Genetically modified parasite lets researchers probe immune system’s memory

Researchers at Washington University School of Medicine in St. Louis and the University of Pennsylvania have found an immune system cell can “remember” a parasite’s attack and help the body mount a more effective defense against subsequent invasions by the same parasite.

The finding, published in the October issue of Nature Medicine, will likely aid efforts to develop a vaccine for Leishmania major, a parasite that infects approximately 12 million people worldwide, causing significant death and disfigurement. It may also help efforts to develop vaccines for other pathogens including AIDS and tuberculosis.

Scientists have known that successful recovery from Leishmania infection immunizes humans and animals against subsequent infection. But previous experiments led researchers to suspect that this immunity resulted from the presence of a very small population of parasites that remained in the host even after full recovery. Loss of this minimal parasite remnant seemed in some studies to result in loss of immunity.

For the new study, immunologists at the University of Pennsylvania infected mice with a genetically modified form of Leishmania created by microbiologists at Washington University School of Medicine. The modified Leishmania lacks an enzyme required for DNA synthesis and can be completely wiped out by the mouse immune system.

Researchers found that after the mice had cleared the Leishmania parasite, a type of T cell — the CD4+ central memory T cell — still reacted to the parasite in the test tube. Mice who never had Leishmania and were given injections of these T cells fought off the parasite more effectively than mice that didn’t get the T cells. “This partial immunization suggests that we may need to look at generating large populations of these memory T cells at the time of vaccination,” says study coauthor Stephen Beverley, Ph.D., the Marvin A. Brennecke Professor and head of the Department of Molecular Microbiology.

Researchers also found evidence that another class of T cells may stay primed to fight a new infection when a small remnant population of parasites persists. Beverley speculates that the presence of this second type of T cell, along with the central memory T cell, may be key to providing full protection.

Senior investigator Phillip Scott, Ph.D., professor of microbiology and immunology at the School of Veterinary Medicine at the University of Pennsylvania, has conducted additional experiments that showed central memory T cells can maintain their “memory” of Leishmania and respond to new infections at least 5 months after initial infection.

Because T cells orchestrate the immune system’s fight against other diseases, including tuberculosis and AIDS, scientists believe the new insights will be help efforts to develop other vaccines. “We are so much better at understanding how the immune system responds than we are at making a vaccine,” Beverley notes. “These new results may help us better direct the immune response toward long-term vaccination.”