A new computational model developed by a team of Virginia
Tech researchers and published in PLoS
Computational Biology provides a framework to better understand responses
of macrophage cells of the human immune system.

As the security guards of the body, macrophage cells must
identify and respond to a pathogen attack while causing as little damage as
possible to host cells. An excessive or prolonged immune response could lead to
serious acute and chronic inflammatory diseases such as multiple sclerosis, Type
II diabetes, and even sepsis. Therefore, studying how the macrophage immune
response could be altered or reprogrammed by sequential pathogen attacks, known
as priming and tolerance, is of vital importance to the field.

Jianhua Xing, assistant professor of biological sciences,
collaborated with experimental immunologist Liwu Li, and computational
biologist John Tyson, both professors of biological sciences, to develop the
model with Yan Fu of Beijing,
China, a
student in the interdisciplinary doctoral program in genetics, bioinformatics,
and computation biology. Trevor Glaros of Greencastle,
Pa., a student in the biological sciences
doctoral program in the College
of Science, performed the
experimental analyses regarding the endotoxin priming and tolerance in primary
murine macrophages. All are affiliated with the Fralin Life Science Institute
at Virginia Tech.

“The concept of priming refers to the fact that if
macrophages are exposed to a small dose of bacterial endotoxins, they are
primed to respond strongly to a second exposure to a large dose of endotoxin.
The concept of tolerance refers to the fact that if macrophages are exposed to
a large dose of bacterial endotoxins initially, they are temporarily resistant
to endotoxin challenges afterwards,” Xing said.

The Virginia Tech team used the Metropolis algorithm, a
computer simulation technique widely used in physics and chemistry, to
enumerate possible molecular mechanisms giving rise to priming and tolerance.

The results of the model, supported by numerous experimental
observations, may guide future experimental studies to identify molecules
contributing to macrophage priming and tolerance.

“Because macrophage responses are highly diverse,
additional modeling studies and experimental tests will be needed to understand
better how well-mannered macrophages protect us from infection and how unruly
macrophages damage our health,” Tyson said. “We are convinced that
mathematical modeling will provide novel insights into macrophage behavior,
with significant medical implications.”

Source: Virginia Institute of Technology