Infectious diseases remain the world's number one leading
cause of death in children and young adults.
Now, with emerging epidemic threats like Zika, Ebola, SARS, TB and
others, massive increases in antimicrobial resistance, and the time and
cost for developing new antimicrobial drugs and therapeutics, scientists
are worried about finding ever new ways to outpace infectious diseases.
‘The new 3-D culture model incorporates an important immune defense cell type found in the intestine, macrophages, which are key cells targeted by Salmonella.’
One exciting approach to address this problem is the use of
predictive tissue culture models that can more accurately reflect how
our own bodies respond to pathogens.
The historical lack of such sophisticated models has greatly slowed
the ability to understand infectious disease from both the host and
pathogen perspective. Central to the development of tissue models that
can better predict how humans respond to infection is the understanding
that cells and tissues in our bodies function in a three-dimensional
Accordingly, cell-based models of tissues made in the
laboratory must be developed with the same appreciation for the 3-D
tissue microenvironment encountered by pathogens in the body.
While this research concept has long been appreciated by the cancer
and regenerative medicine world, the infectious disease world has been
slower to get on board.
Now, an ASU Biodesign Institute team that was first to develop and
apply 3-D tissue models to study bacterial infectious disease nearly two
decades ago - and spearheaded the adoption of 3-D tissue models as a
new paradigm to study infectious disease - has reported their latest
advancement in 3-D intestinal model development.
The new study, a collaboration between Arizona State University and
NASA's Johnson Space Center, was led by Cheryl Nickerson, a researcher
at ASU's Biodesign Institute and professor in the School of Life
Their united goal is to develop more realistic models of intestinal
tissue to thwart Salmonella, a leading cause of food poisoning and
systemic disease worldwide with many varieties causing severe and
sometimes fatal infections with an economic impact in the billions of
"We engineered our advanced 3-D co-culture model to incorporate an
important immune defense cell type found in the intestine, macrophages,
which are key cells targeted by Salmonella during infection and are
important for its disease-causing potential," said Nickerson,
corresponding author of the study. "The inclusion of macrophages along
with epithelial cells allows for synergistic contributions of different
cell types to be evaluated during infection so that host-pathogen
interactions can be studied in a more physiologically relevant context.
The strains of Salmonella used in this study included those that
cause gastroenteritis and life-threatening bloodstream infections,
including multidrug resistant Salmonella strain D23580 (which belongs to
a group of Salmonella isolates identified as ST313) which are
responsible for devastating epidemics of invasive bloodstream infections
in sub-Saharan Africa.
The study continues the pioneering work of Nickerson's team using
NASA bioreactor technology to develop 3-D cell-based tissue models with
increasing complexity that better recapitulate human tissues to bridge
the gap between traditional cell culture and animal models currently
used in infectious disease research.
This is the first time that immune cells have been incorporated into
a 3-D intestinal model developed using the NASA rotating wall vessel
(RWV) bioreactor and the first application of this co-culture system to
study infections that target the human gut.
"Our co-culture model thus offers a powerful new tool in
understanding enteric [gut] pathogenesis and may lead to unexpected
pathogenesis mechanisms and therapeutic targets that have been
previously unobserved or unappreciated using other intestinal cell
culture models," said Nickerson.
In addition to 3-D architecture and inclusion of immune cells, other
complex factors of the tissue microenvironment must also be considered
when building better tissue models for infection. These factors include
physical forces, such as the flow of fluids over the cell surface, and
different oxygen levels. This is important in order to capture the
complex and dynamic interactions between the host and the pathogen,
which govern the outcome of the infection process.
To incorporate these additional factors into their new 3-D
co-culture model development, the authors grew Salmonella under
different oxygen levels (high and low) that it encounters before and
during intestinal infection to better recapitulate the natural infection
process, and used dynamic bioreactor technology to culture cells under
physiological fluid shear levels found in the intestinal tract.
"It's a real challenge for researchers to accurately model all of
the steps involved in the initiation and progression of host-pathogen
interactions in the laboratory due to all of the complex factors in the
human body that contribute to infection," said Barrila, lead co-author
of the international study, along with colleague Jiseon Yang.
"By harnessing the naturally low fluid shear environment generated
by the NASA RWV bioreactor during model development combined with the
use of physiologically relevant oxygen conditions during infection, we
have come several steps closer to achieving our ultimate goal of
recreating this complex 3-D microenvironment."
To test this new co-culture model in infection studies, Nickerson's
team challenged it with different strains of Salmonella bacteria, each
of which had distinct host adaptations, antibiotic resistance profiles,
and disease phenotypes.
Interestingly, the response of this new model to infection with the
different types of Salmonella was very different for each strain, thus
demonstrating the model's ability to distinguish between these closely
related pathogens based on their infection characteristics.
Specifically, important differences were observed between the bacterial
strains in model colonization (adherence, invasion and intracellular
survival) and intracellular co-localization patterns in epithelial and
"One important advantage of using this 3-D multicellular in vitro
host model system is the ability to visualize the co-localization
patterns of different pathogens within the different host cell types. I
believe that these platforms can advance our knowledge of a variety of
enteric diseases of both infectious (bacterial and viral) and
non-infectious etiologies (IBS/IBD, drug toxicity, etc)," said Yang.
These findings demonstrate the value of this model as a powerful new
tool that integrates the response of different cell types to understand
The Nickerson team is now focused on building in further complexity
into their 3-D tissue models, so that layer by layer, they can reach the
ultimate goal of growing and fully mimicking whole 3-D organs, and add
even more immune cells to the mix to provide researchers a hierarchical
series of advanced new tools to study health and disease.
Nickerson adds that "the future of this field is limitless, and we
are still in the infancy of learning how to build more realistic and
complex models of native human tissues to better understand
host-pathogen interactions and infectious disease mechanisms. These
findings are urgently needed for new vaccine and drug development to
outpace infectious disease. It is thus exciting to see the infectious
disease world begin to embrace 3-D tissue models."