1. Malaria parasite developmental biology

Malaria is a parasitic disease caused by the protozoan parasites of the genus Plasmodium. The annual 300-500 million malaria cases and the resulting >1 million deaths are a major public health problem and huge burden for economic development in many regions of the world. Malaria parasite transmission from the vertebrate host to the mosquito vector requires sexual development of the parasite in the vertebrate host, a process termed gametocytogenesis. While the transition from asexual multiplication to sexual differentiation is triggered by many external factors, the underlying molecular mechanisms are still poorly understood. Our study focuses on functional analysis of two Puf RNA-binding protein family proteins, PfPuf1 and PfPuf2, both of which are preferentially expressed in gametocytes of the malaria parasite P. falciparum. The Puf protein family are evolutionarily conserved translational repressors in eukaryotes. They bind to the cis-acting elements residing in the 3' untranslated region (3'UTR) of cytoplasmic mRNAs and block the translation of these mRNAs. We use in vitro biochemical and molecular approaches and in vivo genetic knockout to study the functions of PfPuf1 and 2 during the sexual development of the malaria parasite.

2. Malaria parasite epigenetics

Genomic DNA in eukaryotes is packed with histones into chromatin, which serves as the scaffold on which the basic cellular processes of DNA replication, repair, and transcription take place. The structure of chromatin dynamic, affected by three major processes: 1) ATP-dependent chromatin remodeling complex such as SWI/SNF; 2) eviction and incorporation of variant histones such as H2A.Z and H3 variants; and 3) covalent, posttranslational modifications of histones. The histone tails are subject to various including phosphorylation, acetylation, methylation, ADP-ribosylation, ubiquitination, and sumoylation. Different modifications affect the histone‑DNA interactions and act sequentially or in combination to create an epigenetic code termed “the histone code”.  Enzymes that regulate these processes have become potential targets for developing novel chemotherapy of diseases.

The malaria parasites also have a typical nucleosomal organization involving core and variant histones that are dynamically modified throughout development. The parasite genome encodes most of the histone modification enzymes. Recent studies suggest that they could serve as key regulators of gene expression and many cellular processes are probably controlled epigenetically. This includes the antigenic switch, mediated by the monoallelic expression of some 60 var genes.  Our research in this area focuses on the enzymes conferring modifications on the lysine residues in the N-terminal tails of the core histones H3 and H4 using the P. falciparum system. Our study employs parasite transfection and gene knockout, chromatin immunoprecipitation, microarrays and other gene expression analysis.

3. Vivax malaria population and epidemiology

P. vivax is the most globally widespread of the four malaria parasite species that infect humans (P. falciparum, P. vivax, P. ovale, and P. malariae), and the major malaria outside Africa. The prevalence of P. vivax has been increasing lately, reaching ~70–80 million cases per year. Although rarely fatal, it is a major cause of morbidity. The parasite has several distinguishing biological characteristics including selective invasion of Duffy positive (almost absent in West Africa), preference to infect reticulocytes (difficult to culture), development of hypnozoites in the liver (responsible for relapses), ability to complete sporogonic development at lower temperatures (responsible for presence in temperate zones). We are interested in the characteristics of vivax malaria epidemiology under different environmental conditions – different temperature, vector compositions, disease treatment regimens, etc. Also we want to study the molecular evolution of vaccine candidate genes, and the population structures of the parasite with different endemic settings.

Relevant Publications (from 2001):

Plasmodium falciparum malaria

Cui, L., Miao, J., Furuya, T., Li, X., Su, X.-z., and Cui, L. 2007. PfGCN5-mediated histone H3 acetylation plays a key role in gene expression in Plasmodium falciparum. Eukaryotic Cell (in press)

Yang, Z., Zhang, Z., Sun, X., Wan, W., Cui, L., Zhang, X., Zhong, D., Yan, G., Cui, L. 2007. Molecular analysis of chloroquine resistance in Plasmodium falciparum in Yunnan Province, China. Trop. Med. Pub. Health (in press)

Cui L., J. Miao, and L. Cui. 2007. Cytotoxic effect of curcumin on malaria parasite Plasmodium falciparum: Inhibition of histone acetylation and generation of reactive oxygen species. Antimicrob. Agents Chemotherapy 51, 488-494.

