Kafatos:Povelones, Michael

 

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Current Research Interests
I am a postdoctoral fellow in the Kafatos/Christophides lab at Imperial College London. My research focuses on how the innate immune system of the mosquito recognizes and eliminates malaria parasites. Widely considered to be passive carriers of malaria, mosquitoes are actually amazing parasite killers. In fact, the vast majority of the parasites ingested when a mosquito bites a malarious person are attacked and eliminated before they can mount an infection. It is the few parasites that survive (even one is sufficient), that are ultimately responsible for disease transmission.

The mosquito has multiple lines of defense against invading pathogens, but the most potent is found in its blood, called hemolymph. Parasites migrate through the gut epithelium in order to escape the harsh digestive conditions of the gut lumen. Here they come into contact with the hemolymph. Two leucine-rich repeat (LRR) containing proteins, LRIM1 and APL1C, are essential for mosquito immune defense in this compartment. These proteins circulate in the mosquito hemolymph in a disulfide-bonded dimer (Povelones 2009). If either LRIM1 or APL1C is knocked-down by RNAi, the complex is undetectable in the hemolymph and parasite survival is massively increased. Before parasites are killed, the complement-like protein TEP1 is localized on their surface, marking them for destruction. The LRIM1/APL1C complex physically interacts with a proteolytically processed and highly reactive form of TEP1. The interaction stabilizes TEP1 in the hemolymph and is required for its localization to parasites during midgut invasion. When the LRIM1/APL1C complex is knocked-down, TEP1 fails to localize and the invading parasites are not killed. This immune pathway leading to parasite killing could be an important cause of natural refractoriness in non-vector mosquitoes (Habtewold, 2008). We recently discovered that the LRIM1/APL1C complex can also interact with 3 other members of the TEP family. Two of these were previously characterized to contribute to mosquito antibacterial defense reactions. We found that one of these, TEP3, also functions in mosquito immune reactions against parasites (Povelones, 2011). Understanding the mechanism of parasite killing, and how some parasites manage to escape, may open the door to novel control strategies.

Additionally, we have found that LRIM1 and APL1C are defining members of a protein family, collectively named LRIMs (pronounced L-rims) (Povelones, 2009; Waterhouse 2010). Bioinformatic searches using specific features shared between LRIM1 and APL1C has uncovered approximately 20 family members falling into four distinct sub-families in the mosquito species Anopheles gambiae, Aedes aegypti and Culex quinquefasciatus. This family is not found in any other organism. Given the central role of LRR proteins in host defense in plants and animals, we are currently investigating the hypothesis that the repertoire of LRIMs may help the mosquito neutralize diverse pathogens, including the agents of human and animal diseases that they transmit.


 * Povelones et al. Structure-Function Analysis of the Anopheles gambiae LRIM1/APL1C Complex and its Interaction with Complement C3-Like Protein TEP1. PLoS Pathogens (2011) vol. 7 (4) pp. e1002023
 * Waterhouse et al. Sequence-structure-function relations of the mosquito leucine-rich repeat immune proteins. BMC Genomics (2010) vol. 11 pp. 531
 * Jaramillo-Gutierrez et al. Mosquito immune responses and compatibility between Plasmodium parasites and anopheline mosquitoes. BMC Microbiol (2009) vol. 9 pp. 154
 * Povelones et al. Leucine-rich repeat protein complex activates mosquito complement in defense against Plasmodium parasites. Science (2009) vol. 324 (5924) pp. 258-61
 * Habtewold et al. Transmission Blocking Immunity in the Malaria Non-Vector Mosquito Anopheles quadriannulatus Species A. PLoS Pathog (2008) vol. 4 (5) pp. e1000070


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