Source: PENNSYLVANIA STATE UNIVERSITY submitted to
INTERACTIONS BETWEEN INSECTS AND PATHOGENS/PARASITES FOR DISEASE CONTROL
Sponsoring Institution
National Institute of Food and Agriculture
Project Status
TERMINATED
Funding Source
HATCH
Reporting Frequency
Annual
Accession No.
0225789
Grant No.
(N/A)
Project No.
PEN04445
Proposal No.
(N/A)
Multistate No.
(N/A)
Program Code
(N/A)
Project Start Date
Jul 1, 2011
Project End Date
Jun 30, 2016
Grant Year
(N/A)
Project Director
Cui, LI.
Recipient Organization
PENNSYLVANIA STATE UNIVERSITY
208 MUELLER LABORATORY
UNIVERSITY PARK,PA 16802
Performing Department
Entomology
Non Technical Summary
The recent upsurge of many vector-borne diseases in the world and the emergence of new diseases in many geographical regions are of great concern for public health. As a result of global warming and increased international travel, there is a tendency toward globalization of vector-borne infectious disease. Traditionally, vector-borne diseases have been mitigated by chemical suppression of vector populations, but the evolution of resistance of arthropod vectors to insecticides has become an increasingly serious problem. Concerns about environmental pollution by chemical pesticides have also limited their applications. Therefore, in this project, we will study the developmental biology of the malaria parasites, identify factors affecting the transmission success to and from insects of drug resistant pathogens, and develop and evaluate the Late Life Acting insecticide approach in vector control. This study will apply some cutting-edge technologies including parasite transgenics and genomics, quntitative biology, and mathmetical modeling. By elucidating molecular interactions between host and pathogens of human and animal diseases, rational and novel disease control measures may be developed. The recent resurgence of many vector-borne diseases is to a large extent due to the evolution and spread of drug resistance. Elucidation of the metabolic pathways in gene regulation may lead to the finding of novel drug targets, which will have great potential for overcoming increasing resistance to current drugs. Similarly, development and evaluation of Late Life Acting insecticides could have broad application since many vector/parasite systems have features in common, thus discoveries made in one system may be applied to other systems. In this regard, this project will generate information relevant to vector-borne disease controls both within the US and in other disease-endemic countries.
Animal Health Component
(N/A)
Research Effort Categories
Basic
(N/A)
Applied
(N/A)
Developmental
(N/A)
Classification

Knowledge Area (KA)Subject of Investigation (SOI)Field of Science (FOS)Percent
2113110103020%
2113110105020%
2113110110240%
2113110111020%
Knowledge Area
211 - Insects, Mites, and Other Arthropods Affecting Plants;

Subject Of Investigation
3110 - Insects;

Field Of Science
1030 - Cellular biology; 1102 - Mycology; 1110 - Parasitology; 1050 - Developmental biology;
Goals / Objectives
1. To investigate the mechanisms of transcriptional and translational regulations during sexual development and differentiation of the malaria parasites. 2. To identify factors affecting the transmission success to and from insects of drug resistant pathogens. 3. To further develop and evaluate the Late Life Acting insecticide approach, focusing on the potential for use of fungal insect pathogens in novel biopesticides. This will include research to better understand the ecology of disease transmission to better define the level and nature of transmission blocking required from a novel product in different epidemiological settings. One important focus will be the environmental conditions favoring spore attachment to the insect cuticle and germination. Coupled with this we will examine how ultrastructural components of the insect cuticle affect fungal transmission. This project will be built on the current momentum, the initial focus for this research will be mosquitoes and malaria. However, we anticipate extension of this research via complementary activities applying the knowledge and techniques to other pest vector problems.
Project Methods
Objective 1 - To understand the effector molecules involved in the interactions, research will focus on the molecular mechanisms of gametocytogenesis of the parasite using molecular tools and genetic manipulation. We will specifically examine the roles of epigenetic and translational regulators in regulating these developmental transitions. Proteins involved in the molecular interactions will be studied by genetic manipulations using yeast hybridization systems and through genetic knockouts of important genes. We will employ DNA microarray and mass spectrometry technologies to determine the global changes in gene expression and protein synthesis. These molecular studies will focus on the two most important species of human malaria, P. falciparum and P. vivax, but may extend to other species for comparative analysis. Genetic variation and population genetics of the malaria parasite will also be studied in order to understand their distribution and intimate relationships with local vector species. Since P. vivax malaria is on the rise in recent years (Zhou et al., 2005), and research on this parasite has lagged significantly behind that on P. falciparum, we will study many aspects of this parasite including culture techniques, developmental biology, and interactions with the hosts. To study the functions of chromatin remodeling enzymes in transcription regulation, evolutionarily conserved enzymes and their complexes will be identified through sequence comparison, expression of recombinant enzymes, determination of their catalytic activities, and their responses to inhibitors or activators. In vivo functions will be determined by genetic manipulation and their effect on parasite growth and development, and the sensitivity of the parasite to the inhibitors or activators. The complexes will be purified using tandem affinity tag purification technology and determined by high-accuracy tandem mass spectrometry. This study will provide comprehensive understanding of the contribution of transcriptional and translational control in regulating parasite development. Objective 2 - Infected mice are subject to various treatment regimens (duration, dose, inter-pulse interval) and transmission success to mosquitoes assayed, with the fate of resistant parasites assayed at various stages during infection, as well as transmission from mosquitoes. Objective 3 - In order to move the biopesticide approach forward we have identified two main areas for research and development. First we need to develop practical and effective delivery systems to maximize probability of infection and then quantify the infection prevalence (proportion of mosquitoes infected) and intensity (how many spores picked up per mosquito) achievable in field settings - i.e. what the level of infection is. Second, we need to better understand the impact of fungal infection on vectorial capacity across a range of conditions and environmental contexts. This information tells us what contribution to malaria control we expect for a given level of infection in different settings - i.e. what infection does.

Progress 07/01/11 to 06/30/16

Outputs
Target Audience:Results derived from this study have been delivered to the scientific community through publications in scientific journals and presentations at the society meetings (Annual meetings of the American Society of Tropical Medicine and Hygiene, and annual meetings of the American Society of Entomology), seminars, workshops, formal instruction, public open meetings, and school visits. Results from the studies have been presented at the "International Centers of Excellence in Malaria Research" annual workshops during the past five years. The results have also been presented recently at the International Congress of Tropical Medicine and Malaria held in Brisbane, Australia. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?This project provides training of a number of graduate students and postdocs. How have the results been disseminated to communities of interest?The results are disseminated to the communities of interest through publications and meeting presentations. What do you plan to do during the next reporting period to accomplish the goals? Nothing Reported

Impacts
What was accomplished under these goals? Our team focuses on vector-borne diseases using a multidisciplinary approach. During the tenure of this grant, we determined how climate changes affect the disease dynamics, and disease vectorial competence. We elucidated the evolution of insecticide resistance in disease vectors and developed the concepts of evolution-proof biological insecticides - insect pathogenic fungi. We have also investigated the fungal fauna which invaded the insect world, and determined the behavior-manipulating properties of fungi. With regard to malaria, we studied the epidemiology of the disease using both field applied and modeling approaches. We have tested the possibility of changing the housing structure in African countries to reduce malaria transmission. We have begun to elucidate the genetics of malaria parasites underlying drug resistance through clinical follow ups and laboratory genetic manipulations. These studies comprehensively addressed various aspects of vector borne diseases and will serve as the foundation for guiding control efforts.

