Retroviruses are single-stranded RNA viruses capable of integrating cells’ genomic DNA, including germ cells. Through a process called retrotransposition, the retrovirus has become an important part of the genome of each person. On average, 45% of the DNA of a person is of retroviral origin, and some of the better preserved copies are termed “endogenous retroviruses” (ERV).
A new study entitled “MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses” published in Science by Dr. Ming Zeng, part of Dr. Bruce Beutler’s group from Center for the Genetics of Host Defense at the University of Texas Southwestern Medical Center in Dallas, revealed that endogenous retroviruses (ERV) have a crucial function in the immune responses against bacterial and viral pathogens.
“Most scientists have become used to the view that retroviruses are generally harmful,” said Dr. Beutler, winner of the Nobel Prize in Physiology or Medicine in 2011 and Professor and Director of Center for the Genetics of Host Defense from the University of Texas Southwestern, in a press release. “We have found that ERV fulfill at least one beneficial function critical to producing protective antibodies,” added Dr. Beutler.
In this study, the research team found that when B cells are stimulated by large polymeric antigens like polysaccharides from bacterial capsular and viral capsids, it induces antibody responses through B cell receptors (BCR) that are called T cell–independent type 2 (TI-2) antibodies. This type of immune response needs ERV. The researchers used T cell–independent type 2 (TI-2) antigens to immunize mice that induced an up-regulation of endogenous retrovirus (ERV) RNAs in antigen-specific mouse B cells. The RNA molecules were detected by a mitochondrial antiviral signaling protein (MAVS)-dependent RNA sensing pathway. The RNA molecules are also copied to DNA by an enzyme called reverse transcriptase, which is recognized by cGAS-cGAMP-STING pathway. These signaling pathways induce a constant wave of signaling that promote specific immunoglobulin M production.
The MAVS and cGAS proteins involved in this study were discovered by Dr. Zhijian “James” Chen, Professor of Molecular Biology and the Center for Genetics of Host Defense and a Howard Hughes Medical Institute Investigator.
“These findings suggest that both the RNA and DNA sensing pathways play an important role in detecting ERV and activating adaptive immune responses,” said Dr. Chen, who is the George L. MacGregor Distinguished Chair in Biomedical Science.
Dr. Ming Zeng, postdoctoral researcher and first author of the study, said that mutations in the enzyme TREX1, which normally performs the degradation of the DNA molecules of retroviruses in the cell, are involved in autoimmune disease.
Dr. Zeng said that the capacity of ERV DNA to stimulate B cells appears to be a physiological process, allowing the T-independent antibody response to occur.
“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,” said Dr. Gunilla Karlsson Hedestam, Professor at the Department of Microbiology, Tumor and Cell Biology at Karolinska Institutet.
Dr. Beutler said that most likely the “physiological” activation of ERV in B cells could be a connection linking inflammation and cancer.
The researchers concluded that ERV and MAVS or cGAS pathways maybe be crucial players of the TI-2 B cell signaling pathway.