Abstract

Malaria is a leading cause of human death and illness, causing each year 400-600 million cases of clinical malaria and 2-3 million deaths. Transmission of malaria is dependent upon successful completion of parasite development in the mosquito. A key step in this process is sporozoite invasion of the mosquito salivary gland. The hypothesis of this research project is that Plasmodium falciparum sporozoite invasion of anopheline salivary glands requires the ligand MAEBL to recognize specific salivary gland receptors. MAEBL is a paralogue of erythrocyte binding proteins known to be essential for merozoite invasion of erythrocytes. We predict that the function of MAEBL in sporozoites requires post-translational processing and distribution to the sporozoite surface prior to invasion and release from the surface during entry into the salivary glands. We expect that receptors recognized by MAEBL are specifically located on the distal lateral lobes of the salivary glands. Our hypothesis is based upon the following observations. First, targeted disruption of the P. berghei MAEBL produced sporozoites that could not attach to or invade mosquito salivary glands. Second, the full-length form of MAEBL expressed during oocyst development is present only as lower molecular weight forms in mature midgut sporozoites. Third, sporozoites attach to and preferentially infect the distal lateral lobes of the female salivary glands in areas that have region- specific surface molecules. Based on these observations, the primary aims of my application are to determine what is the functional form of MAEBL, when midgut sporozoites invade the salivary glands, and what is the role of MAEBL in this invasion process. In addition, we will seek to identify other midgut sporozoite molecules that may have a role in salivary gland invasion. The long-term goal of this research is to better understand the biology of malaria sporozoites in mosquitoes to enhance effectiveness of vector-based anti-malarial intervention.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI033656-12
Application #
7083591
Study Section
Special Emphasis Panel (ZRG1-VB (01))
Program Officer
Rogers, Martin J
Project Start
1994-07-01
Project End
2010-02-28
Budget Start
2006-03-01
Budget End
2007-02-28
Support Year
12
Fiscal Year
2006
Total Cost
$329,570
Indirect Cost

  Institution

Name
University of Notre Dame
Department
Biology
Type
Schools of Arts and Sciences
DUNS #
824910376
City
Notre Dame
State
IN
Country
United States
Zip Code
46556

  Publications

Peng, Kaitian; Goh, Yun Shan; Siau, Anthony et al. (2016) Breadth of humoral response and antigenic targets of sporozoite-inhibitory antibodies associated with sterile protection induced by controlled human malaria infection. Cell Microbiol 18:1739-1750
Campbell, Christopher O; Santiago, Daniel N; Guida, Wayne C et al. (2014) In silico characterization of an atypical MAPK phosphatase of Plasmodium falciparum as a suitable target for drug discovery. Chem Biol Drug Des 84:158-68
Balu, Bharath; Campbell, Christopher; Sedillo, Jennifer et al. (2013) Atypical mitogen-activated protein kinase phosphatase implicated in regulating transition from pre-S-Phase asexual intraerythrocytic development of Plasmodium falciparum. Eukaryot Cell 12:1171-8
Siddiqui, Asim A; Xainli, Jia; Schloegel, Jesse et al. (2012) Fine specificity of Plasmodium vivax Duffy binding protein binding engagement of the Duffy antigen on human erythrocytes. Infect Immun 80:2920-8
Auliff, Alyson M; Balu, Bharath; Chen, Nanhua et al. (2012) Functional analysis of Plasmodium vivax dihydrofolate reductase-thymidylate synthase genes through stable transformation of Plasmodium falciparum. PLoS One 7:e40416
Balu, Bharath; Maher, Steven P; Pance, Alena et al. (2011) CCR4-associated factor 1 coordinates the expression of Plasmodium falciparum egress and invasion proteins. Eukaryot Cell 10:1257-63
McHenry, Amy M; Barnes, Samantha J; Ntumngia, Francis B et al. (2011) Determination of the molecular basis for a limited dimorphism, N417K, in the Plasmodium vivax Duffy-binding protein. PLoS One 6:e20192
Fonager, Jannik; Franke-Fayard, Blandine M D; Adams, John H et al. (2011) Development of the piggyBac transposable system for Plasmodium berghei and its application for random mutagenesis in malaria parasites. BMC Genomics 12:155
Balu, Bharath; Singh, Naresh; Maher, Steven P et al. (2010) A genetic screen for attenuated growth identifies genes crucial for intraerythrocytic development of Plasmodium falciparum. PLoS One 5:e13282
McHenry, A M; Barnwell, J W; Adams, J H (2010) Plasmodium vivax DBP binding to Aotus nancymaae erythrocytes is Duffy antigen dependent. J Parasitol 96:225-7

Showing the most recent 10 out of 28 publications