Endogenous retroviruses important in immune response
A new study in Science, in which researchers from Karolinska Institutet participated, shows that retroviruses may not only be harmful to humans. According the findings, so called endogenous retroviruses, which are included in the genome of each person, could play an important role in the body’s immune defense against common bacterial and viral pathogens.
Retroviruses are best known for causing contagious scourges, such as AIDS or cancer. They are able to insert into the genomic DNA of cells that they infect, including germ cells. Millions of years ago, retroviruses were included in the human genome through a process called retrotransposition. About 45 percent of a person’s DNA is of retroviral origin, and some of the better preserved copies are termed endogenous retroviruses (ERV). These genetic elements do not cause infection, and it has been unclear if they have any function at all.
Writing in the journal Science, researchers at UT Southwestern Medical Center and Karolinska Institutet have found that when B cells are activated by large polymeric antigens such as polysaccharides of bacteria, they rapidly produce protective antibodies in what is termed the type II T-independent antibody response. This response, central to the body’s defense against common bacterial and viral pathogens, is dependent on ERV.
“We believe that, once retroviruses have become part of the host germline, they are subject to selection for beneficial effects just like any other part of the genome, and their ability to activate an innate immune response seems to have been utilized to the benefit of the host,” says Dr. Gunilla Karlsson Hedestam, Professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet.
The research team shows that within activated B cells the ERV are driven to express RNA copies of themselves, which in turn are copied into DNA by an enzyme called reverse transcriptase. The RNA copies of endogenous retroviruses are detected by a protein called RIG-I, and the DNA copies are detected by another protein called cGAS. These two proteins send further signals that enable the B cells to sustain their activated state, proliferate, and produce antibodies.
“Mice lacking elements of the RIG-I or cGAS pathways show diminished responses to type II T-independent antigens, and mice lacking both pathways show almost no antibody response at all to these antigens. Moreover, reverse transcriptase inhibiting drugs also partially inhibit the type II T-independent antibody response”, observes Gunilla Karlsson Hedestam.
Principal investigator of this current study has been Dr. Bruce Beutler, Professor and Director of UT Southwestern Center for the Genetics of Host Defense, who shared the 2011 Nobel Prize in Physiology or Medicine. The work was funded by donations from the Lyda Hill Foundation and the Kent and JoAnn Foster Family Foundation, and by NIH grants.
- View a commentary in Science about the findings
- View a press release from UT Southwestern Medical Center
MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses
Ming Zeng, Zeping Hu, Xiaolei Shi, Xiaohong Li, Xiaoming Zhan, Xiao-Dong Li, JianhuiWang, Jin Huk Choi, Kwan-wenWang, Tiana Purrington, Miao Tang, Maggy Fina, Ralph J. De Berardinis, Eva Marie Y. Moresco, Gabriel Pedersen, Gerald M. McInerney, Gunilla B. Karlsson Hedestam, Zhijian J. Chen, Bruce Beutler
Science online 18 December 2014, doi: 10.1126/science.1257780