Publications

  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Hu, Y., Zhou, G., Ruan, Y., Lee, M.-C., Xu, X., Deng, S., Bai, Y., Zhang, J., Morris, J., Liu, H., Wang, Y., Fan, Q., Li, P., Yang, Z., Yan, G., Cui, L. 2016. Seasonal dynamics and micro-geographical spatial heterogeneity of malaria along the China-Myanmar border. Acta Trop. 157, 12-19.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Sriwichai, P., Samung, Y., Sumroypol, S., Kiattibutr, K., Kumpitak, C., Payakapon, A., Kaewkungwal, J., Yan, G., Cui, L., Sattabongkot, J. 2016. Natural human Plasmodium infections in major Anopheles mosquitoes in western Thailand. Parasit. Vectors 9, e17.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Day T & Read A. 2016. When does high-dose antimicrobial chemotherapy prevent the emergence of resistance? PLoS Computational Biology. 12, e1004689.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Thomas MB, Read AF.2016. The threat (or not) of insecticide resistance for malaria control. Proc Natl Acad Sci U S A. 113, 8900-2.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Greischar MA, Mideo N, Read AF, Bj�rnstad ON.2013. Predicting optimal transmission investment in malaria parasites. Evolution. 70(7):1542-58.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Ohm JR, Teeple J, Nelson WA, Thomas MB, Read AF, Cator LJ.2016. Fitness consequences of altered feeding behavior in immune-challenged mosquitoes. Parasit Vectors. 9:113.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Greischar MA, Mideo N, Read AF, Bj�rnstad ON. 2016. Quantifying Transmission Investment in Malaria Parasites. PLoS Comput Biol. 12(2):e1004718
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Waite JL, Lynch PA, Thomas MB. 2016. Eave tubes for malaria control in Africa: a modelling assessment of potential impact on transmission. Malar J. 15(1):449.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Shapiro LL, Murdock CC, Jacobs GR, Thomas RJ, Thomas MB. 2016. Larval food quantity affects the capacity of adult mosquitoes to transmit human malaria. Proc Biol Sci. 283(1834).
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Murdock CC, Sternberg ED, Thomas MB. 2016. Malaria transmission potential could be reduced with current and future climate change. Sci Rep. 6:27771
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Thomas S, Ravishankaran S, Justin JA, Asokan A, Mathai MT, Valecha N, Thomas MB, Eapen A. 2016. Overhead tank is the potential breeding habitat of Anopheles stephensi in an urban transmission setting of Chennai, India. Malar J. 15(1):274.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Loreto RG, Hughes DP. 2016. Disease in the Society: Infectious Cadavers Result in Collapse of Ant Sub-Colonies. PLoS One. 11(8):e0160820.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Hughes DP, Ara�jo JP, Loreto RG, Quevillon L, de Bekker C, Evans HC. 2016. From So Simple a Beginning: The Evolution of Behavioral Manipulation by Fungi. Adv Genet. 94:437-69.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Loreto RG, Hughes DP. 2016. Disease Dynamics in Ants: A Critical Review of the Ecological Relevance of Using Generalist Fungi to Study Infections in Insect Societies. Adv Genet. 94:287-306.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Gupta, B., Parker, D.M., Wang, M., Reddy, B.P.N., Yan, G., Sattabongkot, J., Cui, L. 2016. Microgeographically diverse Plasmodium vivax populations at the Thai-Myanmar border. Infect. Genet. Evol. 45, 341-346.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Wang, Z., Cabrera, M., Yang, J., Yuan, L., Shrestha, S., Gupta, B., Li, X., Liang, X., Kemirembe, K., Shrestha, S., Brashear, A., Cao, Y., Porcella, S., Miao, J., Yang, Z., Su, X., Cui, L. 2016. Genome-wide association analysis identifies genetic loci associated with resistance to multiple antimalarials in Plasmodium falciparum from China-Myanmar border. Sci. Rep. 6, e33891.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Zhou, G., Lo, E., Zhong, D., Wang, X., Wang, Y., Malla, S., Lee, M.-c., Yang, Z., Cui, L., Yan, G. 2016. Impact of interventions on malaria in internally displaced persons along the China-Myanmar border: 2011-2014. Malar. J. 15, e471.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Shrestha, S., Li, X., Ning, G., Miao, J., Cui, L. 2016. The RNA-binding protein PfPuf1 functions in the maintenance of gametocytes in Plasmodium falciparum. J. Cell Sci. 129, 3144-3152.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Guo, S., Zhang, W., He, L., Tan, G., Myat Phone Kyaw, Wang, B., Cui, L. 2016. Rapid evaluation of artesunate quality with a specific monoclonal antibody-based lateral flow dipstick. Anal. Bioanal. Chem. 408, 6003-6008.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Xu, X., Zhou, G., Wang, Y., Hu, Y., Ruan, Y., Fan, Q., Yang, Z., Yan, G., Cui, L. 2016. Fine-scale mapping reveals microgeographic heterogeneity of border malaria during the elimination phase in Yunnan Province, China. Emerg. Infect.Dis. 22, 1353-1360.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Baum, E., Sattabongkot, J., Sirichaisinthop, J., Kiattibutr, K., Jain, A., Taghavian, O., Lee, M.-C., Davies, D. H., Cui, L., Felgner, P.L., Yan, G. 2016. Common asymptomatic and submicroscopic malaria infections in western Thailand revealed in longitudinal molecular and serological studies: a challenge to malaria elimination. Malar. J. 15, e333.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Guo, S., He, L., Tisch, D.J., Kazura, J., Mharakurwa, S., Mahanta, J., Herrera, S., Wang, B., Cui, L. 2016. Pilot testing of dipsticks as point-of-care assays for rapid diagnosis of poor-quality artemisinin drugs in endemic settings. Trop. Med. Health. 44, e15.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Wang, X., Zhou, G., Zhong, D., Wang, X., Wang, Y., Yang, Z., Cui, L., Yan, G. 2016. Life-table studies revealed significant effects of deforestation on the development and survivorship of Anopheles minimus larvae. Parasit. Vectors 9, e323.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Chang, X., Zhong, D., Lo, E., Fang, Q., Bonizzoni, M., Wang, X., Lee, M.-C., Zhou, G., Zhu, G., Chen, X., Cui, L., Yan, G. 2016. Landscape genetic structure and evolutionary genetics of insecticide resistance gene mutations in Anopheles sinensis. Parasit. Vectors. 9, e228.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Lo, E., Nguyen, J., Oo, W., Hemming, E., Zhou, G., Yang, Z., Cui, L., Yan, G. 2016. Examining Plasmodium falciparum and P. vivax clearance subsequent to antimalarial drug treatment in the Myanmar-China border area based on quantitative real-time polymerase chain reaction. BMC Infect. Dis. 16, e154.
  • Type: Journal Articles Status: Published Year Published: 2016 Citation: Wang, Q., Zhao, Z., Zhang, X., Li, X., Zhu, M., Li, P., Yang, Z., Wang, Y., Yan, G., Shang H., Cao, Y., Fan, Q., Cui, L. 2016. Naturally acquired antibody responses to Plasmodium vivax and Plasmodium falciparum merozoite surface protein 1 (MSP1) C-Terminal 19 kDa domains in an area of unstable malaria transmission in Southeast Asia. PLoS One 11, e0151900.


