomers, of which, 12 were synthesised and screened against C. parvum in vitro. Two Phylomers exhibited significant growth inhibition (81.2-83.8% inhibition; P < 0.05), one of which consistently 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 exhibited positive interactions with IMPcp and IMPch during primary and recapitulation yeast two-hybrid screening and did not interact with either of the human IMPDH proteins. The present study highlightsthe potential of Phylomer peptides as target validation tools for Cryptosporidium and other organisms and diseases because of their ability to bind with high affinity to target proteins and disrupt function. G R A P H I C A L A B S T R A C T

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The genome of Cryptosporidium hominis

Cited by 503 publications

References 29 publications

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

Apicomplexan Energy Metabolism: Carbon Source Promiscuity and the Quiescence Hyperbole

The origins of apicomplexan sequence innovation

Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides

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