Karen Day, PhD, Professor; Chair of Department

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I run a multidisciplinary malaria research group that aims to understand the transmission of malaria and to better define control strategies. We take laboratory findings, especially genomics, to the field to investigate the epidemiology of malaria as well as the converse i.e. taking observations from the field to the laboratory to identify molecular mechanisms of parasite biology. The group offers a unique training in translational research combining the disciplines of epidemiology, immunology, molecular parasitology, genomics, bioinformatics and genetics in population based studies. We are investigating :

Parasite Genomics and the Epidemiology of Malaria
Robert Koch studied malaria infected communities on the North Coast of Papua New Guinea in 1905. He reported that children experienced serious illness whereas adults developed immunity that protected against disease but not infection per se. This pattern of age-dependant acquisition of immunity has proven to be a standard feature of the epidemiology of malaria. The slow acquisition of immunity to malaria is believed to be a consequence of exposure to the range of antigenically diverse parasites in an endemic area. The ability to describe the genetic diversity of malaria in terms of single nucleotide polymorphisms (SNP’s) in the malaria genome allows us to investigate the role of antigenic diversity in the pathogenesis and transmission success of the malaria parasite. It is my long-term research goal to rewrite the epidemiology of malaria in the context of the genomic diversity of Plasmodium spp.

Over the past decade my group has focused research on the molecular epidemiology of Plasmodium falciparum in Papua New Guinea and Thailand at both the population and within host level. It is now my intention to extend these studies to other endemic areas to gain a global understanding of the epidemiology of malaria. With this aim in mind I have set up collaborations in South-East Asia, India, Zimbabwe, South America and West Africa. We continue to develop parasite typing systems exploring diversity in both putatively neutral (microsatellite and housekeeping) genes, antigen genes as well as loci relevant to drug and vaccine resistance to gain a better understanding of the global population structure of P. falciparum and its relevance to the epidemiology of malaria. This research goal will exploit information generated by the Malaria Genome Project. We continue to develop new approaches to fuse population genetics, genomics and epidemiology. I am also extending our diversity studies to the other important human malarias, P. vivax and P. malariae, with collaborators.

Var Gene Diversity
Experiments in humans as well as animal models indicate that immunity to malaria is variant specific. The major molecular target of variant-specific immunity to P. falciparum is believed to be the erythrocyte membrane protein PfEMP1 encoded by the var genes. Genome analysis has revealed that a single parasite clone has approximately 40 to 60 var genes and cross isolate comparisons have shown that independent clones have different var repertoires. Each var gene encodes a PfEMP 1 variant that is expressed on the surface of the mature blood stages and immature transmission stages. Differential expression of var genes is responsible for the parasites ability to undergo clonal antigenic variation whereby the parasite switches surface antigens and evades the host immune response. Variation also allows the parasite to re-infect previously exposed hosts as well as establish chronic infection necessary to achieve transmission to the mosquito vector. Variant-specific immunity to this antigen is thought to protect against malaria morbidity by regulating parasite density as well as limit transmission. The molecule appears to be more immunogenic than other surface antigens that are being tested for malaria vaccines.

Given the proposed importance of immunity to PfEMP1 in protection against malaria, it is essential that we gain a better understanding of diversity in this molecule and how such diversity influences the development of protective immunity. The relevance of this investigative approach can be seen by comparison with our understanding of the epidemiology of influenza. The biomarker for susceptibility to influenza A is the absence of immunity to variable sequence of the haemaglutinin and neuraminidase molecules. By analogy, it could be considered that of all of the antigens encoded by the malaria genome, immunity to PfEMP1 variants and sequence variability of genes encoding PfEMP 1 would be the equivalent biomarkers in the malaria transmission system. The first critical step towards tying together sequence and serological diversity is to define the extent of sequence diversity of var genes in different geographic regions and develop the bioinformatics tools to adequately characterize such data. Dr Alyssa Barry has developed a population genetic framework for such studies and is building on this and current bioinformatic tools in collaboration with colleagues Dr Gil McVean and Ella Chase at the University of Oxford to further explore this fascinating area of malaria biology.

Host Polymorphims and the Innate Immune Response to Malaria
The mechanisms whereby various red cell polymorphisms protect against malaria is a problem that has long fascinated parasitologists and evolutionary biologists. To date, the mechanism of protection against severe malaria afforded by heritable hemoglobinopathies, such as sickle cell trait and the thalassemias, is yet to be elucidated. We are currently exploring the role of the acute phase response as a possible explanation or marker for this protection. This is being investigated in two geographical locations, Papua New Guinea and Gabon.