Progress 10/01/14 to 09/30/15

Outputs
Target Audience:Results derived from this study have been delivered to the scientific community through publications in scientific journals and presentations at the society meetings, seminars, workshops, formal instruction, public open meetings, and school visits. Results from the studies have been presented recently at "International Conference on Vivax Malaria" held in Indonesia in May 2014, and the "International Centers of Excellence in Malaria Research" annual workshop in Colombia in August 2014. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided?Dr. Liwang Cui has provided overall supervision on the planning and execution of the 'drug resistance' component of the project. The National Institutes of Health provided financial support for this study and training of 6 postdoctoral scholars. How have the results been disseminated to communities of interest?The results are disseminated to the communities of interest through publications and talks. What do you plan to do during the next reporting period to accomplish the goals?We will use the next generation sequencing technology and genome-wide association studies to identify additional markers in the genome that mediate resistance to commonly used antimalarial drugs. We will also determine how the transmission blocking drugs (primaquine and tafenoquine) will interact with other drug combinations.

Impacts
What was accomplished under these goals? Vector-borne diseases still cause significant mortality and morbidity in the world. Our team aims to obtain a better understanding of vector-borne diseases using multidisciplinary approaches with focuses on climatic changes, resistance of vectors to insecticides, and resistance of the pathogens to chemotherapies. The emergence of artemisinin resistant parasite in Southeast Asia raises serious concern on malaria therapy. We have determined the contribution of mutations in a newly identified molecular marker of resistance, the K13 gene in the malaria parasites. We also performed field surveillance to determine the clinical efficacy of the current treatment. We also evaluated the genetic polymorphisms of hrp2 gene and its effect on the rapid diagnostic test-based malaria diagnosis. To address the malaria elimination in this region, we have performed temporal-spatial modeling of malaria transmission at the microgeographical scale and documented parasite movement across the international border through population genetic analysis. These comprehensive studies will guide the local malaria elimination campaigns.

Publications

  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Li, P., Xing, H., Zhao, Z., Yang, Z., Cao, Y., Yan, G., Sattabongkot, J., Cui, L.,* Fan, Q.* 2015. Genetic diversity of Plasmodium falciparum histidine-rich protein 2 in the China-Myanmar border area. Acta Trop. 152, 26-31.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Bhavna Gupta, B. P. Niranjan Reddy, Qi Fan, Guiyun Yan, Jeeraphat Sirichaisinthop, Jetsumon Sattabongkot, Ananias A. Escalante, and Liwang Cui. 2015. Molecular evolution of PvMSP3? block II in Plasmodium vivax from diverse geographic origins. PLoS One 10, e0135396.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Cui, L., Mharakurwa, S., Ndiaye, D., Rathod, P.K., Rosenthal, P.J. 2015. Antimalarial drug resistance: activities and findings of the ICEMR network. Am. J. Trop. Med. Hyg. 93, S57-68.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Li, Q., Yang, F., Liu, R., Luo, L., Yang, Y., Zhang, L., Liu, H., Zhang, W., Fan, Z., Yang, Z., Cui, L.,* He, Y.* 2015. Prevalence and molecular characterization of glucose-6-phosphate dehydrogenase deficiency at the China-Myanmar Border. PLoS One 10, e0134593.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Wang, Y., Yang, Z., Yuan, L., Zhou, G., Lee, M.-C., Fan, Q., Xiao, Y., Cao, Y., Yan, G., Cui, L. 2015. Clinical efficacy of dihydroartemisinin-piperaquine for the treatment of uncomplicated Plasmodium falciparum malaria at the China-Myanmar border. Am. J. Trop. Med. Hyg. 93, 577-583.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Parker, D.M., Matthews, S.A., Sirichaisinthop, J., Kiattibutr, K., Yan, G., Zhou, G., Lee, M.-C., Fan, Q., Li, P., Sattabongkot, J., Cui, L. 2015. Microgeography and molecular epidemiology of malaria at the Thailand-Myanmar border in the malaria pre-elimination phase (2011-2012). Malar. J. 14, e198.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Lo, E., Zhou, G., Oo, W., Lee, M.-C., Baum, E., Felgner, P., Yang, Z., Cui, L., Yan, G. 2015. Plasmodium falciparum malaria transmission between internally displaced persons settlement and local villages in the Myanmar-China border area. Infect. Genet. Evol. 33, 189-196.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Wang, Z., Shrestha, S., Li, X., Miao, J., Yuan, L., Cabrera, M., Grube, C., Yang, Z., Cui, L. 2015. Prevalence of K13-propeller polymorphisms in Plasmodium falciparum from China-Myanmar border in 2007-2012. Malar. J. 14, e168.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Baum,E., Sattabongkot, J., Sirichaisinthop, J., Kiattibutr, K., Davies, H., Jain, A., Lo, E., Lee, M.-C., Randall, A. Z., Molina, D.M., Liang, X., Cui, L., Felgner, P. L., Yan, G. 2015. Frequent unrecognized submicroscopic and asymptomatic Plasmodium falciparum and P. vivax infections revealed by molecular and serological markers in western Thailand. Malar. J. 14, e95.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Yuan, L., Wang, Y., Parker, D., Gupta, B., Yang, Z., Liu, H., Fan,Q., Cao, Y., Lee, M., Zhou, G., Yan, G., Baird, J. K., Cui, L. 2015. Therapeutic responses of Plasmodium vivax malaria to chloroquine and primaquine treatment in northeastern Myanmar. Antimicrob. Agents Chemother. 59, 1230-1235.
  • Type: Journal Articles Status: Published Year Published: 2015 Citation: Cui, L., Lindner, S., Miao, J. 2015. Translational regulation during stage transitions in malaria parasites. Ann. NY Acad. Sci. 1342, 1-9.


