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C H A P T E R 17 Medical implications of molecular parasitology Richard D. Pearson 1 , Erik L. Hewlett 2 and William A. Petri, Jr. 3 1 Department of Medicine and Department of Pathology, University of Virginia School of Medicine, Charlottesville, VA, USA; 2 Department of Medicine and Department of Pharmacology, University of Virginia School of Medicine, Charlottesville, VA, USA; and 3 Department of Medicine and Department of Microbiology, University of Virginia School of Medicine, Charlottesville, VA, USA BACKGROUND The history of anti-parasitic therapy dates to antiquity. Healers have for millennia known of the therapeutic efficacy of various leaves, roots and bark. Effective therapy for malaria, for example, was identified long before the etiology and life cycle of Plasmodium spp. were defined. While the Greeks were attributing intermittent fevers to bad air, native South Americans were successfully administering extracts of the bark of the cinchona tree to treat malaria. As the science of chemistry advanced in the nineteenth and twentieth centuries, biologically active molecules such as quinine from the cinchona tree were isolated and characterized. In other instances organic compounds were found empirically to have therapeutic activity. Congeners were subsequently synthesized and screened. Those with the greatest efficacy and least toxicity were adopted for therapy, usually without an understanding of the mechanism of action. Governments seeking to protect military or colonial personnel often supported these efforts. Many of the anti-parasitic drugs that are currently in use were identified in this manner (Table 17.1). One of the most interesting examples began with the observation by Paul Ehrlich, the father of modern medicinal chemistry, and his colleagues in 1891 that methylene blue dye was effective in the treatment of malaria. Two decades later, difficulty in acquiring quinine during WWI led German scientists to synthesize Molecular Medical Parasitology ISBN 0–12–473346–8 433 Copyright © 2003 Elsevier Science Ltd. All rights of reproduction in any form reserved.
434 MEDICAL IMPLICATIONS TABLE 17.1 Anti-parasitic drugs discussed in this chapter Drug Use Treatment of malaria and other Apicomplexa Quinine Treatment of chloroquine-resistant P. falciparum and other Plasmodium spp.; effective against asexual erythrocytic phase Used with clindamycin for treatment of Babesia spp. Quinidine Treatment of chloroquine-resistant P. falciparum when parenteral therapy is required; effective against asexual erythrocytic phase Chloroquine Suppressive prophylaxis and treatment of the asexual erythrocytic phase of P. vivax, P. ovale and P. malariae, and susceptible P. falciparum Mefloquine Prophylaxis and occasionally treatment of chloroquine-resistant P. falciparum; effective against asexual erythrocytic phase of other Plasmodium spp. Doxycycline Used for suppressive prophylaxis in areas where there is endemic chloroquine-resistant P. falciparum and with quinine for the treatment of chloroquine-resistant P. falciparum Atovaquone/Proguanil (Malarone) Used for suppressive prophylaxis and treatment of chloroquine-resistant P. falciparum Primaquine Radical cure of the pre-erythrocytic hypnozoites of P. vivax and P. ovale Artemisinin derivatives (Qinghaosu) Treatment of Plasmodium spp. in the asexual erythrocytic phase, Artesunate including chloroquine-resistant P. falciparum Artemether Pyrimethamine/short-acting Used with quinine to treat asexual erythrocytic phase of sulfonamides chloroquine-resistant P. falciparum acquired in areas where resistance is not common Also used for the treatment of Toxoplasma gondii Pyrimethamine-sulfadoxine Presumptive treatment of chloroquine-resistant P. falciparum in (Fansidar) areas where isolates are sensitive Clindamycin Used with steroids for treatment of ocular Toxoplasma gondii in immunocompetent hosts; used with pyrimethamine for T. gondii encephalitis in persons with AIDS who cannot tolerate sulfonamides Used with quinine for treatment of Babesia spp. Spiramycin Toxoplasma gondii during pregnancy and in the neonate Treatment of Kinetoplastida: trypanosomes and Leishmania Nifurtimox Trypanosoma cruzi Benznidazole Trypanosoma cruzi Eflornithine Trypanosoma brucei gambiense (hemolymphatic or central nervous system involvement) Suramin Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (hemolymphatic stage) Pentamidine isethionate Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (hemolymphatic stage) Leishmania spp. (alternative) Pneumocystis carinii (alternative) Melarsoprol B Trypanosoma brucei gambiense and Trypanosoma brucei rhodesiense (late disease with central nervous system involvement) (Continued) MEDICAL APPLICATIONS
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Molecular Medical Parasitology
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Molecular Medical Parasitology Edit
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Contents List of contributors Prefa
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List of contributors Mark Blaxter,
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LIST OF CONTRIBUTORS ix Richard. J.
