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


Retroviruses are best known for causing contagious scourges such as AIDS, or more sporadically, cancer.  However, researchers at UT Southwestern Medical Center and Karolinska Institutet 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.  The team 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.

The team observed 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 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.

These findings suggest that both the RNA and DNA sensing pathways play an important role in detecting ERV and activating adaptive immune responses.

The current study found that 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.

The researchers note 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.  However, 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.

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.

The team 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.  A new pathway which will need to be investigated.

Source:  UT Southwestern Medical Center

 

Hypothetical model of signaling events in the TI-2 antibody response.  Upon BCR engagement by TI-2 antigen, signaling from the BCR via Btk and NF-κB leads to transcriptional activation of numerous ERV genes. Resulting transcripts are translated to produce reverse transcriptase(s) (RT), endogenous MLV Env, and possibly other ERV proteins. The activity of RT enzymes results in retrotranscription of ERV mRNAs and consequent elevation of ERV cDNA in the cytoplasm of the same cell. These ERV mRNAs and cDNAs engage the RIG-I/MDA5-MAVS and the cGAS-STING pathways, respectively, to stimulate B cell activation and proliferation, and antigen-specific antibody production in a cell-intrinsic manner. Signaling from MAVS, but not cGAS-STING, activates NF-κB.  MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses.  Beutler et al 2014.

Hypothetical model of signaling events in the TI-2 antibody response. Upon BCR engagement by TI-2 antigen, signaling from the BCR via Btk and NF-κB leads to
transcriptional activation of numerous ERV genes. Resulting transcripts are translated to produce reverse transcriptase(s) (RT), endogenous MLV Env, and possibly other ERV proteins. The activity of RT enzymes results in retrotranscription of ERV mRNAs and consequent elevation of ERV cDNA in the cytoplasm of the same cell. These ERV mRNAs and cDNAs engage the RIG-I/MDA5-MAVS and the cGAS-STING pathways, respectively, to stimulate B cell activation and proliferation, and antigen-specific antibody production in a cell-intrinsic manner. Signaling from MAVS, but not cGAS-STING, activates NF-κB. MAVS, cGAS, and endogenous retroviruses in T-independent B cell responses. Beutler et al 2014.

One comment

  • Laura,
    This details how autoimmune diseases start read to the end and there is one sentence that tells how this happens

    Like

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