Philadelphia, PA - Researchers at the University of Pennsylvania Schoolof Medicine have published the first study to test the role of RNAchemical modifications on immunity. They have demonstrated that RNAfrom bacteria stimulates immune cells to orchestrate destruction ofinvading pathogens. Most RNA from human cells is recognized as beingself and does not stimulate an immune response to the same extent asinvading bacteria or viruses. The researchers hypothesize that if thisself-recognition fails, then autoimmune diseases such as systemic lupuserythematosus could result.
The research was a collaborative work led by Drew Weissman, MD, PhD, of the Division of Infectious Diseases and Katalin Karikó,PhD, of the Department of Neurosurgery. The investigators publishedtheir findings in the August issue of Immunity. "We think this studywill open a new area of research in understanding how our immunesystems protect us," says Weissman.
"One application of our findings is that scientists will beable to design better therapeutic RNAs, including anti-sense orsmall-interfering RNAs, for treating diseases such as cancer andsingle-gene genetic diseases," saysKarikó.
RNA is the genetic material that programs cells to makeproteins from DNA's blueprint and specifies which proteins should bemade. There are many types of RNA in the cells of mammals, such astransfer RNA, ribosomal RNA, messenger RNA, and all of them havespecific types of chemical tags, or modifications. In contrast, RNAsfrom bacteria have fewer or no modifications.
Another type of RNA in mammalian cells is found inmitochondria, the powerhouses of cells. Mitochondrial RNA is thought tohave originated from bacteria millions of years ago. Similar to RNAfrom bacteria, mitochondrial RNA has fewer chemical tags. It is theabsence of modifications that causes RNA from bacteria and mitochondriato activate the immune response. The researchers suggest that thesemodifications have evolved in animals as one of the ways for the innateimmune system to discriminate self from non-self.
When a tissue is damaged by injury, infection, or inflammation,cells release their mitochondrial RNA. This RNA acts as a signal to theimmune system to recognize the damage and help defend and repair thetissue.
Conversely, the presence of the modifications on the othertypes of RNA does not activate an immune response and thus allows theinnate immune system to discriminate self from non-self. "We showedthat special proteins on the surface of immune cells, called Toll-likereceptors, are instrumental in recognizing bacterial and mitochondrialRNA," explains Weissman. The amount of modification on the RNA isimportant because as little as one or two tags per RNA molecule couldprevent or suppress the immune reaction.
The authors concluded that the potential of RNA to activateimmunity seems to be inversely correlated with the extent of itschemical modification and may explain why some viral RNA that is overlymodified evades immune surveillance. The authors plan to investigatewhether longer RNAs with specific tags will be useful for deliveringtherapeutic molecules to diseased cells.
This study was funded by the National Institutes of Health. Co-authors are Michael Buckstein and Houping Ni, both from Penn.
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