Miao, J., X. Li,  Z. Liu, C. Xue, H. Bujard, L. Cui. 2006. Immune responses in mice induced by prime-boost schemes of the Plasmodium falciparum apical membrane antigen 1 (PfAMA1)-based DNA, protein and recombinant modified vaccinia Ankara vaccines. Vaccine 24, 6187-6198.

Miao J., Q. Fan, L. Cui, J. Li, J. Li and L. Cui. 2006. The malaria parasite Plasmodium falciparum histones: organization, expression, and acetylation. Gene 369, 53-65.

Fan, Q., J. Li, M. Kariuki and L. Cui.  2004. Characterization of PfPuf2, member of the Puf family RNA-binding proteins from the malaria parasite Plasmodium falciparum. DNA Cell Biol. 23, 753-760.

Fan, Q., L. An and L. Cui.  2004. PfADA2, a Plasmodium falciparum homologue of the transcriptional coactivator ADA2 and its in vivo association with the histone acetyltransferase PfGCN5. Gene 336, 251-261.

Fan, Q., L. An and L. Cui.  2004.  Plasmodium falciparum histone acetyltransferase: A yeast GCN5 homologue involved in chromatin remodeling. Eukaryotic Cell 3, 264-276.

Cui, L., Q. Fan, and J. Li.  2002. The malaria parasite Plasmodium falciparum encodes members of Puf RNA binding protein family with conserved RNA binding activity. Nucleic Acids Res. 30, 4607-4617.

Cui, L., K. A. Rzomp, Q. Fan, S. K. Martin, and J. Williams.  2001.  Plasmodium falciparum: Differential display analysis of gene expression during gametocytogenesis.  Exp. Parasitol. 99, 244-254.

Plasmodium vivax malaria

Udomsangpetch, R., Somsri, S., Panichakul, T., Chotivanich, K., Sirichaisinthop, J., Yang, Z., Cui, L., and J. Sattabongkot. 2007. Short-term in vitro culture of field isolates of Plasmodium vivax using umbilical cord blood. Parasitol. Int. 56, 65-69.

Yang Z., Miao, J., HuangY., Li X., Putaporntip C., Jongwutiwes S., Gao Q., Udomsangpetch R., Sattabongkot J., and L. Cui. 2006. Genetic structures of geographically distinct Plasmodium vivax populations assessed by PCR/RFLP analysis of the merozoite surface protein 3b gene. Acta Trop. 100, 205-212.

Vichchathorn P., R. Jenwithisuk, S. Leelaudomlipi, S. Tungpradabkul, S. Hongeng, L. Cui, J. Sattabongkot, R. Udomsangpetch. 2006. Induction of specific immune responses against the Plasmodium vivax liver-stage via in vitro activation by dendritic cells. Parasitol. Int. 55, 187-193.

Sattabongkot, J., Yimamnuaychoke, N., Leelaudomlipi, S., Rasmeesothat, M., Jenwithisuk, R., Coleman, R.E., Udomsangpetch, R., L. Cui, Brewer, T.G. 2006.  Establishment of a human hepatocyte line that supports in vitro development of the exoerythrocytic stages of the malaria parasites Plasmodium falciparum and P. vivax. Am. J. Trop. Med. Hyg. 74, 708-715.

Jangpatarapongsa, K., J. Sirichaisinthop, J. Sattabongkot, L. Cui, S.M. Montgomery, S. Looareesuwan, M. Troye-Blomberg, and R. Udomsangpetch. 2006. Memory T cells protect against Plasmodium vivax infection. Microbes Infect. 8, 680-686.

Cui, L., Q. Fan, Y. Hu, S.A. Karamycheva, J. Quackenbush, B. Khuntirat, J. Sattabongkot, J. M. Carlton. 2005. Gene discovery in Plasmodium vivax through sequencing of ESTs from mixed blood stages. Mol. Biochem. Parasitol.144, 1-9.

