Bio:
My name is April Clayton, and I am a first year JHMI BCMB (Biochemistry, Cellular, and Molecular Biology) graduate student. I did my undergraduate studies at Erskine College in South Carolina, where I received BS degrees in Biology and Chemistry. I have just recently joined the Dimopoulos Group and have began two very exciting and interesting projects aimed to explore and molecularly characterize the mosquito's innate immune response to
Plasmodium falciparum, the causal agent of human malaria.
Current research:
Exploring Plasmodium-Anopheles gambiae Interactions: Molecular Characterization of the Mosquito's Anti-Plasmodium Defense System.
The African mosquito,
Anopheles gambiae, is the vector for the causal agent of human malaria,
P. falciparum. The vector and the malaria parasite encounter a series of interactions involving the parasite's development and proliferation throughout the mosquito in order to continue the cycle of transmission. The innate immune system of the mosquito is able to defend against
Plasmodium infection via the Toll, Imd (Immune Deficiency) and JAK-STAT signaling pathways. The Toll, Imd pathways in insects are activated in response to bacteria and fungi and lead to the production of antimicrobial peptides (AMPs) and the expression of other immune effector genes. Recent work in our group has provided insight into the downstream signaling events of the two pathways and has also shown that the Imd pathway is more efficient in mediating anti-P. falciparum defense than the Toll pathway (L. Garver
et al., 2009). Current research also concerning mosquito-malaria immunity indicates that the mosquito employs its antibacterial defense system to defend against
P. falciparum (Y. Dong et al., 2006). The presence of bacteria in the midgut, a primary site for P. falciparum invasion and development, also results in an immune response comprising the induction of AMPs and other immune-specific genes that act against
Plasmodium (Y. Dong et al., 2009).
SPECIFIC AIMS
1. Test whether the A. gambiae intracellular peptidoglycan recognition protein LA (PGRP-LA) may function as a pattern recognition receptor that activates the immune response upon
Plasmodium infection. In the Drosophila Imd pathway, PGRPLC and PGRPLE are responsible for Imd
pathway activation upon gram-negative bacteria infection. There are 7 PGRP genes in
A. gambiae. A. gambiae PGRPLC has been indicated as playing central roles in antibacterial & anti-P. falciparum defense (Lin
et al., 2007; Meister et al., 2009; Christophides
et al., 2002) and PGRPLB is up-regulated following P. falciparum infection (Dimopoulos
et al., 2002). I will specifically look at the intracellular PGRPLA by using RNAi
to assess the effect of PGRPLA knockdown (KD) on the mosquito's capacity to defend against
P. falciparum infection. If PGRPLA is indeed a receptor of
P. falciparum-and therefore an activator of the Imd pathway-, then the mosquito will have increased susceptibility to
P. falciparum infection upon KD of PGRPLA.
2. Identify candidate immune factors that regulate the mosquito's anti-P. falciparum defense. Since some immune factors of antibacterial defense have been implicated in anti-Plasmodium defense, I aim to look at Caudal as a potential immune factor in
P. falciparum defense. In Drosophila, Caudal is a developmental transcription factor as well as an innate immune regulator of AMP gene expression. RNAi of Caudal in
Drosophila led to AMP over-expression, changes in midgut microbiota composition, midgut cell apoptosis, and mortality (J. Ryu
et al., 2008). I will use RNAi silencing to determine Caudal's effect on
P. falciparum infection, AMP expression, and midgut microbiota
composition. My preliminary studies have indicated a role of
Caudal in the defense against bacteria and Plasmodium.
These experiments will help us to understand the mosquito-Plasmodium
interactions involved in anti-malarial defense. These studies
will be followed up with more detailed analyses and may in the
future contribute to the development of novel vector control
strategies and methods to block parasite transmission in the
mosquito.
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