Researchers at the Johns Hopkins Bloomberg School
of Public Health have determined a new mechanism by which the
mosquitoes’ immune system can respond with specificity to infections
with various pathogens, including the parasite that causes malaria in
humans, using one single gene. Unlike humans and other animals, insects
do not make antibodies to target specific infections. According to the
Johns Hopkins researchers, mosquitoes use a mechanism known as
alternative splicing to arrange different combinations of binding
domains, encoded by the same AgDscam gene, into protein repertoires that
are specific for different invading pathogens. The researchers’
findings were published October 18 in the journal Cell Host & Microbe and could lead to new ways to prevent the spread of a variety of mosquito born illnesses.
Mosquitoes
and other insects use their primitive innate immune systems to
successfully fight infections with a broad spectrum of viruses,
bacteria, fungi and parasites, despite the lack of antibodies that are
part of the more sophisticated human immune system. The effectiveness of
the human immune system is to a large degree based on the ability to
produce an enormous variety of antibodies containing different
immunoglobulin domains that can specifically tag and label a pathogen
for destruction. This great variety of pathogen-binding antibodies is
achieved by combining different immunoglobulin gene segments and further
mutate them through mechanisms called somatic recombination and
hypermutation. While mosquitoes also have genes encoding immunoglobulin
domains, they lack these specific mechanisms to achieve pathogen
recognition diversity.
The Johns Hopkins
researchers discovered a different way by which mosquitoes can combine
immunoglobulin domains of a single gene called AgDscam (Anopheles gambiae
Down Syndrome Cell Adhesion Molecule) to produce a variety of
pathogen-binding proteins. The AgDscam gene is subjected to a mechanism
called alternative splicing that combines different immunoglobulin
domains into mature AgDscam proteins, depending on which pathogen has
infected the mosquito. The researchers showed that this alternative splicing is guided by the immune signal transducing pathways
(analogous to electrical circuits) that they previously demonstrated to
activate defenses against different malaria parasites and other
pathogens. While alternative splicing of the AgDscam gene does not
nearly achieve the degree of pathogen recognition diversity of human
antibodies, it does nevertheless vastly increase the variety of pathogen
binding molecules.
“Using antibodies to fight
infection is like fishing with a harpoon—it’s very targeted. The
mosquito’s innate immune system is more like fishing with a net—it
catches a bit of everything,” explained George Dimopoulos, PhD, senior
investigator of the study and professor with the Johns Hopkins Malaria Research Institute.
“However, we discovered that immune pathway-guided alternative splicing
of the AgDscam gene renders the mosquito’s immune net, so to speak,
more specific than previously suspected. The mosquito’s immune system
can come up with approximately 32,000 AgDscam protein combinations to
target infections with greater specificity.”
Dimopoulos and his group are developing a malaria control strategy based on mosquitoes that have been genetically modified to possess an enhanced immune defense against the malaria parasite Plasmodium. One obstacle to this approach is the great variety of Plasmodium strains that may interact somewhat differently with the mosquito’s immune system.
“Some
of these strains may not be detected by the engineered immune system
proteins that mediate their killing. Our new discovery may provide the
means to create genetically modified mosquitoes that can target a
broader variety of parasite strains, like casting a net rather than
shooting with a harpoon,” said Dimopoulos.
Malaria kills more than 800,000 people worldwide each year. Many are children.
“Anopheles
NF-kB –Regulated Splicing Factors Direct Pathogen-Specific Repertoires
of the Hypervariable Pattern Recognition Receptor AgDscam” was written
by Yuemei Dong, Chris M. Cirimotich, Andrew Pike, Ramesh Chandra and
George Dimopoulos.
source: http://www.jhsph.edu/news/news-releases/2012/dimopoulos_antibiodies.html