Progress 10/01/13 to 09/30/14

Outputs
Target Audience: Results derived from this study have been delivered to the scientific community through publications in scientific journals and presentations at the society meetings, seminars, workshops, formal instruction, public open meetings, and school visits. Results from the drug resistance studies and the malaria transmission ecology studies have been presented recently at the New York Academy of Sciences Symposium “Malaria 2014: Advances in Pathophysiology, Biology and Drug Development” in April 2014 and the “International Centers of Excellence in Malaria Research” annual workshop in Peru, August 2014. Results from the malaria transmission ecology and control research were also presented at: NIH-BEI workshop entitled “Bridging vector and allied arthropod biology for innovation and discovery”, NIH, May 2014; Laboratory of Excellence (LabEx) IntegrativeBiology of Emerging Infectious Diseases (IBEID) meeting entitled “Can one anticipate the next emerging infectious diseases in Europe?”, Pasteur Institute, Paris, September 2014; Institute of Medicine Forum on Microbial Threats workshop entitled “Vector-Borne Diseases: Exploring the Environmental, Ecological, and Health Connections”, Keck Center, Washington DC, September 2014. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Dr. Liwang Cui has provided overall supervision on the planning and execution of the ‘drug resistance’ component of the project. The National Institutes of Health provided financial support for this study and training of 5 postdoctoral scholars. The malaria transmission ecology and control research involved the participation (and ongoing training) of 3 PhD students and 5 postdoctoral researchers during this reporting period. How have the results been disseminated to communities of interest? The results are disseminated to the communities of interest through publications and talks. What do you plan to do during the next reporting period to accomplish the goals? For the “drug resistance” component, we will try to determine the artemisinin resistance mechanism through whole genome sequencing and association analysis. For the malaria transmission and control research we aim to continue work exploring the effects of environmental temperature on malaria transmission using temperature data from local transmission settings to help explain dynamics of malaria. We also aim to advance our work developing novel control tools with semi-field evaluations of new control devices conducted over the next 12 months.

Impacts
What was accomplished under these goals? Vector-borne diseases still cause significant mortality and morbidity in the world. Our team aims to obtain a better understanding of vector-borne diseases using multidisciplinary approaches with focuses on climatic changes, resistance of vectors to insecticides, and resistance of the pathogens to chemotherapies. To decipher the molecular mechanisms of drug resistance, we explored the potential of Pfmrp1 polymorphism in mediating drug resistance. We evaluated whether parasites collected from Southeast Asia display any growth advantage during in vitro culture. To further study parasite drug resistance at the sexual stages, we developed a novel high throughput assay for a flow cytometry-based method. For our field-based study, we investigated the risk factors of malaria in Southeast Asia and ecological determinants for continued malaria transmission. Key accomplishments in the transmission ecology and control research include the development of novel mosquito control interventions that are currently being tested in Africa. One of these is a technology called an ‘eave tube’, which provides a focal target for contacting malaria mosquito vectors with insecticides (chemical or biological) as they try to enter the house at night via the eaves. So far 700 houses in a village in southern Tanzania have been fitted with eaves tubes in a pilot study as part of a collaborative project funded by the EU. Basic research also continued to increase understanding of how environmental variation affects the ability of mosquitoes to transmit malaria. This basic research has important implications for understanding current malaria dynamics and predicting possible impacts of future climate change. Of particular note this year was new research demonstrating how small changes in the nutritional quality of larval habitats can have large carry-over effects on the subsequent ability of adult mosquitoes to transmit human malaria parasites. This potential role of larval ecology in malaria transmission has not been demonstrated previously.

Publications

  • Type: Journal Articles Status: Published Year Published: 2014 Citation: He, X., Yan, J., Zhu, X., Wang, Q., Pang, W., Qi, Z., Wang, M., Luo, E., Parker, D.M., Cantorna, M.T., Cui, L., Cao, Y. 2014. Vitamin D inhibits the occurrence of experimental cerebral malaria in mice by suppressing the host inflammatory response. Journal of Immunology 193,1314-1323.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Gupta, B., Xu, S., Wang, Z., Sun, L., Cui, L., Yang, Z. 2014. Plasmodium falciparum multidrug resistance protein 1 (Pfmrp1) gene and its association with in vitro drug susceptibility of parasite isolates from northeast Myanmar. Journal of Antimicrobial Chemotherapy 69,2110-2117.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Li, P. Zhao, Z., Wang, Y., Xing, H., Parker, D.M., Yang, Z., Baum, E., Li, W., Sattabongkot, J., Sirichaisinthop, J., Li, S., Yan, G., Cui, L., Fan, Q. 2014. Nested PCR detection of malaria directly using blood filter paper samples from epidemiological surveys. Malarial Journal 13,e175.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Liu, M., Miao, J., Sullivan Jr., W., Cui, L., Chen, X. 2014. Characterization of TgPuf1, a member of the Puf family RNA-binding proteins from Toxoplasma gondii. Parasites and Vectors 7,e141.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Chen, K., Sun, L., Lin, Y., Hao, M., Feng, G., Wu, Y., Cui, L., Yang, Z. 2014. Competition between Plasmodium falciparum strains in clinical infections during in vitro culture adaptation. Infection, Genetics and Evolution 24,105-110.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: He, L., Nan, T., Cui, Y., Guo, S., Zhang, W., Zhang, R., Zhang, L., Tan, G., Wang, B.,* Cui, L.* 2014. Development of a colloidal gold-based lateral flow dipstick immunoassay for rapid qualitative and semi-quantitative analysis of artesunate and dihydroartemisinin. Malarial Journal 13,e127.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Yuan, L., Hao, M., Wu, L., Zhao, Z., Rosenthal, B. M., Li, X., He, Y., Sun, L., Feng, G., Xiang, Z., Cui, L., Yang, Z. 2014. Refrigeration provides a simple means to synchronize in vitro cultures of Plasmodium falciparum. Experimental Parasitology 140,18-23.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Parker, D., Wood, J., Tomita, S., DeWitte, S., Jennings, J., Cui, L. 2014. Household ecology and out-migration among ethnic Karen along the Thai-Myanmar border. Demographic Research. 30,1129-1156.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Wang, Z.; Liang, X., Liu, M., Siriwat, S., Tan, F., Miao, J., Cui, L. 2014. A flow cytometry-based high-throughput assay targeting all Plasmodium falciparum gametocyte stages. PLoS One 9,e93825.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Qin, Q., Li, Y., Zhong, D., Zhou, N., Chang, X., Li, C., Cui, L., Yan, G., Chen, X. 2014. Insecticide resistance of Anopheles sinensis and An. vagus in Hainan Island, a malaria-endemic area of China. Parasites and Vectors 7,e92.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Zhou, G., Sun, L., Xia, R., Yang, J., Duan, Y., Xu, J., Yang, H., Wang, Y., Lee, M.-C., Xiang, Z., Yan, G., Cui, L., Yang, Z. 2014. Clinical malaria along the China-Myanmar border area in Yunnan, China. Emerging Infectious Diseases 20,681-684.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Glunt, K.D., Paaijmans, K.P., Read, A.F. & Thomas, M.B. 2014. Environmental temperatures significantly change the impact of insecticides measured using WHOPES protocols. Malaria Journal 13:350.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Paaijmans, K.P., Blanford, J.I., Crane, R.G., Mann, M.E., Ning, L., Schreiber, K.V. & Thomas, M.B. 2014. Downscaling reveals diverse effects of anthropogenic climate warming on the potential for local environments to support malaria transmission. Climatic Change.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Murdock, C.C., Luckhart, S. & Thomas, M.B. 2014. Ambient temperature and dietary supplementation interact to shape mosquito vector competence for malaria. Journal of Insect Physiology 67:37-44.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Cator, L.J., Lynch, P.A., Thomas, M.B. & Read, A.F. 2014. Alterations in mosquito behaviour by malaria parasites: potential impact on force of infection. Malaria Journal 13:164.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Sternberg, E.D. & Thomas, M.B. 2014. Local adaptation to temperature and the implications for vector-borne diseases. Trends in Parasitology 30:115-122.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Murdock, C.C., Blanford, S., Hughes, G.L., Rasgon, J.L. & Thomas, M.B. 2014. Temperature alters Plasmodium blocking by Wolbachia. Nature Scientific Reports doi:10.1038/srep03932.
  • Type: Journal Articles Status: Published Year Published: 2014 Citation: Beck-Johnson, L.M., Paaijmans, K.P., Nelson, W.A., Read, A.F., Thomas, M.B. & Bjornstad, O.N. 2013. The effect of temperature on Anopheles mosquito population dynamics and the potential for malaria transmission. PLoS One 8:e79276.