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Preface Parasitology was born as th
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S E C T I O N I MOLECULAR BIOLOGY
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C H A P T E R 1 Parasite genomics M
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TABLE 1.1 Parasite genomes: genome
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GENERATING GENOMICS DATA 7 differen
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GENERATING GENOMICS DATA 9 TABLE 1.
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GENERATING GENOMICS DATA 11 called
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GENERATING GENOMICS DATA 13 200 000
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BIOINFORMATICS AND THE ANALYSIS OF
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THE POST-GENOMICS ERA, AND THE OTHE
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THE PARASITES AND THEIR GENOMES 19
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FURTHER READING 27 treated with a d
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C H A P T E R 2 RNA processing in p
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TRANS-SPLICING 31 cis trans Exon 1
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TRANS-SPLICING 33 snRNPs (small nuc
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TRANS-SPLICING 35 trans cis U2AF35
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RNA EDITING 37 P AAAA... AAAA... AA
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RNA EDITING 39 entire transcript re
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RNA EDITING 41 5 Editing block C Ed
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RNA EDITING 43 microscopy) approach
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FURTHER READING 45 Nilsen, T.W. (19
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C H A P T E R 3 Transcription Arthu
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UNUSUAL MODES OF TRANSCRIPTION IN T
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CLASS I TRANSCRIPTION IN TRYPANOSOM
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CLASS II TRANSCRIPTION OF PROTEIN C
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SL RNA AND U snRNA GENE TRANSCRIPTI
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FURTHER READING 65 and switching in
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C H A P T E R 4 Post-transcriptiona
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POST-TRANSCRIPTIONAL REGULATION IN
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FURTHER READING 87 inhibition, it m
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C H A P T E R 5 Antigenic variation
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ANTIGENIC VARIATION AT THE STRUCTUR
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ANTIGENIC VARIATION AT THE STRUCTUR
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VSG Signal sequence Amino-terminal
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GENETICS OF ANTIGENIC VARIATION 97
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IMMUNE RESPONSES TO TRYPANOSOME INF
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INNATE RESISTANCE, HUMAN SUSCEPTIBI
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ANTIGENIC VARIATION IN MALARIA 107
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FURTHER READING 109 ACKNOWLEDGEMENT
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C H A P T E R 6 Genetic and genomic
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‘FORWARD’ VS. ‘REVERSE’ GEN
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EXAMPLES OF ‘FORWARD’ GENETIC A
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EXAMPLES OF ‘FORWARD’ GENETIC A
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REVERSE GENETICS AND LEISHMANIA VIR
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VALIDATION OF CANDIDATE VIRULENCE G
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S E C T I O N II BIOCHEMISTRY AND C
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C H A P T E R 7 Energy metabolism P
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SUBCELLULAR ORGANIZATION OF AMITOCH
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CELL MEMBRANE Fructose [b] Glucose
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STEPS OF AMITOCHONDRIATE CORE METAB
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ENZYMATIC DIFFERENCES BETWEEN AMITO
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ACTION OF NITROIMIDAZOLE DRUGS 135
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ENVOI 137 unambiguously reflect the
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FURTHER READING 139 Saavedra-Lira,
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THE EMBDEN-MEYERHOF-PARNAS (EMP) PA
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WHY DO TRYPANOSOMATIDAE HAVE GLYCOS
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FURTHER READING 153 for use in agri
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CARBOHYDRATE METABOLISM 155 as a hu
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158 ENERGY METABOLISM - APICOMPLEXA
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172 PROTEIN METABOLISM PROTEINS (1)
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174 PROTEIN METABOLISM the C-termin
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176 PROTEIN METABOLISM and also, to
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178 PROTEIN METABOLISM values rangi
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180 PROTEIN METABOLISM of the plasm
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182 PROTEIN METABOLISM in vivo, in
