Yale Study Explains Complex Infection Fighting Mechanism

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Source:

Yale University

Date:

2006-01-11

URL:

http://www.sciencedaily.com/releases/2006/01/060110231737.htm

Yale Study Explains Complex Infection Fighting Mechanism

Yale School of Medicine researchers report in Nature Immunology how

infection fighting mechanisms in the body can distinguish between a

virus and the healthy body, shedding new light on auto immune disorders.

The infection fighters in question, toll-like receptors (TLRs),

function by recognizing viral, bacterial or fungal pathogens and then

sending signals throughout the immune system announcing that an

infection has occurred.

Viruses change features to avoid being recognized, thereby triggering

the immune response. But TLRs recognize the highly conserved features

of pathogens, features that are often difficult to change without

affecting the punch of the pathogen, said lead author of the study,

Barton of the University of California at Berkeley who

performed the research while in the Section of Immunobiology at Yale

School of Medicine.

He said that one exception to the general view of how TLRs work is

the way TLRs recognize viruses since viruses lack the unique features

of bacterial or fungal pathogens. Because of this, the immune system

has had to find other ways to recognize viral infection.

" In particular, the DNA or RNA that comprise viral genomes can

stimulate certain TLRs, " Barton said. " This strategy comes at an

enormous cost. By targeting the DNA or RNA of viruses, the immune

system runs the risk of accidentally recognizing its own DNA and RNA

as foreign and inappropriately making an immune response against

itself. This autoimmune condition is called systemic lupus

erythematosus or SLE, and can be devastating for those unfortunate

enough to suffer from it. "

The work of senior author Ruslan Medzhitov, professor of

immunobiology, and his colleagues, has focused on trying to

understand how recognition of a body's own DNA is avoided by those

TLRs involved in viral nucleic acid recognition.

" We have known for some time that those TLRs are sequestered in

specialized compartments within cells, " Barton said. " The

significance of this localization, however, was unclear. We have now

shown that the localization is, in fact, a key factor for the

avoidance of self DNA recognition as well as for the optimal

recognition of viral DNA. "

He said the research group was able to construct a modified version

of one of the TLRs, moving it from the specialized internal

compartment within the cell to the cell surface. This engineered

version of the TLR had enhanced recognition of self DNA, yet poor

recognition of viral DNA, proving that isolation of certain TLRs

within these specialized intracellular compartments is an important

checkpoint in maintaining the balance between viral and self nucleic

acid recognition.

" This work has potential implications for our understanding of the

molecular basis of lupus (SLE), " Barton said. " It is possible that

certain mutations in TLRs will affect their localization within the

cell and give them better access to self nucleic acid. Understanding

how this balance is maintained and how it can go wrong is an

important step in the fight against autoimmune disorders. "