Natural GMOs Part 212. Scientists identify new and beneficial function of novel virus DNA inserts in mammal chromosomes during human immune response

Note for readers: Retroviruses are a type of virus that inserts a genetic copy in the chromosomes of the host they infect. This can become a new gene and be inherited generation after generation. This is a mechanism of natural evolution and a source of genetic novelty, as illustrated here in mice (and humans).

Scientists identify new and beneficial function of endogenous retroviruses in immune response

DALLAS – Dec. 18, 2014 – Retroviruses are best known for causing contagious scourges such as AIDS, or more sporadically, cancer.

But researchers at UT Southwestern Medical Center and Karolinska Institutet in Stockholm, Sweden, found that endogenous retroviruses (ERV) also play a critical role in the body’s immune defense against common bacterial and viral pathogens.

“Most scientists have become used to the view that retroviruses are generally harmful,” said Nobel Laureate Dr. Bruce Beutler, Professor and Director of UT Southwestern’s Center for the Genetics of Host Defense. “We have found that ERV fulfill at least one beneficial function critical to producing protective antibodies.”

Retroviruses are able to insert into the genomic DNA of cells they infect, including germ cells. In this way, and by a process called retrotransposition, they have become a major part of the genome of each person. About 45 percent of a person’s DNA is of retroviral origin, and some of the better preserved copies are termed “endogenous retroviruses” (ERV).

Writing in the journal Science, the researchers 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.

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 ERV 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.

Dr. Zhijian “James” Chen, Professor of Molecular Biology and the Center for Genetics of Host Defense and a Howard Hughes Medical Institute Investigator, discovered two of the key proteins examined in the study (MAVS and cGAS).

“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 also an investigator of Howard Hughes Medical Institute and holds the George L. MacGregor Distinguished Chair in Biomedical Science.

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. Moreover, reverse transcriptase inhibiting drugs also partially inhibit the type II T-independent antibody response.

Dr. Ming Zeng, Postdoctoral Researcher in the Center for Genetics of Host Defense and lead author on the study, notes that mutations affecting an enzyme called TREX1, which normally degrades the DNA copies of retroviruses in the cytoplasm, are known to cause an autoimmune disease.

“But it seems that the ability of ERV DNA to activate B cells is physiological: it must happen for this type of T-independent antibody response to occur,” he said.

What about the good vs. bad dichotomy that we have come to hold dear where host vs. retroviral DNA are concerned?

“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 questioned whether this will prove to be an isolated case of ERV being used for “good” purposes, and the possibility that not all may in fact be good.

“Perhaps the ‘physiological’ activation of ERV in B cells might represent a new link between inflammation and cancer,” said Dr. Beutler, who shared the 2011 Nobel Prize in Physiology or Medicine for discovering an important family of receptors that allow mammals to sense infections when they occur, triggering a powerful inflammatory response.

Dr. Beutler is a UT Regental Professor, and holds the Raymond and Ellen Willie Distinguished Chair in Cancer Research, in Honor of Laverne and Raymond Willie, Sr. The goal of the Center for the Genetics of Host Defense is to advance the fundamental understanding of the genetics of immunity to aid in the treatment of infection, disorders of immunity, and autoimmunity.

About UT Southwestern Medical Center
UT Southwestern, one of the premier academic medical centers in the nation, integrates pioneering biomedical research with exceptional clinical care and education. The institution’s faculty includes many distinguished members, including six who have been awarded Nobel Prizes since 1985. Numbering approximately 2,800, the faculty is responsible for groundbreaking medical advances and is committed to translating science-driven research quickly to new clinical treatments. UT Southwestern physicians provide medical care in 40 specialties to about 92,000 hospitalized patients and oversee approximately 2.1 million outpatient visits a year.

About Karolinska Institutet
Karolinska Institutet is one of the world´s leading medical universities. Its mission is to contribute to the improvement of human health through research and education. Karolinska Institutet accounts for over 40 percent of the medical academic research conducted in Sweden and offers the country´s broadest range of education in medicine and health sciences. Since 1901 the Nobel Assembly at Karolinska Institutet has selected the Nobel laureates in Physiology or Medicine.

@ Scientists identify new and beneficial function of endogenous retroviruses in immune response: December 2014 News Releases - UT Southwestern, Dallas, Texas:

MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses.

Science. 2014 Dec 19;346(6216):1486-92. doi: 10.1126/science.346.6216.1486. Zeng M, Hu Z, Shi X, Li X, Zhan X, Li XD, Wang J, Choi JH, Wang KW, Purrington T, Tang M, Fina M, DeBerardinis RJ, Moresco EM, Pedersen G, McInerney GM, Hedestam GB, Chen ZJ,Beutler B.

Multivalent molecules with repetitive structures including bacterial capsular polysaccharides and viral capsids elicit antibody responses through B cell receptor (BCR) crosslinking in the absence of T cell help. We report that immunization with these T cell-independent type 2 (TI-2) antigens causes up-regulation of endogenous retrovirus (ERV) RNAs in antigen-specific mouse B cells. These RNAs are detected via a mitochondrial antiviral signaling protein (MAVS)-dependent RNA sensing pathway or reverse-transcribed and detected via the cGAS-cGAMP-STING pathway, triggering a second, sustained wave of signaling that promotes specific immunoglobulin M production. Deficiency of both MAVS and cGAS, or treatment of MAVS-deficient mice with reverse transcriptase inhibitors, dramatically inhibits TI-2 antibody responses. These findings suggest that ERV and two innate sensing pathways that detect them are integral components of the TI-2 B cell signaling apparatus. Copyright © 2014, American Association for the Advancement of Science PMID: 25525240 [PubMed - in process]


See also
PERSPECTIVE Retroviral help for B cells
Emilie K. Grasset and Andrea Cerutti Science 19 December 2014: 1454-1455.

Note by The Pundit: Similar immune activation mechanisms are likely to apply in human cells to those characterised here in mouse cells.

Update
Meet The Virome:

The Virome in Mammalian Physiology and Disease
Herbert W. Virgin
http://dx.doi.org/10.1016/j.cell.2014.02.032
The virome contains the most abundant and fastest mutating genetic elements on Earth. The mammalian virome is constituted of viruses that infect host cells, virus-derived elements in our chromosomes, and viruses that infect the broad array of other types of organisms that inhabit us. Virome interactions with the host cannot be encompassed by a monotheistic view of viruses as pathogens. Instead, the genetic and transcriptional identity of mammals is defined in part by our coevolved virome, a concept with profound implications for understanding health and disease.

QUOTE: Virome Interactions with Other Kingdoms of Life
The virome can influence the host through interactions with other types of organisms within the microbiome (trans-kingdom interactions herein). Perhaps because of the complexity of these interactions and the difficulty in defining mechanisms for them, the current approach to understanding the virome and
other components of the microbiome is in some ways similar to the earth-centric view of the universe before the Copernican revolution. We tend to view the interactions between components of the microbiome as revolving around us as the center of our metagenomic universe. The real truth is that complex interactions between kingdoms are formative for physiology, and that coinfections are the rule, not the exception. This complexity is very poorly understood