Working
in the emerging field of systems biology, UT Southwestern Medical
Center researchers mathematically predicted how bacteria that cause food
poisoning hijack a cell’s sense of direction and then confirmed those
predictions in living cells.
The
study proposed a new model to explain how mammalian cells establish the
sense of direction necessary to move, as well as the mechanism that a
disease-causing form of Escherichia coli
bacteria employ to hijack that ability. Cells need to orient themselves
for several basic processes, such as keeping biochemical reactions
separated in space and, in the case of immune cells, pursuing pathogens.
Importantly, disruption of the cell’s sense of direction often leads to
human disease.
“This
is a great example of scientists from different fields of research
coming together to solve a complex and important biological problem,”
said Dr. Neal Alto, assistant professor of microbiology and senior
author of the study, published Feb. 17 in Cell.
Systems
biology aims to discover and understand a “circuit theory” for
biology—a set of powerful and predictive principles that will reveal how
networks of biological components are wired to display the complex
properties of living things. The rapidly emerging field requires experts
in several scientific disciplines—including biology, physics,
mathematics and computer science—to come together to create models of
biological systems that consider both the individual parts and how these
parts react to each other and to changes in their environment.
Scientists
from UT Southwestern’s microbiology department and the newly expanded
Cecil H. and Ida Green Comprehensive Center for Molecular, Computational
and Systems Biology teamed up to examine the problem collaboratively.
They initially conceived a mathematical model for their hypothesis of
how the cell would respond during an E. coli-induced infection and then tested their computational predictions in living cells.
“Bacteria
inject protein molecules into human cells with a needle-and-syringe
action,” Dr. Alto said. “The human cell responds by producing a local
actin-rich membrane protrusion at the spot where the bacteria attaches
to the cell.”
For
healthy cells to move normally, these actin polymers push against a
cell’s membrane, protruding and propelling the cell in one direction or
another. When E. coli
molecules are injected, however, actin polymers rush to the site
infection and help bacterial molecules both move within the cell and
establish an internal site of infection.
Robert
Orchard, graduate student of microbiology and the study’s lead author,
said: “By asking ‘How does a bacterial pathogen from outside the cell
regulate the host cells’ actin dynamics within the cell?’ we have
uncovered a fundamentally new molecular circuit involved in mammalian
cell polarity and bacterial infection. These findings provide new
insight into the regulatory mechanisms that control both disease-causing
agents and normal mammalian cell behavior.”
Other
UT Southwestern researchers from the Green Center involved in the work
were Dr. Steven Altschuler and Dr. Lani Wu, both associate professors of
pharmacology; Dr. Gürol Süel, assistant professor of pharmacology; and
Mark Kittisopikul, a student in the Medical Scientist Training Program.
The
National Institutes of Health, the James S. McDonnell Foundation and
The Welch Foundation supported the study. The researchers also received
assistance from the UT Southwestern Live Cell Imaging Facility, which is
supported in part by the National Cancer Institute.
Identification of F-actin as the Dynamic Hub in a Microbial-Induced GTPase Polarity Circuit
