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Mosquito Defense Mechanism Protects Malaria Parasite

The peritrophic matrix (brown line) surrounds the blood meal (red) ingested by the mosquito. A newly discovered enzyme (IMPer) is released in the space between this protective matrix and the structures (yellow) on the gut cell surface, forming a barrier that prevents gut immune activation.Elizabeth Fischer and Carolina Barillas-Mury

Scientists have discovered that a protective barrier in the mosquito’s midgut also serves to protect the parasite that causes malaria. Breaking this barrier activates the mosquito’s immune system and may help defeat these parasites before they infect people.

Malaria is one of the most common infectious diseases in the world and an enormous public health problem. Each year, up to 3 million people die of the disease worldwide. The majority are young children in Sub-Saharan Africa.

Malaria is caused by a single-cell parasite called Plasmodium. Female mosquitoes become infected after feeding on an infected human. Inside the insect, the parasites cross mosquito gut cells. Once on the other side, they multiply and migrate through the mosquito's blood to the salivary glands, where they can infect a new person when the mosquito next bites.

When mosquitoes like Anopheles gambiae—the main vector of malaria—drink blood, the epithelial cells lining their midguts secrete a protective matrix of fibers called the peritrophic matrix (PM). This matrix has large pores that allow digestive enzymes and nutrients to pass through but prevents gut microbes from coming into direct contact with midgut epithelial cells. A research team led by Dr. Carolina Barillas-Mury of NIH’s National Institute of Allergy and Infectious Diseases (NIAID) was studying the area between the PM and epithelial cells—called the mucin layer—when they made an unexpected discovery.

The scientists were studying immunomodulatory peroxidase (IMPer), a protein secreted by midgut epithelial cells in response to a blood feeding, and dual oxidase (Duox), a protein previously shown to kill bacteria and other microbes in fruit flies. In the online edition of Science on March 11, 2010, they reported that the 2 proteins have a new and unexpected function. They are responsible for forming a fine network of proteins that protects beneficial bacteria and allows them to grow in the gut without activating mosquito immune responses.

Surprisingly, they found that this network also protects Plasmodium parasites by preventing mosquitoes from mounting an immune response to kill them. When the researchers turned off the gene for either IMPer or Duox, the mosquito's midgut immune system took over and greatly reduced Plasmodium infection.

This study shows that the barrier formed by IMPer-Duox, while protecting the mosquito’s gut flora, also enables malaria parasites to survive so they can get passed on to humans and cause disease. The researchers believe it might be possible to prevent the formation of the protein barrier by immunizing people with IMPer or the proteins that form the network. Such a vaccine would generate antibodies that, after a mosquito feeds on a human, could disrupt the barrier and activate the mosquito’s immune system to fight the parasite and prevent malaria transmission.

A related peroxidase-Duox system is also found in the mucous membrane of some human tissues, such as the colon. The researchers are now investigating whether a protective protein barrier also forms in people. Such a barrier could potentially play a role in diseases such as chronic inflammatory bowel disease.