Progress 10/01/12 to 09/30/13

Outputs
Target Audience: Results derived from this study have been delivered to the scientific community through publications in scientific journals and presentations at the society meetings, seminars, workshops, formal instruction, public open meetings, and school visits. Result from the drug resistance studies and the malaria transmission ecology studies have been presented recently at the International Centers of Excellence in Malaria Research meeting in Guilin, China, August 2013. Research on malaria transmission and control has been disseminated to audiences including academic researchers (faculty, postdoctoral and graduate), national program researchers in Tanzania and India, school children and the general public. Changes/Problems: Nothing Reported What opportunities for training and professional development has the project provided? Dr. Liwang Cui has provided overall supervision on the planning and execution of the ‘drug resistance’ component of the project. The National Institutes of Health provided financial support for this study and training of three postdoctoral scholars. The National Institutes of Health provided financial support for this study and training of four postdoctoral scholars. Dr. Andrew Read has provided supervision and execution of the “evolution of resistance” component of the project, which trained six PhD students. How have the results been disseminated to communities of interest? The results are disseminated to the communities of interest through publications and talks. One of the outreach activities is the offering of an online course Epidemic – the Dynamics of Infectious Diseases. To reach the broader community we have hosted 3 visits from local schools to our lab so that students could learn about mosquitoes and malaria. We also took part in a ‘Science Café’ event organized by the Education and Outreach?Program of Penn State’s Center for Nanoscale Science. This event was attended by about 50 members of the general public who learned about our novel ways of controlling pests such as mosquitoes and bed bugs using natural microbial pathogens. What do you plan to do during the next reporting period to accomplish the goals? We plan to use the genome-wide association study (HWAS) approach to determine genomic regions in the parasites from a Southeast Asia region that have been under selection and associated with elevated drug resistance. For the malaria transmission and control research we aim to continue work exploring the effects of environmental temperature on malaria transmission using temperature data from local transmission settings to help explain dynamics of malaria. We also aim to advance our work developing novel control tools with semi-field evaluations of two new control devices conducted over the next 12 months.

Impacts
What was accomplished under these goals? Vector-borne diseases still cause significant mortality and morbidity in the world. Our team aims to obtain a better understanding of vector-borne diseases using multidisciplinary approaches with focuses on climatic changes, resistance of vectors to insecticides, and resistance of the pathogens to chemotherapies. To decipher the molecular mechanisms of artemisinin resistance, we used a candidate gene-based approach. Our study using parasite population collected from Southeast Asia, where artemisinin drugs have been used mostly extensively, to elucidate the potential role of the pfatp6 gene in mediating artemisinin resistance. Our result showed that the parasite population displayed tremendous diversity in this gene, but did not carry any obvious signature of drug selection, further emphasizing that this gene is not responsible for the observed changes in clinical responses to artemisinin drugs. Findings on the evolution of drug resistance in malaria parasite included experimental proof of concept that light touch drug regimens reduce rate of transmission of drug resistant parasites to mosquitoes. Research on the modeling of infectious diseases revealed that (1) Hantavirus dynamics: How the risk of zoonotic spillover of hanta virus is shaped by the interaction between the reservoir rodent host and the environment. We develop a mathematical model that can forecast the dynamics up to 14 mos in advance. (2) Malaria dynamics: (i) A new model of vector dynamics that allows prediction of temperature determines abundance (ii) An analysis of malaria virulence among different strains; (ii) A new model of within-host dynamics to explore the evolution of developmental synchrony (Gresichar et al., in revision). (3) Whooping cough: The role of natural immune boosting on maintaining / boosting immunity to respiratory bacteria. We show that such boosting can have very important consequences for disease dynamics and potentially significant implications for design of vaccine policy; (4) Spatiotemoral dynamics of childhood infections: (i) The implications for heterogeneities in rubella incidence for vaccination; (ii) A decision theoretic framework for allocating resources towards vaccination versus palliative care in an outbreak response context; (iv) A new statistical method for fitting gravity models to spatiotemporal incidence data; and (v) a comparative analysis of the metapopulation rescue effect in the persistence of several childhood infections.In addition to the published work I have focused on developing a set of models to better understand vector disease dynamics with particular focus on: (a) developing temperature-dependent stage-structure models for mosquito populations and (b) evolution of life-history in Plasmodium in the mammalian hosts. For the malaria transmission and control research there were three notable accomplishments. (i) Conducted groundbreaking research to demonstrate that mosquitoes infected with malaria parasites behave differently (different biting patterns) to uninfected mosquitoes. These differences could have major implications for understanding disease transmission and for optimizing control interventions such as bed nets. (ii) Conducted groundbreaking research to demonstrate how natural variation in environmental temperature can strongly shape the mechanisms and expression of mosquito immunity. This research has important implications for understanding natural variation in the ability of mosquitoes to transmit malaria (refractoriness) and for the effectiveness of prospective control tools such as genetically modified or transinfected mosquitoes. The research challenges much of the conventional understanding of mosquito immune function that derives from studies conducted under one set of standard insectary conditions. (iii) Together with partners in Europe and Tanzania we obtained a Eu6 million grant from the European Union to develop a new set of mosquito control interventions that can add used together with existing tools (bed nets and insecticide sprays) to develop more effective and sustainable integrated vector management strategies. The project aims to have new interventions being used within 3 years.

