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T. Cruzi Invasion Summary Leishmania Phagosome

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T. Cruzi Invasion Summary Leishmania Phagosome What is happening in invasion? T. cruzi invasion- non phagocytic Phagocytosis Active invasion Yeast Trypanosoma cruzi Actin filaments Lamp-1 T. cruzi invasion summary Leishmania phagosome Treatment for kinetoplastid diseases HAT Early (these drugs cannot cross the blood/brain barrier) Suramin (1916) highly charged compound Mode of action (?) - inhibits metabolic enzymes (NAD+) Pentamidine (some resistance) Mode of action (?) - likely multiple targets Differential uptake of drug - parasite conc. mM quantites Late Melarsoprol (lipophilic) (1947) Highly toxic arsenical - up to 10% treated die Mode of action (?) - possibly energy metabolism Eflornithine (drug has similar affinity to mammalian enzyme) suicide inhibitor of ornithine decarboxylase blocking polyamine biosynthesis Treatments for HAT 1985 2005 Early Stage First-line drugs Pentamidine Pentamidine Suramin Suramin Clinical trials - DB 289 (Phase III) Pre-clinical stage - - Late-stage/CNS First-line drugs Melarsoprol Melarsoprol Eflornithine Clinical trials - Nifurtimox + Eflornithine Pre-clinical stage - - Treatment for kinetoplastid diseases Chagas Acute Nifurtimox 60-90 days Mode of action (?) ROS - then DNA damage Benznidazole 30-120 days Mode of action - thought to inhibit nucleic acid synthesis (ROS?) Chronic Virtually untreatable - just treat symptoms Treatments for Chagas 1985 2005 Acute Stage First-line drugs Benznidazole Benznidazole Nifurtimox Nifurtimox Clinical trials Allopurinal Indeterminate Stage Clinical trials - Benznidazole Chronic Stage First-line drugs - - Clinical trials - - Pre-clinical stage - Antifungal triazoles Cruzipain inhibitor Treatment for kinetoplastid diseases Leishmaniasis Pentavalent antimonial compounds (1947,1950) 10-30 day treatment Pentamidine (for failed cases)(1940) Amphotericine (1959) Drug interacts with plasma membrane ergosterol (also in fungi) Discriminates between ergosterol and cholesterol New formulation w/liposomes readily taken up by macrophages! Allopurinol (experimental in humans, used for dogs) Inhibits hypoxanthine-guanine phosphoribosyltransferase (HGPRTase) - feedback inhibition of purine biosynthesis Treatments for Leishmaniasis New Drug Targets! Putative drug targets kDNA replication, mitochondrial RNA editing RNA processing Fatty acid metabolism - not well studied Cell cycle and differentiation Membrane transport - unique transporters (purines!) ++ ++ Acidocalcisomes - Storage for Ca , Mg , polyphosphates Plant-like vacuolar H+ pyrophosphatase Carbohydrate metabolism - glycosomes, alternative oxidase Drug target validation Is the gene essential for parasite survival? Redundancy Classical gene knockout - diploid organisms Now, RNA interference! Gene Expression http://www.ncbi.nlm.nih.gov/books/bv.fcgi?call=bv.View..ShowTOC&rid=mboc4.TOC&depth=2 Prokaryotic Translation is concurrent with transcription No barrier restricts movement of transcript to translation apparatus Single RNA polymerase synthesizes all RNA species Eukaryotic Transcript must be processed Capping, splicing, polyA addition mRNA is sequestered as RNP in the nucleus, must be transported to cytoplasm Genes are often split - coding sequence is not contiguous 3 different RNA polymerases required to synthesize RNA classes Polycistronic Transcripts Operon - gene cluster DNA mRNA Polycistronic transcript multiple genes Examples: Proteins perform a Carbohydrate degradation coordinated function Amino acid biosynthesis Eukaryotic Transcripts 5’ 7-methylgaunosine cap structure Post-transcriptional modification - after ~ 25 nucleotides Prevents degradation by 5’ exonucleases Helps in the export from the nucleus Poly-adenylated tail Post-transcriptional modification Helps in stability of the mRNA Mature transcript Kinetoplastid Transcription Alternative Splicing Discovered by D. Baltimore - immunoglobin heavy chain Increases the diversity of protein repertoire Improper alternative splicing can lead to disease Cis-Splicing Mechanism Splicing is mediated by the Spliceosome •Several steps in the splicing reaction require ATP Splicesome mediated - simplified Composed of snRNPs Small nuclear ribonucleoprotein Small nuclear U-rich RNA (snRNA) Each complexed with ~ 7 proteins Highly simplified version 