Anopheline mosquitoes transmit malaria, the world's most devastating parasitic disease, of which Anopheles gambiae is the principal vector for malaria in Sub-Saharan Africa. Different populations of mosquitoes vary widely in how readily they become infected with malaria parasites, while some strains do not transmit malaria at all. The mosquitoes' innate immune system is a significant factor that may influence the level of malaria infection; in particular the thioester-containing protein 1 (TEP1) targets malaria parasite for destruction during their initial invasion of the body cavity. The TEP1 gene varies significantl across mosquito populations with two major classes of alleles, TEP1*S and TEP1*R, that have been shown to directly influence the susceptibility to P. falciparum. In this project we will study the structure-function relationship between TEP1 alleles and their interaction with a mosquito-specific family of leucine-rich repeat proteins, the LRIM1/APL1 family. We will also study the diversity of structure and function associated with three closely-related LRR proteins APL1A, APL1B and APL1C, that influence the specificity of the TEP1 immune response. Finally, we will study the structure and function of three CLIP domain serine protease homologs (SPHs) that regulate downstream effects of TEP1 deposition, specifically melanization. The results of this project will shed light on the mechanism of mosquitoes' natural immunity to malaria infection and support the development of new vector-based transmission-blocking strategies.

Public Health Relevance

Anopheles gambiae thioester-containing protein 1 (TEP1), is a central factor in the innate immune response of mosquitoes to malaria infection. TEP1 has many similarities to complement factor C3 but a novel mechanism or regulation involving two mosquito-specific leucine-rich repeat proteins, LRIM1 and APL1C. This project addresses fundamental unanswered questions regarding the molecular mechanism of LRIM1/APL1C-mediated activity of TEP1 and interactions with other proteins within the APL1 LRR and CLIP protease family.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM114358-05
Application #
9395913
Study Section
Vector Biology Study Section (VB)
Program Officer
Somers, Scott D
Project Start
2015-04-01
Project End
2019-12-31
Budget Start
2018-01-01
Budget End
2018-12-31
Support Year
5
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Temple University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
057123192
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Baxter, Richard H G; Contet, Alicia; Krueger, Kathryn (2017) Arthropod Innate Immune Systems and Vector-Borne Diseases. Biochemistry 56:907-918
Lin, Lin; Rodrigues, Frederico S L M; Kary, Christina et al. (2017) Complement-Related Regulates Autophagy in Neighboring Cells. Cell 170:158-171.e8
Meyer, Peter A; Socias, Stephanie; Key, Jason et al. (2016) Data publication with the structural biology data grid supports live analysis. Nat Commun 7:10882
Baxter, Richard H G (2016) Chemosterilants for Control of Insects and Insect Vectors of Disease. Chimia (Aarau) 70:715-720