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184 PROTEIN METABOLISM PROLINE Poly
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186 PROTEIN METABOLISM CO 2 Dec-SAM
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188 PROTEIN METABOLISM a cMDH has b
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190 PROTEIN METABOLISM Urea ARGININ
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192 PROTEIN METABOLISM been describ
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194 PROTEIN METABOLISM absence of g
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198 PURINES AND PYRIMIDINES enable
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200 PURINES AND PYRIMIDINES provide
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202 PURINES AND PYRIMIDINES activit
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204 PURINES AND PYRIMIDINES physiol
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206 PURINES AND PYRIMIDINES Amitoch
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208 PURINES AND PYRIMIDINES their a
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210 PURINES AND PYRIMIDINES FIGURE
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214 PURINES AND PYRIMIDINES protein
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220 PURINES AND PYRIMIDINES in Plas
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222 PURINES AND PYRIMIDINES whereas
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226 TRYPANOSOMATID CARBOHYDRATES AF
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228 TRYPANOSOMATID CARBOHYDRATES In
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230 TRYPANOSOMATID CARBOHYDRATES po
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232 TRYPANOSOMATID CARBOHYDRATES LP
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234 TRYPANOSOMATID CARBOHYDRATES re
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236 TRYPANOSOMATID CARBOHYDRATES sc
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A. sAP COOH [T][T](S/T)(S/T)(S/T)SS
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240 TRYPANOSOMATID CARBOHYDRATES Cr
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242 INTRACELLULAR SIGNALING protein
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244 INTRACELLULAR SIGNALING FIGURE
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246 INTRACELLULAR SIGNALING 212.5 2
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248 INTRACELLULAR SIGNALING cycle.
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250 INTRACELLULAR SIGNALING V-H -A
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252 INTRACELLULAR SIGNALING domain)
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254 INTRACELLULAR SIGNALING the kno
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256 INTRACELLULAR SIGNALING from in
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258 INTRACELLULAR SIGNALING FIGURE
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260 INTRACELLULAR SIGNALING ESAG4 (
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262 INTRACELLULAR SIGNALING and ind
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264 INTRACELLULAR SIGNALING ATPase
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266 INTRACELLULAR SIGNALING G11XG
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268 INTRACELLULAR SIGNALING a diffe
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270 INTRACELLULAR SIGNALING rapid l
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272 INTRACELLULAR SIGNALING cells w
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274 INTRACELLULAR SIGNALING PfPPJ i
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276 INTRACELLULAR SIGNALING is cont
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278 PLASTIDS, MITOCHONDRIA, AND HYD
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298 HELMINTH SURFACES Important exc
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300 HELMINTH SURFACES protease inhi
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302 HELMINTH SURFACES volume, there
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304 HELMINTH SURFACES projecting si
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306 HELMINTH SURFACES schistosome t
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308 HELMINTH SURFACES re-establish
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310 HELMINTH SURFACES hepatic cells
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312 HELMINTH SURFACES lungs. Larvae
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314 HELMINTH SURFACES cuticle, whic
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316 HELMINTH SURFACES cuticle in th
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318 HELMINTH SURFACES mec-8 or sym-
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320 HELMINTH SURFACES current, when
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322 HELMINTH SURFACES The cuticle-h
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324 HELMINTH SURFACES are typically
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326 HELMINTH SURFACES or carrier pr
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328 HELMINTH SURFACES of tyrosine-b
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330 HELMINTH SURFACES blood. The ge
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332 HELMINTH SURFACES Mutations in
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334 HELMINTH SURFACES in the hypode
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336 HELMINTH SURFACES (including H-
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338 HELMINTH SURFACES Blaxter, M.L.
