Sandia researchers take new approach to studying how cells respond to pathogens

April 03, 2007

ALBUQUERQUE, N.M. -- A Sandia National Laboratories research team led by Anup Singh is taking a new approach to studying how immune cells respond to pathogens in the first few minutes and hours of exposure.

Their method looks at cells one at a time as they start trying to fight the invading pathogens.

Called the Microscale Immune Studies Laboratory (MISL) Grand Challenge, the work is in its second of three years of funding by the internal Laboratory Directed Research and Development (LDRD) program. Sandia is partnering on the project with the University of Texas Medical Branch (UTMB) at Galveston and the University of California, San Francisco (UCSF).

Sandia is a National Nuclear Security Administration (NNSA) laboratory.

Singh says the researchers are interested in studying the early events in immune response when a pathogen invades a body. Understanding the early steps could lead to better ways to diagnose and stop disease before there are symptoms and development of more effective therapeutics.

Most existing research into how immune cells respond has been done by looking at large cell populations. The Sandia researchers say information gathered from a large population of cells may mask underlying mechanisms at the individual cell level.

"Cells have different life cycles, just like any living being. And not all cells are exposed to the pathogen at the same time," Singh says. "We wanted to look at cells in the same life cycle and same infectious state. This can only be done cell by cell. We also want to study populations, but one cell at a time."

The research is possible because of advances in several Sandia-developed tools, including: Real immune cells are short-lived outside of bodies. To do the type of experiments they wanted, the researchers needed cells that can stay alive more than a couple of hours, have the ability grow and represent a relevant model of human immune cells. They obtained "immortalized mouse immune cells" from a collaborator at UCSF that have the needed life span, and are accepted as a model system by the immunology research community.

"We're starting with robust and well-characterized cells, which really simplifies development of our new technologies and methods," Singh says. "We'll soon be working with other cell types, though, like white blood cells directly isolated from human patients. Our approach is designed to be flexible enough to handle many different cell types, and it also minimizes the number of cells needed for analysis, so it should enable us to do some unique studies on rare cell types."

Proteins in the cells of interest are tagged with fluorescent molecules, essentially colored dyes. The dyes range from green to red and give researchers the opportunity to track proteins and see, for example, the dynamic cellular production of proteins or protein-binding processes inside or on the surface of the cells.

The team is developing one platform with two complementary microfluidic modules -- one for trapping and imaging viable cells during stimulation with pathogens. The other combines cell preparation steps, cell selection and sorting followed by analysis of protein content in the selected cell subpopulations.

"In effect, we are taking many work-horse technologies such as confocal microscopy, flow cytometry and immunoassays and combining them into one compact, miniaturized platform using our unique microfluidic and imaging tools," Singh says.

Hyperspectral fluorescence imaging with multivariate curve resolution (MCR) is used to image the tagged proteins and provide quantitative measurements on multiple proteins simultaneously. The goal is to analyze as many as 10 to 40 proteins and cellular stains at a time in three dimensions.

The end results of the imaging and protein analysis are large amounts of data that must be categorized and understood. Computational modeling is then used to develop network models from experimental data and predictive modeling generates hypotheses to be tested next.

Singh says using an integrated microfluidic platform sets Sandia apart from the rest of the world. Sandia researchers have been working in the area of microfluidics -- the science of designing, manufacturing, and formulating devices and processes that deal with volumes of fluid on the order of nanoliters -- since the 1990s and have a good understanding about how to use microfluids to analyze cell activity. The microfluidic platform is fast and highly parallel and can perform hundreds of measurements 50 to 100 times faster than alternate methods.

Singh says the end goal is to make a benchtop miniaturized system expected in about two years. It would be placed in Biosafety Level 3 or 4 labs to study immune response to highly pathogenic organisms. He notes the integrated platform, biological reagents and computational models developed under this project have applicability beyond infectious disease research. These technologies can also be used for studying cellular signaling involved in diseases such as cancer or by pharmaceutical companies for biomarker discovery.
-end-
More information can be obtained at roswell.ca.sandia.gov/anup

Sandia is a multiprogram laboratory operated by Sandia Corporation, a Lockheed Martin company, for the U.S. Department of Energy's National Nuclear Security Administration. Sandia has major R&D responsibilities in national security, energy and environmental technologies, and economic competitiveness.

Release and images are available at http://www.sandia.gov/news/resources/releases/2007/microscale.html

Sandia news media contact: Mike Janes, mejanes@sandia.gov, (925) 295-2447

Sandia National Laboratories' World Wide Web home page is located at http://www.sandia.gov. Sandia news releases, news tips, science photo gallery, and periodicals can be found at the News Center button.

DOE/Sandia National Laboratories

Related Immune Response Articles from Brightsurf:

Boosting chickens' own immune response could curb disease
Broiler chicken producers the world over are all too familiar with coccidiosis, a parasite-borne intestinal disease that stalls growth and winnows flocks.

Cells sacrifice themselves to boost immune response to viruses
Whether flu or coronavirus, it can take several days for the body to ramp up an effective response to a viral infection.

Children's immune response more effective against COVID-19
Children and adults exhibit distinct immune system responses to infection by the virus that causes COVID-19, a finding that helps explain why COVID-19 outcomes tend to be much worse in adults, researchers from Yale and Albert Einstein College of Medicine report Sept.

Which immune response could cause a vaccine against COVID-19?
Immune reactions caused by vaccination can help protect the organism, or sometimes may aggravate the condition.

Obesity may alter immune system response to COVID-19
Obesity may cause a hyperactive immune system response to COVID-19 infection that makes it difficult to fight off the virus, according to a new manuscript published in the Endocrine Society's journal, Endocrinology.

Immune response to Sars-Cov-2 following organ transplantation
Even patients with suppressed immune systems can achieve a strong immune response to Sars-Cov-2.

'Relaxed' T cells critical to immune response
Rice University researchers model the role of relaxation time as T cells bind to invaders or imposters, and how their ability to differentiate between the two triggers the body's immune system.

A novel mechanism that triggers a cellular immune response
Researchers at Baylor College of Medicine present comprehensive evidence that supports a novel trigger for a cell-mediated response and propose a mechanism for its action.

Platelets exacerbate immune response
Platelets not only play a key role in blood clotting, but can also significantly intensify inflammatory processes.

How to boost immune response to vaccines in older people
Identifying interventions that improve vaccine efficacy in older persons is vital to deliver healthy ageing for an ageing population.

Read More: Immune Response News and Immune Response Current Events
Brightsurf.com is a participant in the Amazon Services LLC Associates Program, an affiliate advertising program designed to provide a means for sites to earn advertising fees by advertising and linking to Amazon.com.