Fig. 4 (a) Children participating in field work in Papua New Guinea. (b) Papua New Guinea.

Genetic epidemiological studies on the north coast of Papua New Guinea have shown that α+-thalassemia trait reaches very high frequencies (86%). This thalassemia is a result of deletions (3.7 or 4.2 kb) or inactivation by a point mutation of one of the duplicated α-globin genes. The heterozygous and homozygous α+-thalassemia genotypes are (-α/αα) and (-α/-α), respectively. Heterozygotes do not present any clinical symptoms whereas homozygotes experience mild, hemolytic anemia and reduced erythrocyte indices. Individuals homozygous for α+-thalassemia have also been shown to be protected against severe falciparum malaria as well as all cause admissions to hospital with other infections. The fact that the protection is afforded against other infectious diseases has lead us to challenge the dogma that the thalassemias protect by virtue of a direct interaction between the parasite and the red cell. The non-specific innate immune system seems like a good candidate for a generalized mechanism of protection. Current field and laboratory studies with colleagues Drs Heather Imrie, Pascal Michon, Steve Allen, Freya Fowkes, Angela O’Donnell and Sir David Weatherall in collaboration with the Papua New Guinea Institute of Medical Research are investigating possible mechanisms of protection.

Sickle cell hemoglobin (HbS) is the most frequent abnormal Hb trait found in populations of African origin and is the result of an amino acid substitution on the β chain of Hb. Individuals who are carriers of the heterozygous sickle cell trait (HbAS) have substantial protection against severe P. falciparum malaria compared to those with normal Hb (HbAA). To date, studies on the differences in hematological parameters in HbS genotypes have been inconsistent and deemed clinically insignificant. Although considered clinically insignificant, these changes may affect regulation of other factors, such as the innate immune response, particularly in the face of malaria infection. Epidemiological research has focused in Gabon with colleagues Drs Heather Imrie and Freya Fowkes, in collaboration with Florence Migot-Nabias, Phillipe Deloran and Adrian Luty.

Quorum sensing
Quorum sensing (QS) is well described for bacteria, but has not yet been studied in malaria. It is the regulation of gene expression in response to fluctuations in cell population density, and is mediated by signaling molecules released into the environment. Both in vitro studies and epidemiological data from my laboratory provide evidence that malaria parasites exhibit QS.

	Fig. 5 Taken from Malaria: principles and practice of malariology Eds. Wernsdorfer, WH & McGregor, Sir I

A combination of proteomics, genomics and metabolomics will be used the identify parasite factor(s) responsible for QS in biological assays exploring transmission, asexual growth and induction/suppression of production of inflammatory cytokines with colleagues Merali and Rodriguez from NYU. We aim to find three types of chemical signals mediating (1) how a single parasite senses how many neighboring malaria parasites are in the blood of an infected human (2) the decision to transmit to the mosquito and (3) interaction with the human immune system. Discovery of these signals may allow us to stop malaria transmission and treat infection more effectively.

Taxonomy of Avian Malaria Parasites
The bird malaria parasites are taxonomically diverse and infect a wide range of bird species. Their relevance to bird health and their potential importance as zoonotic agents has received limited attention. Description of the epidemiology and ecology of bird malaria requires the availability of suitable molecular markers to define species and strains of the diverse Plasmodium species infecting birds. The development of such tools and the eventual description of the epidemiology of bird malaria in specific transmission situations is a new research goal. This research will be greatly facilitated by the sequencing of the genome of Plasmodium gallinaceum underway at the Sanger Centre as well as close collaboration with colleagues Dr Catherine Cosgrove and Professor Ben Sheldon at the Edward Grey Institute of Ornithology, University of Oxford and Dr Susan Perkins, American Museum of Natural History. We will explore the use the avian malaria system to evaluate malaria vaccination strategies.