Publications

  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Miao, J., Lawrence, M., Parker, D., Jeffers, V., Ge, Y., Sullivan Jr., W. J., Cui, L. 2013. Extensive lysine acetylation occurs in evolutionarily conserved metabolic pathways and parasite-specific functions during Plasmodium falciparum intraerythrocytic development. Mol. Microbiol. 89, 660-675.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Miao M., Wang, Z., Yang, Z., Yuan, L., Parker, D.M., Putaporntip, C., Jongwutiwes, S., Xangsayarath, P., Pongvongsa, T., Moji, H., Tuong, T. D., Abe, T., Nakazawa, S., Myat Phone Kyaw, Yan, G., Sirichaisinthop, J., Sattabongkot, J., Mu, J., Su, X.-z., Kaneko, O., Cui, L. 2013. Genetic diversity and lack of artemisinin selection signature on the Plasmodium falciparum ATP6 in the Greater Mekong Subregion. PLoS One 8, e59192.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Cator, C.J., Thomas, S., Paaijmans, K.P., Ravishankaran, S., Justin, J.A., Mathai, M.T., Read, A.F., Thomas, M.B. & Eapen, A. 2013. Characterizing microclimate in urban malaria transmission settings: a case study from Chennai, India. Malaria Journal 12:84.
  • Type: Journal Articles Status: Published Year Published: 2012 Citation: Klepac, P., Bj�rnstad, O.N., Metcalf, C.J.E and Grenfell, B.T. 2012. Optimizing reactive responses to outbreaks of immunizing infections: balancing case management and vaccination. PLoS ONE 7(8):e41428.
  • Type: Journal Articles Status: Published Year Published: 2012 Citation: Metcalf, C.J.E, Lessler, J., Klepac, P., Morice, A., Grenfell, B.T. and Bj�rnstad, O.N. 2012. Structured models of infectious disease: inference with discrete data. Theoretical Population Biology 82: 275-282.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Thomas M.B. 2013. Community Corner: Modulating Malaria with Wolbachia. Nature Medicine 19, 974-975.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: George J., Blanford S., Jenkins. N.E, Thomas M.B. & Baker T.C. 2013. Mosquitoes attracted by fatal fungus. PLoS One 8 (5), e62632.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Anderson R.D., Blanford S., Jenkins N.E. & Thomas M.B. 2013. Discriminating fever behavior in houseflies. PLoS One 8(4), e62269.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Blanford J.I., Blanford S., Crane R.G., Mann M.E., Paaijmans K.P., Schreiber K.V. & Thomas M.B. 2013. Implications of temperature variation for malaria parasite development across Africa. Nature Scientific Reports 3, 1300.
  • Type: Journal Articles Status: Published Year Published: 2013 Citation: Paaijmans K.P., Cator L.J. & Thomas M.B. 2013. Temperature-dependent pre-bloodmeal period and temperature-driven asynchrony between parasite development and mosquito biting rate reduce malaria transmission intensity. PLoS One 8(1), e55777
  • Type: Book Chapters Status: Published Year Published: 2012 Citation: Paaijmans K.P. & Thomas M.B. 2012. Relevant temperature in mosquito and malaria biology. In: Ecology and control of vector-borne diseases (Vol. 3): Ecology of vector-parasite interactions (W Takken & CJM Koenraadt, eds.). Wageningen Academic Publishers, Wageningen, pp 103-122.


Progress 10/01/11 to 09/30/12

Outputs
OUTPUTS: The recent increase of many vector-borne diseases in the world and the emergence of new diseases in many geographical regions are of great concern for public health. There are many contributing factors leading to the rises in vector-borne diseases. Our team aims to obtain a better understanding of vector-borne diseases using multidisciplinary approaches with focuses on climatic changes, resistance of vectors to insecticides, and resistance of the pathogens to chemotherapies. To decipher the molecular mechanisms of artemisinin resistance we procured malaria parasites from Southeast Asia and determined their 'in vitro' drug sensitivity profile. Our study has determined that parasites collected from this endemic area displayed a wide range of sensitivities to currently used antimalarial drugs, and our genome-wide analytic tool may reveal the molecular mechanisms of resistance. Using genetic tools, we have investigated the role of potential molecular markers such as 'pfapt6' gene in artemisinin resistance and our results confirmed the lack of association of this gene with artemisinin resistance. Another hypothesis we have about drug resistance is that patient treatment regimens affect the transmission of resistant malaria parasites to mosquitoes and hence their spread in the population. Our recent experiments provided additional evidence supporting this assumption. This finding should have broad implications in resistance management. We have also begun testing how immunity alters the selection imposed by drug treatment on transmission, and how altering resource levels within hosts can affect the probability of resistance emergence. Work has continued to investigate the effects of environmental factors on the various life history traits of mosquitoes and parasites/pathogens that combine to determine the spatial and temporal patterns of disease transmission. Key findings this year include demonstration of how temperature affects mosquito immune function and the capacity to successfully incubate the malaria parasite, and also how immune responses appear to impact mosquito feeding behavior and parasite transmission. This research is helping to improve the utility of models to explain current disease dynamics and the likely impacts of climate change, and to inform control strategies. Research is also continuing on the development of novel interventions for control of mosquito vectors, including fungal biopesticides and chemical insecticides that have novel modes of action. This research included theoretical work to evaluate control potential of candidate products with different performance characteristics, as well as product development focused on storage, persistence, formulation etc. We are also extending this work to other pest targets such as bed bugs and houseflies where conventional chemicals are failing due to evolution of resistance. We applied our previously developed statistical framework to analyze within-host dynamics of malaria to study variation among strains in virulence. We have continued on our two modeling efforts on merozoite production and on how temperature affects the vectorial capacity of 'Anopheles' mosquitoes. PARTICIPANTS: Dr. Liwang Cui has provided overall supervision on the planning and execution of the 'drug resistance' component of the project. The National Institutes of Health provided financial support for this study and training of three postdoctoral scholars. Dr. Matthew Thomas has led the research examining the effects of environmental factors on the vector-parasite interaction. This research has been funded largely by a grant from the NSF. The project currently supports two postdoctoral researchers and a research technician, with additional involvement of a PhD student. Further projects, funded by the NIH, are exploring the effects of temperature on aspects of mosquito immune function and on the transmission ecology in diverse transmission settings in India (grants supporting two further postdocs and technician). Dr. Thomas is also leading research exploring novel control tools such as biopesticides based on fungal entomopathogens. Dr. Andrew Read has been leading the research examining the evolution of drug,insecticide and vaccine resistance in vector-borne diseases. Dr. Bjornstad has led the research involving modeling of disease dynamic. Dr. David Hughes has been examining the relationship between host behavior and co-evolved entomopathogens in tropical forests. He is expanding this to agroecosystems to study ways to reduce the vectoring of plant disease by hemipteran insects and their mutualistic ant partners. TARGET AUDIENCES: Results derived from this study have been delivered to the scientific community through publication in scientific journals and presentations at the society meetings. Result from the drug resistance studies and the malaria transmission ecology studies have been presented recently at the International Centers of Excellence in Malaria Research meeting in Goa, India, August 2012. Results from the co-evolved entomopathogenic work has been presented at an international conferences on terrestrial ecology (Brazil) as well as in the social media following extensive coverage on sites such as BBC, CNN and others. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Drug resistance is a serious concern for control of vector-borne diseases such as malaria. Especially, Southeast Asia has been the epicenter of antimalarial drug resistance. Our determination of the molecular basis of drug resistance in 'Plasmodium falciparum' from this region provided tools for more efficient resistance management and disease control. Research on novel biopesticides is providing key information for product development.

