RESEARCH ACTIVITIES D.

Transcription

1 REEARCH ACTVTE D. yafruddin Eijkman nstitute for Molecular Biology, Jakarta Hasanuddin University Medical Researrch Center, Makassar 9045, ndonesia

2 Current research activities 1. Molecular biology of the energy transducing membrane in the malarial parasite 2. Molecular basis of the antimalarial drug resistance 3. Malaria in Pregnancy 1. Antimalarial drug discovery

3 History of antimalarial drug resistance ntroduced irst Report Difference of Resistance (years) Quinine Chloroquine Proguanil ulphadoxine pyrimethamine Mefloquine Atovaquone Artemisinin

4 Polymorphisms in the pfcrt gene associated with chloroquine resistance pfcrt codes for Chloroquine Transporter Protein (PfCRT) pfcg4 pfcg3 pfcrt pfcg9 pfcg1 2kb M74, N75, K76T, A220, Q271E, N326, 356T and R371 K76T is used as molecular markers for chloroquine resistance in P. falciparum field isolates. The 76T allelic distribution declines significantly in Malawi when chloroquine was replaced with P in 1993 Their roles in P. vivax and P. chabaudi were not proven. Other modulatory factor(s)? EJKMAN NTTUTE

5 Polymorphisms in pfmdr1 gene associated with chloroquine resistance Plasmodium falciparum multidrug resistance 1(Pfmdr1) codes for P-glycoprotein homologues 1 (Pgh1) Rochbah et al.2005) Controversy of in vivo results and genetic crossing analysis Allelic replacement experiment (Reed et al, 2000) 184, 1034C, 102D and 1246 confers chloroquine resistance and modulate sensitivity to Quinine, Mefloquine, Halofantrin, and Artemisinin EJKMAN NTTUTE

6 Map of the dhfr-ts gene of the malarial parasite Chromosome bp DHR Junction T JR76 JR78 JR79 JR77 Restriction enzymes Nla for 16Val Tai and Mae for 50Arg Tsp5091 for 51le Xmn for 59Arg Bsr for 108Asn, crf for 108Thr Alu for er N is the most common allele 108T+16V confers resistance to Cycloguanil but retains sensitivity to Pyrimethamine EJKMAN NTTUTE

7 Map of pppk-dhps gene of the malaria parasite ocated on chromosome 8 pppk nt1784 Pf3717 PfR199 dhps PfR186 RP analysis MspA1 for 436/A Ava for A437 ok for K540E BstU1 and Bsl1 for A581 Mwo for A613/T 437 is the most common allele PfJR82 PfJR84 Pf153 PfRJR83 PfRJR85 Pf165R EJKMAN NTTUTE

8 Extrachromosomal genomes in the malarial parasites CO Cytb CO 6kb EJKMAN NTTUTE

9 Predicted econdary tructure of the putative apocytochrome b of Plasmodium berghei A E P 50 R N27, 33, 217 Antimycin A 14, 215 Diuron H M V H Q A T A A V V V T H T A A V P H C W V R H P N M H Qi NH 2 1 N T 0 N H T K V N N 0 T V A P N N W N C P N Q H R E W M133 W C R Qo A W T V M Q W P 144 V W C P T V T P D N A D H P T N K R V P Q N N K V V V N T 250 M K T P V284 K N A V V A Q A V D N P D T A K P P Qi 1. Budimulja et al, Mol. Biochem. Parasitol, 84: yafruddin et al Mol Biochem. Parasitol, 104: iregar et al, Parasitol nt, 57: E Q R N 300 T P Q V P E Qo P A C Q W A M C W P T T Q W 268N 268C P Q D R E R A K M V V Q N K K T H D COO- Q N A Cytoplasmic 131, N245, 264 Mucidin 141, T142 tigmatellin 123, 131, 137, Myxothiazol M133, 144, 258, 267, 268, 271, K272, P275, 280, 283, V284 Atovaquone Matrix EJKMAN NTTUTE

10 NTERMTTENT CREENN AND TREATMENT OR NTERMTTENT PREVENTVE THERAP OR CONTRO O MAARA N PRENANC N NDONEA Acronym : (TOP-MiP) creening and Treatment or Prevention of Malaria in Pregnancy

11 OBJECTVE Primary To determine if intermittent preventive treatment (PTp) with dihydroartemisininpiperaquine (DHP) or intermittent screening and treatment (Tp-DHP) with RDTs in the 2nd and 3rd trimester is more effective than the current strategy of single screening and treatment (Tp-DHP) among women protected by long lasting insecticide treated nets (Ns) in areas with relatively low P.falciparum and P.vivax transmission in ndonesia econdary To assess the effectiveness of the processes of delivery of Tp as currently implemented in ndonesia under operational conditions; To determine the acceptability, feasibility and cost effectiveness of Tp, Tp, and PTp alongside the randomised control trial

12 patial Repellent Products for Control of Vector-borne Disease a multi-site trial Repellen spasial* untuk penanggulangan penyakit tular vektor * Obat/Alat pengusir nyamuk ruangan

13 Program oals and Objectives OA: Evaluate the public health impact of one spatial repellent (R) product to reduce and prevent transmission of Plasmodium spp. and dengue viruses. OBJECTVE: 1. Provide a quantitative estimate of protective efficacy (PE) 2. Provide inputs into program-relevant questions of optimization and application: the intervention coverage needed to reduce transmission, the range of transmission contexts in which spatial repellents function ow, moderate and high baseline transmission intensity usceptible and resistant mosquito populations Varying vector biting behaviors (indoor/outdoor/mixed) community effect (benefit) and/or diversion (increased) 3. Confirm and measure the entomological correlates of reduced infection 4. Drive efforts to acquire full recommendation of R products for inclusion in disease control programs by generating rigorous evidence to be considered and used by public health stakeholders. Program Kick-off Meeting Washington DC Nov

14 Conceptualizing patial Repellency Potential failure to feed overall ncreased time searching for blood meal and/or resting sites Potential lag-time to recovery for host seeking ncreased probability for non-chemical mortality & nterruption in pathogen transmission repellency Toxicity Program Kick-off Meeting Washington DC Nov

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16 Thank you Terima kasih

17 Program Kick-off Meeting Washington DC Nov