1. U1 base-pairs with the 5’ splice-site 2. U2 binds/pairs with the branch point; also pairs with U6 in the assembled spliceosome 3. U4 pairs with U6 in snRNPs, but releases during spliceosome assembly 4. U5 interacts with both exons (only 1-2 nt adjacent to intron); helps bring exons together 5. U6 displaces U1 at the 5’ splice-site (pairs with nt in the intron); it also pairs with U2 in the catalytic center of the spliceosome Trans-splicing: 1st discovered in trypanosomes To date: ALL coding sequences are trans-spliced! Gene A Gene B Gene C Gene D Gene E DNA Trans-splicing Polyadenylation Polycistronic No evidence of transcript operons SL RNA AAAA AAAA Individual mRNAs each AAAA AAAA with a SL and poly A tail AAAA Comparison of cis- and trans-splicing transesterification Lariat Y-branch intermediate intermediate transesterification Intramolecular Intermolecular Comparison of Spliceosomes New Technology - SMaRT Defects in alternative splicing can lead to human disease Use of artificial trans-splicing to “repair” and give rise to a functional mRNA Spliceosome-mediated RNA Trans-splicing www.intronn.com Correcting at the pre-mRNA level! Trypanosomatid Mitochondrial RNA editing Single mitochondrion Unique mitochondrial DNA Catenated structure composed of mini- and maxicircles Size of molecules varies with species (15-80 kb) (1 - 2.5 kb) 50 maxicircles/network 5000-10,000 minicircles/network Maxicircle Minicircle 20 kb 1 kb Minicircles were initially thought to be nonfunctional, just a structural component Maxicircle sequence Initial sequencing of the T. brucei maxicircles demonstrated that it encoded apocytochrome b, subunits 1 and 2 of cytochrome c oxidase (cox) and some unassigned reading frames (MURFs) (some later turned out to be subunits of NADH dehydrogenase). However some pseudogene features – e.g. cox2 had a –1 frameshift and this was conserved between kinetoplastid species. Sequence determination of cox2 cDNA in 1984 showed an insertion at the precise position of the frameshift converting GA to UUGUAU. This wasn’t accepted at first – there were 50 maxicircles and maybe one had the difference or the gene was encoded in the nucleus. Extensive analysis showed no conventional cox2 genes existed in the nucleus or mitochondrion but a mechanism of adding in U’s was way too outlandish to be accepted at that time. Maxicircle Sequence Sequencing of other mitochondrial cDNAs and their comparison to the genomic sequence showed not only the addition of U’s but also their deletion. In 1986 the first CAUTIOUS paper on a “co- or post-transcriptional nucleotide insertion process” was published (Benne et al.,1986 Cell 46, 819-826 - 18 page paper). Although the data showed deletion of one U, the authors didn’t dare to conclude that this form of editing could also occur. Other groups of investigators found similar editing processes and the number of edited trypanosomatid RNAs expanded. The mystery of missing AUG translational start codons was solved as these are provided by RNA editing by both addition and deletion of U’s Mitochondrial RNA editing Cryptic mRNAs produced Cell mRNA sequence DOES NOT exactly correspond with genomic DNA sequence * * ** ** * Requires insertion of uridine residues ** *** (u) or deletion (*) to create a * *** functional ORF **** *** * * Extreme example is ND7 *** * ** * >90% of mRNA is edited *** Process is more active in *** ** ** ** procyclic form parasites **** **** * Minicircles encode gRNAs (guide **** ** * *** RNAs) that act as templates for * * *** **** insertion and deletion (1991) * *** * Process is essential (2001) * ** ****** Demonstrated by gene silencing in Edited T. brucei ND7 mRNA bloodstream form parasites Maxicircle Comparison Ribosomal RNA sequences ARE NOT edited Insertional RNA editing Primary transcript (Maxicircle encoded) 5' GCGGAGAAAAAAGAAAGGGUCUUUUAAUG (A)n ::|:|||| ||:|||||||| 3'-UUUUUUUUUU CAGAAAAUUACppp5' U A Guide RNA U A (Minicircle encoded) Poly(U) tail U C A A Anchor C U U U U A Editing Edited mRNA 5' GCGGAGAAAAAAUGAAAUGUGUUGUCUUUUAAUG (A)n ::|:||||||||||||||:||||||||||||| 3'-UUUUUUUUUUUUUACUUUAUACAACAGAAAAUUACppp5' Pan-editing of the L. tarentolae A6 mRNA Precursor mRNA Edited mRNA Precursor mRNA Edited mRNA Precursor mRNA Edited mRNA Precursor mRNA Edited mRNA Mechanism of RNA Editing Insertion Deletion RNA Editing Proteins Mediated by Protein Complex.
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