Malaria is a devastating disease that kills approximately 429,000 people annually and threatens half of the world's population. Malaria is caused by protozoan Plasmodium parasites that alternate between human and mosquito hosts. Given its impacts on human health and economic development, a considerable effort has been made to control malaria using strategies that target parasites in both of its hosts. There has been a recent push to shift our focus from malaria control to eradication. This effort combined with emerging problems such as drug resistant parasites and mosquito insecticide resistance require the urgent development of new strategies to control disease transmission. The main vector for malaria in Africa is Anopheles gambiae. For malaria transmission to occur, the vector must first be infected. The mosquito has a sophisticated immune arsenal providing multiple layers of protection as parasites travel through different tissues. One of the most potent barriers is formed by the mosquito complement-like pathway, which is responsible for one of the biggest bottlenecks Plasmodium faces across its entire life cycle. Our work is aimed at dissecting the molecular mechanisms of the mosquito complement system. Given its importance in Plasmodium killing, considerable attention by us and others has been focused on identifying complement components and their mechanism of action in Anopheles gambiae, the main African malaria vector. We have developed a new cutting-edge proteomics approach to directly identify components of this pathway. Our method takes advantage of the fact that complement components localize to microbial surfaces. This proteomic approach will identify factors required for mosquito complement and, when combined with gene silencing, will delineate the hierarchical assembly of factors required for complement activation. We have recently identified a complex of two C-type lectins (CTL4/CTLMA2) as a new component of mosquito complement. Interestingly, when the CTL complex is silenced, there is a dramatic increase in parasite killing, suggesting that the CTL complex is a negative regulator of mosquito complement. Silencing the CTL complex also renders mosquitoes more sensitive to bacterial infections. We will understand how this complex and its partners select between Plasmodium and bacterial defense by targeting specific immune effector pathways. Our work will greatly advance the understanding of how complement controls malaria parasite burden and, as this approach can be applied to other models, also has the potential to transform the study of vector disease transmission.

Public Health Relevance

Disease transmission by mosquitoes requires that pathogens, such as malaria parasites, must first infect the mosquito by overcoming its immune system. We have recently identified novel immune regulators that when removed from the mosquito lead to increased parasite killing. We are characterizing these regulators to develop new ways to block disease transmission by mosquitoes.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI139060-03
Application #
9915885
Study Section
Vector Biology Study Section (VB)
Program Officer
Costero-Saint Denis, Adriana
Project Start
2018-05-04
Project End
2023-04-30
Budget Start
2020-05-01
Budget End
2021-04-30
Support Year
3
Fiscal Year
2020
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Veterinary Sciences
Type
Schools of Veterinary Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104