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340 ENERGY METABOLISM IN HELMINTHS
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360 NEUROTRANSMITTERS CO 2 H NH 2 G
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362 NEUROTRANSMITTERS TABLE 15.1 An
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364 NEUROTRANSMITTERS more arms tha
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366 NEUROTRANSMITTERS the surroundi
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368 NEUROTRANSMITTERS proteins requ
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370 NEUROTRANSMITTERS FIGURE 15.11
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372 NEUROTRANSMITTERS FIGURE 15.13
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374 NEUROTRANSMITTERS sensitivity t
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376 NEUROTRANSMITTERS TABLE 15.3 Cl
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378 NEUROTRANSMITTERS crossed the c
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380 NEUROTRANSMITTERS have been tes
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Page 397 and 398: 384 NEUROTRANSMITTERS Davis and Str
Page 399 and 400: 386 NEUROTRANSMITTERS Cephalic gang
Page 401 and 402: 388 NEUROTRANSMITTERS myoexcitation
Page 403 and 404: 390 NEUROTRANSMITTERS is phosphoryl
Page 405 and 406: 392 NEUROTRANSMITTERS many other an
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Page 411 and 412: 398 DRUG RESISTANCE of some of the
Page 413 and 414: 400 DRUG RESISTANCE It is now estim
Page 415 and 416: 402 DRUG RESISTANCE is again assume
Page 417 and 418: 404 DRUG RESISTANCE An alternative
Page 419 and 420: 406 DRUG RESISTANCE clinical eviden
Page 421 and 422: 408 DRUG RESISTANCE FIGURE 16.4 Fol
Page 423 and 424: 410 DRUG RESISTANCE Using similar s
Page 425 and 426: 412 DRUG RESISTANCE whether these r
Page 427 and 428: 414 DRUG RESISTANCE FIGURE 16.5 Str
Page 429 and 430: 416 DRUG RESISTANCE FIGURE 16.6 Try
Page 431 and 432: 418 DRUG RESISTANCE has permitted e
Page 433 and 434: 420 DRUG RESISTANCE FIGURE 16.7 Dru
Page 435 and 436: 422 DRUG RESISTANCE near future. Th
Page 437 and 438: 424 DRUG RESISTANCE million new inf
Page 439 and 440: 426 DRUG RESISTANCE some 50 million
Page 441 and 442: 428 DRUG RESISTANCE pharynx, the bo
Page 443 and 444: 430 DRUG RESISTANCE efforts for glo
Page 445: 432 DRUG RESISTANCE and resistance
Page 449 and 450: 436 MEDICAL IMPLICATIONS TABLE 17.1
Page 451 and 452: 438 MEDICAL IMPLICATIONS transmissi
Page 453 and 454: 440 MEDICAL IMPLICATIONS H 2 C H H
Page 455 and 456: 442 MEDICAL IMPLICATIONS parasites
Page 457 and 458: 444 MEDICAL IMPLICATIONS neuropsych
Page 459 and 460: 446 MEDICAL IMPLICATIONS of toxic f
Page 461 and 462: 448 MEDICAL IMPLICATIONS Future con
Page 463 and 464: 450 MEDICAL IMPLICATIONS Melarsopro
Page 465 and 466: 452 MEDICAL IMPLICATIONS prevention
Page 467 and 468: 454 MEDICAL IMPLICATIONS resulting
Page 469 and 470: 456 MEDICAL IMPLICATIONS for S. ste
Page 471 and 472: 458 MEDICAL IMPLICATIONS are though
Page 473 and 474: 460 MEDICAL IMPLICATIONS FIGURE 17.
Page 475 and 476: 462 MEDICAL IMPLICATIONS Marr, J.J.
Page 477 and 478: 464 INDEX Aldolase, 143 Plasmodium
Page 479 and 480: 466 INDEX Ascofuranone, 143 ASCUT-1
Page 481 and 482: 468 INDEX Cnidarians, RNA trans-spl
Page 483 and 484: 470 INDEX Entamoeba, 125 Ca 2 metab
Page 485 and 486: 472 INDEX Glucose-6-phosphate dehyd
Page 487 and 488: 474 INDEX Ivermectin, 398, 427, 455
Page 489 and 490: 476 INDEX Maduramicin, 412 Major va
Page 491 and 492: 478 INDEX Nitric oxide: neurotransm
Page 493 and 494: 480 INDEX calcium-binding proteins,
Page 495 and 496: 482 INDEX Pyrimidine transport, 200
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484 INDEX Succinate:rhodoquinone ox
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486 INDEX genome, 21 survey sequenc
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488 INDEX U small nuclear RNA (snRN
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