Selected Publications

1. Alyssa E. Barry, Aleksandra Leliwa-Sytek, Livingston Tavul, Heather Imrie, Florence Migot-Nabias, Gilean A.V. McVean, Day, K.P. Population genomics of the immune evasion (var) genes of Plasmodium falciparum. PLoS Pathogens. 2007 Mar 13;3(3);e34.
2. Imrie, H., Fowkes, F., Michon, P., Tavul, L., Reeder, J. and Day, K.P. Low prevalence of an acute phase response in asymptomatic children from a malaria endemic area of Papua New Guinea. Am. J. Trop. Med. Hyg. 2007 Feb:76(2);280-4.
3. Volkman SK, Lozovsky E, Barry AE, Bedford T, Bethke L, Myrick A, Day KP, Hartl DL, Wirth DF, Sawyer SA. Genomic heterogeneity in the density of noncoding single-nucleotide and microsatellite polymorphisms in Plasmodium falciparum. Gene 2007 Jan 31:387(1-2);1-6.
4. Cosgrove, C.L., Day, K.P., & Sheldon, B.C. Co-amplification of Leucocytozoon by PCR diagnostic tests for avian malaria: a cautionary note. J Parasitology. 2006 Dec:92(6);1362-5.
5. Cosgrove, C. L., Knowles, S. C. L., Day, K. P. & Sheldon, B. C. No evidence for malaria infection during the nestling phase in a passerine bird. Parasitology. 2006 Dec:92(6);1302-4.
6. Barry, A. E., Leliwa, A., Man, K., Kasper, J.M., Hartl, D.L., Day, K.P. Variable SNP density in aspartyl protease genes of the malaria parasite Plasmodium falciparum. Gene. 2006 Jul 19:376(2);163-73.
7. Imrie, H., Fowkes, F. J.I., Michon, P., Tavul, L., Hume, J.C.C., Piper, K.P., Reeder, J.C., Day, K.P. Haptoglobin levels are associated with haptoglobin genotype and alpha+ -thalassemia in a malaria endemic area. Am. J. Trop. Med. Hyg. 2006 June;74(6):965-71.
8. Fowkes, F, Imrie, H, Migot-Nabias, F, Michon, P, Justice, A, Deloron, P, Luty, A, and Day, KP. Association of haptoglobin levels with age, parasite density, and haptoglobin genotype in a malaria-endemic area of Gabon. Am. J. Trop. Med. Hyg. 2006 Jan;74(1):26-30.
9. Barry, A.E. (Postdoctoral Member of Dr Day’s Lab). Malaria epidemiology: Insights from the genome of the malaria parasite, Molecular and Genetic Medicine. 2005;1 (2) : 76-86
10. Dyer, M., and Day, K. P. Regulation of the rate of asexual growth and commitment to sexual development by diffusible factors from in vitro cultures of Plasmodium falciparum. Am J Trop Med Hyg. 2003;68:403-409. (#J58012)
11. Volkman, S. K., Barry, A. E., Lyons, E. J., Nielsen, K. M., Thomas, S. M., Choi, M., Thakore, S. S., Day, K. P., Wirth, D. F., and Hartl, D. L. Recent origin of Plasmodium falciparum from a single progenitor. Science. 2001;293:482-484. (#J58018)
12. Anderson, T. J., Haubold, B., Williams, J. T., Estrada-Franco, J. G., Richardson, L., Mollinedo, R., Bockarie, M., Mokili, J., Mharakurwa, S., French, N., Whitworth, J., Velez, I.D., Brockman, A.L., Nosten, F., Ferreira, M.U. and Day, K.P. Microsatellite markers reveal a spectrum of population structures in the malaria parasite Plasmodium falciparum. Mol Biol Evol. 2000;17(10):1467-1482. (#J58024)
13. Bruce, M. C., Donnelly, C. A., Alpers, M. P., Galinski, M. R., Barnwell, J. W., Walliker, D., and Day, K. P. Cross-species interactions between malaria parasites in humans. Science. 2000;287:845-848. (#J58029)
14. Hayward, R. E., Tiwari, B., Piper, K. P., Baruch, D. I., and Day, K. P. Virulence and transmission success of the malarial parasite Plasmodium falciparum. Proc Natl Acad Sci USA. 1999;96:4563-4568. (#J58033)
15. Paul, R. E., Packer, M. J., Walmsley, M., Lagog, M., Ranford-Cartwright, L. C., Paru, R., and Day, K. P. Mating patterns in malaria parasite populations of Papua New Guinea. Science. 1995;269:1709-1711. (#J58040)
16. Wood MJ, Cosgrove CL, Wilkin EA, Knowles CI, Day KP & Sheldon BC. Within-population prevalence and lineage distribution of avian malaria in blue tits Cyanistes caeruleus. Molecular Ecology 2007. In Press