# Targeting mosquito complement to alter the specificity of the innate immune response

> **NIH NIH R01** · UNIVERSITY OF PENNSYLVANIA · 2021 · $402,500

## Abstract

SUMMARY
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.

## Key facts

- **NIH application ID:** 10137181
- **Project number:** 5R01AI139060-04
- **Recipient organization:** UNIVERSITY OF PENNSYLVANIA
- **Principal Investigator:** Michael Joseph Povelones
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $402,500
- **Award type:** 5
- **Project period:** 2018-05-04 → 2023-04-30

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10137181

## Citation

> US National Institutes of Health, RePORTER application 10137181, Targeting mosquito complement to alter the specificity of the innate immune response (5R01AI139060-04). Retrieved via AI Analytics 2026-05-23 from https://api.ai-analytics.org/grant/nih/10137181. Licensed CC0.

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