# The protease network that regulates innate immunity in mosquitoes

> **NIH NIH R01** · KANSAS STATE UNIVERSITY · 2020 · $543,800

## Abstract

PROJECT SUMMARY
The innate immune system of mosquitoes is a critical determinant of their vector competence. This includes
the ability to support development and transmission of the protozoan parasite species in the genus
Plasmodium by Anopheles mosquitoes, the principal vectors of human malaria world-wide. Insight into the
regulation of innate immune effector mechanisms remains incomplete, but is vitally important to our
fundamental understanding of host-pathogen interactions in this most important human vector-borne
disease. The long-term goal is to understand immune system regulation in An. gambiae to inform current
and future vector control strategies. The objective of this application is to globally identify mechanisms of
immune system regulation by determining the interactions within the extracellular protease network that
activate and link opsonization to melanization in the context of distinct microbial infections. The rationale for
the proposed research is that detailed information on the protease network that regulate mosquito immunity
could be employed to predict long-term efficacy of novel vector control strategies that employ microbial
agents, and manipulate infection outcome. Guided by our preliminary data, the following three specific aims
will be pursued: (1) Determine the interactions of proteases and their homologs that are critical for mosquito
immunity; (2) Assess the impact of the protease network on immunity and mosquito fitness; and (3)
Visualize the immunoregulatory network in mosquitoes using network science. Under the first aim, we will
test the hypothesis that clip-serine proteinases and their homologs form functional modules that are
required for optimal immune responses by defining their cleavage patterns, genetic interactions, and precise
biochemi-cal function. Under the second aim, the potential effect of the protease network on pathogen
resistance and tolerance as well as mosquito fitness will be assessed using common microbial challenge
models and life table analyses. Under the third aim standard network science approaches will be used to
visualize all protease interactions in the system as a static multilayered network and to analyze this network
to infer proteolytic flow through that links opsonization and melanization and to identify the key molecules
that control immunity. The proposed research is innovative, as it will for the first time evaluate protease
cascades as a single, integrated network that controls mosquito humoral immunity during diverse immune
challenges. Additionally, this project will use network science as a highly innovative approach to the study of
mosquito innate immunity, which if successful will be transformative to the field of insect immunology. This
project is significant as it will provide comprehensive understanding of the contribution of the protease
network to mosquito health as well as the limitations of the system in overcoming infection. Ultimately, this
knowledge could be emplo...

## Key facts

- **NIH application ID:** 9984952
- **Project number:** 5R01AI140760-03
- **Recipient organization:** KANSAS STATE UNIVERSITY
- **Principal Investigator:** Kristin Michel
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2020
- **Award amount:** $543,800
- **Award type:** 5
- **Project period:** 2018-09-13 → 2023-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/9984952

## Citation

> US National Institutes of Health, RePORTER application 9984952, The protease network that regulates innate immunity in mosquitoes (5R01AI140760-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/9984952. Licensed CC0.

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