Receptor holds the key to mosquito immune response

Researchers identify gene used to recognize pathogens

Researchers at the Johns Hopkins Bloomberg School of Public Health have identified a gene in the Anopheles gambiae mosquito's DNA that is central to the insect's ability to defend against infectious pathogens, including Plasmodium, the parasite that causes malaria in humans. Potentially, a mosquito with an enhanced capacity to recognize and kill Plasmodium would be unable to transmit malaria. The researchers' findings appear in the June 20, 2006, edition of the journal PLoS Biology.

Insects do not have antibodies, which are essential for pathogen recognition in humans. Instead, insects rely on a limited number of genes coding for adhesive proteins (pattern-recognition receptors) that can adhere to molecular patterns on a pathogen's surface.

"Each pathogen has its own unique combination of surface patterns. The immune systems of the mosquito and other insects primarily rely on recognizing the pattern of a specific pathogen to activate an immune response that kills the invader," explained George Dimopoulos, PhD, senior author of the study and assistant professor in the Bloomberg School's Malaria Research Institute. The AgDscam gene--short for Anopheles gambiae Down syndrome cell adhesion molecule gene--is an essential factor of the mosquito's immune system and can produce thousands of receptors with different pathogen-binding specificities. AgDscam appears to be capable of recognizing a broad range of different pathogens, and can thereby carry out a function for which a large number of genes would have been needed. Studies previously conducted by other researchers identified an immunity-related function of the Dscam gene in fruit flies.

The researchers found that when the AgDscam gene was deactivated, or "silenced", the mosquitoes died at a greater rate from bacterial infections. They also found that the numbers of Plasmodium increased 65 percent in the gut of mosquitoes with the silenced gene. The findings suggest that better knowledge of how the AgDscam gene is involved in killing Plasmodium could be used to develop novel ways to control malaria.

The AgDscam gene has 101 protein-coding regions, called exons, that can be spliced together in different combinations to produce over 31,000 possible splice-forms that function as receptors. When the mosquitoes were exposed to different pathogens such as bacteria, fungi and parasites, the AgDscam gene produced an array of different splice-forms with different interaction properties. When the researchers cut AgDscam protein levels in half, they could link AgDscam's function with the immune system, as the mosquitoes became less resistant to infection. The results showed that infected mosquitoes produced AgDscam splice-forms (receptors) that were better in recognizing--and defending against--the invading pathogen.

"AgDscam is in a way similar to antibodies; different combinations of immunoglobulin domains, which are coded by spliced exons, are used to produce a broad range of receptors. Now we need to learn more about AgDscam's association with the malaria parasite. A mosquito with an enhanced capacity to recognize and kill Plasmodium would not transmit malaria," said Dimopoulos.

In a previous study published in the June 8, 2006, edition of PLoS Pathogens, the Hopkins researchers determined that mosquitoes employ the same immune factors to fight off bacterial pathogens as they do to kill malaria-causing Plasmodium parasites.

"AgDscam, a hyper variable immunoglobulin domain containing receptor of the Anopheles gambiae innate immune system" was written by Yuemei Dong, Harry Taylor and George Dimopoulos. Dong and Dimopoulos are with the W. Harry Feinstone Department of Molecular Microbiology and Immunology at the Johns Hopkins Bloomberg School of Public Health. Taylor is currently with Meharry Medical College.

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The study was supported by grants from the National Institute of Allergy and Infectious Disease, the World Health Organization Training in Tropical Diseases program, the Ellison Medical Foundation and the Johns Hopkins Malaria Research Institute.


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