Mascorro, C., K. Zhao, B. Khuntirat, J. Sattabongkot, G. Yan, A. Escalante and L. Cui. 2005. Molecular evolution and intragenic recombination of the merozoite surface protein MSP-3a from the malaria parasite Plasmodium vivax in Thailand. Parasitology 131, 25-35.

Sattabongkot, J., T. Tsuboi, G. E. Zollner, J. Sirichaisinthop and L. Cui.  2004.  Plasmodium vivax Transmission: Chances for Control? Trends Parasitol.  20, 192-198.

Cui, L., C. N. Mascorro, K. A. Rzomp, Q. Fan, B. Khuntirat, G. Zhou, H. Chen, G. Yan and J. Sattabongkot.  2003.  Genetic diversity and multiple infections of Plasmodium vivax malaria in western Thailand.  Am. J. Trop. Med. Hyg. 68, 613-619.

Cui, L., A. A. Escalante, M. Imwong and G. Snounou.  2003.  The genetic diversity of Plasmodium vivax populations. Trends Parasitol.  19, 220-226.

Other malaria-related

Waitayakul, A., S. Somsri, J. Prachumsri, S. Looareesuwan, L. Cui, R. Udomsangpetch. 2006. Natural human response to salivary gland proteins of Anopheles mosquito. Acta Trop. 98, 66-73.

Zhou, G., J. Sirichaisinthop, J. Sattabongkot, J. Jones, O. N. Bjørnstad, G. Yan, and L. Cui. 2005. Spatio-temporal distribution of falciparum and vivax malaria incidences in Thailand. Am. J. Trop. Med. Hyg. 72, 256-262.

Miscellaneous

Fan, Q., Li, S., Wang, L., Zhang, B., Ye, B., Zhao, Z., and Cui, L. 2007. The genome sequence of the multinucleocapsid nucleopolyhedrovirus of the Chinese oak silkworm Antheraea pernyi. Virology (in press)

Cui, L., Cheng, X., Li, L., and Li, J. 2007. Identification of Trichoplusia ni ascovirus 2c virion structural proteins. J. Gen. Virol. (in press)

Li, J., L. Cui, D.L. Rock and J. Li. 2005. Novel glycosidic linkage in Aedes aegypti chorion peroxidase: N-mannosyl tryptophan. J. Biol. Chem. 280, 38513-38521.

Shen, M., X. Yang, D. Cox-Foster and. L. Cui.  2005. The role of varroa mites in infections of Kashmir bee virus (KBV) and deformed wing virus (DWV) in honey bees.  Virology 342, 141-149.

Shen, M., L. Cui, N. Ostiguy and D. Cox-Foster.  2005. Intricate transmission routes and interactions between picorna-like viruses (Kashmir bee virus and sacbrood virus) with the honey bee host and the parasitic varroa mite. J. Gen. Virol. 86, 2281-2289.

Barr, N. B., L. Cui, and B. A. McPheron. 2005. Molecular systematics and sequence analysis of a nuclear gene, period, in the genus Anastrepha (Tephritidae).  Ann. Entomol. Soc. Am.  98, 173-180.

Liu, F., L. Cui, D. Cox-Foster and G. Felton. 2004. Characterization of a salivary gland lysozyme in larval Helicoverpa zea. J. Chem. Ecol. 30, 2439-2457.

Zhao, K. and L. Cui.  2003.  Molecular characterization of the major virion protein gene from the Trichoplusia ni ascovirus.  Virus Genes 27, 93-102.

Rajasekariah, G. R., J. R. Ryan, S. R. Hillier, L. Yi, J. W. Stiteler, L. Cui, A. M. Smithyman and S. K. Martin.  2001.  Optimisation of an ELISA for the serodiagnosis of visceral leishmaniasis using in vitro derived promastigote antigens. J. Immunol. Methods 252, 105-119.

Cui, L., G. R. Rajasekariah and S. K. Martin.  2001.  A nonspecific nucleoside hydrolase from Leishmania donovani: Implications for purine salvage by the parasite. Gene 280, 153-162.