Publications

  • Feng, Y., X. Zhu, Q. Wang, Y. Jiang, H. Shang, L. Cui, and Y. Cao. 2012. Allicin enhances host pro-inflammatory immune responses and protects against acute murine malaria infection. Malar. J. 11:e268.
  • Gillrie, M. R., K. Lee, M. Monestier, D. C. Gowda, L. Cui, T. T. Hien, N. P. Day, and, M. Ho. 2012. 'Plasmodium falciparum' histones induce human endothelial pro-inflammatory response and barrier dysfunction. Am. J. Pathol. 180:1028-1039.
  • Kerr, P. J., E. Ghedin, J. V. DePasse, A. Fitch, I. M. Cattadori, P. J. Hudson, D. C. Tscharke, A. F. Read, and E. C. Holmes. 2012. Evolutionary history and attenuation of myxoma virus on two continents. PLoS Pathogens (In Press).
  • Barclay, V. C., D. Sim, B. H. K. Chan, L. A. Nell, M. A. Rabaa, A. S. Bell, R. F. Anders, and A. F. Read. 2012. The evolutionary consequences of blood-stage vaccination on the rodent malaria 'Plasmodium chabaudi'. PLoS Biology 10:e1001368.
  • Bell, A. S., S. Huijben, K. P. Paaijmans, D. Sim, B. H. K. Chan, W. A. Nelson, and A. F. Read. 2012. Enhanced transmission of drug-resistance parasites to mosquitoes following drug treatment in rodent malaria. PLoS One. 7:e37172. http://dx.doi.org/10.1371/journal.pone.0037172.
  • Blanford, S., N. E. Jenkins, R. Christian, B. H. K. Chan, N. Luisa, O. Michael, L. Koekemoer, M. Coetzee, A. F. Read, and M. B. Thomas. 2012. Storage and persistence of a candidate fungal biopesticide for use against adult malaria vectors. Malaria Journal (In Press).
  • Blanford, S., N. E. Jenkins, A. F. Read, and M. B. Thomas. 2012. Evaluating the lethal and pre-lethal effects of a range of fungi against adult mosquitoes. Malaria Journal (In Press).
  • Atkins, K. E., A. F. Read, N. J. Savill, K. G. Renz, A. F. M. Fakhrul Islam, S. W. Walkden-Brown, and M. E. Woolhouse. 2012. Vaccination and reduced cohort duration can drive virulence evolution: Marek's disease virus and intensified agriculture. Evolution (In Press).
  • Atkins, K. E., A. F. Read, N. J. Savill, K. G. Renz, S. W. Walken-Brownand, and M. E. J. Woolhouse. 2011. Modeling Marek's disease virus (MDV) infection: Parameter estimates for mortality rate and infectiousness. BMC Veterinary Research 7:70.
  • Barbarin, A. M., N. E. Jenkins, E. G. Rajotte, and M. B. Thomas. 2012. A preliminary evaluation of the potential of Beauveria bassiana for bed bug control. Journal of Invertebrate Pathology 111:82-85.
  • Cator, L. J., P. A. Lynch, A. F. Read, and M. B. Thomas. 2012. Do malaria parasites manipulate mosquitoes Trends in Parasitology (In Press).
  • Che, P., L. Cui, O. Kutsch, L. Cui, and Q. Li. 2012. Developing a high throughput screening assay for antimalarial drug discovery. Assay Drug Dev. Tech. 10:61-68.
  • Cui, L., Z. Wang, H. Jiang, D. Parker, H. Wang, X. Su, and L. Cui. 2012. Lack of association of the S769N mutation in 'Plasmodium falciparum' SERCA (PfATP6) with resistance to artemisinins. Antimicrob. Agents Chemother 56:2546-2552.
  • Cui, L., Z. Wang, J. Miao, M. Miao, R. Chandra, H. Jiang, X. Su, and L. Cui. 2012. Mechanisms of 'in vitro' resistance to dihydroartemisinin in 'Plasmodium falciparum'. Mol. Microbiol. 86:111-128.
  • Darbro, J. M., P. Johnson, M. B. Thomas, S. Ritchie, B. H. Kay, and P. A. Ryan. 2012. Effects of 'Beauveria bassiana' on survival, blood-feeding success and fecundity of 'Aedes aegypti'; in laboratory and semi-field conditions. American Journal of Tropical Medicine and Hygiene 86:656-664.
  • Das, A., A. R. Anvikar, L. J. Cator, R. C. Dhiman, A. Eapen, N. Mishra, B. N. Nagpal, N. Nanda, K. Raghavendra, A. F. Read, S. K. Sharma, O. P. Singh, V. Singh, P. Sinnis, H. C. Srivastav, S. A. Sullivan, P. L. Sutton, M. B. Thomas, J. M. Carlton, and N. Valecha. 2012. Malaria in India: The Center for the Study of Complex Malaria in India. Acta Tropica 121:267-273.
  • Liu, X., Z.-Y. Tao, Q. Fang, X.-M. Wang, H. Zhang, J. A. Stoute, H. Xia, and L. Cui. 2012. A case of congenital 'Plasmodium vivax' malaria from a temperate region in Central China. Malar. J. 11:182. http://www.malariajournal.com/content/11/1/182.
  • Lynch, P. A., U. Grimm, M. B. Thomas, and A. F. Read. 2012. Prospective malaria control using entomopathogenic fungi: comparative evaluation of impact on transmission and selection for resistance. Malaria Journal (In Press).
  • Metcalf, C. J. E., G. H. Long, N. Mideo, J. D. Forester, O. N. Bjornstad, and A. L. Graham. 2012. Revealing mechanisms underlying variation in malaria virulence: effective propagation and host control of uninfected red blood cell supply. Journal of the Royal Society Interface 9:2804-2813.
  • Murdock, C. C., K. P. Paaijmans, A. S. Bell, J. King, J. F. Hillyer, A. F. Read, and M.B. Thomas. 2012. Complex effects of temperature on mosquito immune function. Proceedings of the Royal Society of London Series B. 279:3357-3366.
  • Murdock, C. C., K. P. Paaijmans, A. F. Read, D. Cox-Foster, and M. B. Thomas. 2012. Rethinking vector immunology: the role of environmental temperature in shaping resistance. Nature Reviews Microbiology (In Press).
  • Paaijmans, K. P., S. Blanford, B. K. Chan, and M. B. Thomas. 2012. Warmer temperatures reduce the vectorial capacity of malaria mosquitoes. Biology Letters 8:465-468.
  • Parker, D., R. Lerdprom, W. Srisatjarak, G. Yan, J. Sattabongkot, J. Wood, J. Sirichaisinthop, and L. Cui. 2012. Monitoring of antimalarial drug resistance in 'Plasmodium falciparum' at sentinel sites of Thailand. Malar. J. 11:e290.
  • Schneider, P., A. S. Bell, D. G. Sim, A. J. O'Donnell, S. Blanford, K. P. Paaijmans, A. F. Read, and S. E. Reece. 2012. Virulence affects drug sensitivity and transmission success in the rodent malaria, 'Plasmodium chabaudi'. Proceedings of the Royal Society of London Series B. http://rspb.royalsocietypublishing.org/content/early/2012/09/17/rspb. 2012.1792.full.
  • Thomas, M. B., H. C. J. Godfray, A. F. Read, H. van den Berg, B. E. Tabashnik, J. C. van Lenteren, J. K. Waage, and W. Takken. 2012. Lessons from agriculture for the sustainable management of malaria vectors. PLoS Medicine 9(7):e1001262.
  • Miao, M., Z. Yang, H. Patch, A. A. Escalante, and L. Cui. 2012. 'Plasmodium vivax' populations revisited: an investigation of 'vivax' mitochondrial genomes with a focus on the parasites from the temperate zone. BMC Evol. Biol. 12:e22.
  • Wang, Z., D. Parker, H. Meng, L. Wu, J. Li, Z. Zhao, R. Zhang, Q. Fan, H. Wang, L. Cui, and Z. Yang. 2012. In vitro sensitivity of 'Plasmodium falciparum' from China-Myanmar border area to major ACT drugs and polymorphisms in potential target genes. PLoS ONE 7:e30927.
  • Zhu, X., Y. Pan, Y. Li, L. Cui, and Y. Cao. 2012. L-Arginine supplement enhances host immunity during early-stage 'Plasmodium yoelii' 17XL infection. Parasite Immunol. 34:412-420.
  • Zhu, X., Y. Pan, Y. Li, Y. Liu, H. Shang, D. C. Gowda, L. Cui, and Y. Cao. 2012. Targeting Toll-like receptors by chloroquine protects mice from experimental cerebral malaria. Int. Immunopharmacol. 13:392-397.
  • Anderson, R. D., S. Blanford, and M. B. Thomas. 2012. House flies delay fungal infection by fevering - at a cost. Ecological Entomology (In Press).


