|
author |
Robert Sutter
| title |
Role of Chromatin Structure in Immune Sensing of DNA
| abstract |
The innate immune system uses pattern recognition receptors (PRRs) to sense microbial-associated molecular patterns (MAMPs). When a PRR binds a MAMP, this leads to a signal
cascade through the cell resulting in transcription and production of inflammatory cytokines,
such as interferon. MAMPs are molecules that are typically distinct from any molecules
expressed by the human body. However, some PRRs bind to DNA, which is necessary for and
not distinct from human cells. These PRRs binds DNA in order to detect viral infections and then
create an interferon response to fight off the viral infection. This begs the question of how the
PRR can distinguish between host and non-host DNA to prevent the erroneous production of
interferon. Since the host cell has a tremendous amount of DNA, the DNA must be extremely
organized and structured to fit all of the DNA into the cell. The cell does this by wrapping the
DNA around a circular protein called a histone and together, the DNA wrapped around the
histone is called a nucleosome. Perhaps this structure also serves a dual purpose of organizing
the DNA and preventing host DNA from being sensed by PRRs. We hypothesized that host cell
DNA in a nucleosome will not cause an interferon response while nucleosomal DNA without the
histone will cause an interferon response. Also, we hypothesized that histones will actively
inhibit the DNA sensor instead of just blocking the DNA sensor from binding to the DNA. We
investigated the first hypothesis by stimulating cells with either nucleosomes or nucleosomal
DNA and measuring the interferon response. We tested the second hypothesis by stimulating
cells with either plasmid, histone and plasmid, or histone and measured the interferon response.
Our data showed that a smaller interferon response is produced by nucleosomes versus
nucleosomal DNA and that histones actively inhibit DNA sensors. This provides a mechanism
for how cells can distinguish between host and non-host DNA and avoid erroneous interferon
signaling.
| school |
The College of Liberal Arts, Drew University
| degree |
B.S. (2021)
|
advisor |
Brianne Barker
|
committee |
Stephen Dunaway Bjorg Larson
|
full text | RSutter.pdf - requires Drew uLogin |
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