Progress 10/01/10 to 09/30/11

Outputs
OUTPUTS: The recent upsurge of many vector-borne diseases in the world and the emergence of new diseases in many geographical regions are of great concern for public health. Important contributing factors leading to the rises in vector-borne diseases include climatic changes, resistance of vectors to insecticides, and resistance of the pathogens to chemotherapies. Our research team aims to obtain a better understanding of vector-borne diseases using multidisciplinary approaches. To study the mechanism of drug resistance in malaria parasites in the face of emerging artemisinin resistance in Southeast Asia, we have begun to procure malaria parasites from this region and determine their in vitro sensitivity to a panel of commonly used antimalarial drugs. Our study has begun to reveal the profile of drug resistance in these parasites and by using a genome-wide analytic tool we want to determine the molecular mechanisms underpinning the resistance phenotype. Another hypothesis we have about drug resistance is that patient treatment regimens affect the transmission of resistant malaria parasites to mosquitoes and hence their spread in the population. We have tested the assumption within-host selection does indeed translate into between host (mosquito) transmission. It does. We have demonstrated experimentally that conventional wisdom (overwhelming chemical force) very effectively selects for resistant mutants and ensures they reach transmissible frequencies. Other treatment regimens are equally effective at restoring host health but can keep resistant mutants from being transmitted. We have also begun testing how immunity alters the selection imposed by drug treatment on transmission. We are also investigating the effects of environmental factors (especially temperature) on the various life history traits of mosquitoes and parasites/pathogens that combine to determine the spatial and temporal patterns of disease transmission. This research is helping to improve the utility of models to explain current disease dynamics and the likely impacts of climate change. Further research is exploring the potential for development of novel interventions for control of mosquito vectors. We developed a new statistical framework to analyze determinants of within-host dynamics of malaria. The method was applied to a murine malaria models system to reveal unique new insights on the relative roles of resource limitation and innate and adaptive immunity on parasite regulation. Two related modeling efforts are ongoing. The first looks at determinants of circadian synchrony in merozoite production. The other is focused on understanding how temperature affects the vectorial capacity of 'Anopheles' mosquitoes. PARTICIPANTS: Dr. Liwang Cui has provided overall supervision on the planning and execution of the 'drug resistance' component of the project. The National Institutes of Health provided financial support for this study and training of three postdoctoral scholars. Dr. Matthew Thomas has led the research examining the effects of environmental factors on the vector-parasite interaction. This research has been funded largely by a grant from the NSF. The project currently supports two postdoctoral researchers and a research technician, with additional involvement of a PhD student. A further project funded by the NIH is beginning to explore the effects of temperature on aspects of mosquito immune function. Dr. Thomas is also leading research exploring novel control tools such as biopesticides based on fungal entomopathogens. Dr. Andrew Read has been leading the research examining the evolution of drug and insecticide resistance in vector-borne diseases. Dr. Bjonstad has led the research involving modeling of disease dynamic. Dr. David Hughes has been examining the relationship between host behavior and co-evolved entomopathogens in tropical forests. TARGET AUDIENCES: Results derived from this study have been delivered to the scientific community through publication in scientific journals and presentations at the society meetings. Result from the drug resistance studies has been presented recently in the international centers of excellence in malaria research in September 2011. Results from the co-evolved entomopathogenic work has been presented at an international conferences on terrestrial ecology (Brazil) as well as in the social media following extensive coverage on sites such as BBC, CNN and others. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.

Impacts
Drug resistance is a serious concern for control of vector-borne diseases such as malaria. Especially, Southeast Asia has been the epicenter of antimalarial drug resistance. Our determination of the molecular genotypes of drug resistance genes in 'Plasmodium falciparum' from this region provided baseline information for further elucidation of mechanisms underpinning emergence of drug resistance.

Publications

  • Yang, Z., C. Li, M. Miao, Z. Zhang, X. Sun, H. Meng, J. Li, Q. Fan, and L. Cui. 2011. Multidrug-resistant genotypes of Plasmodium falciparum, Myanmar. Emerging Infectious Diseases 17:498-501.
  • Paaijmans, K. P. and M. B. Thomas. 2011. Health: Wealth versus warming. Nature Climate Change 1:349-350.