Nav: Home

Confronted with sepsis, key immune mechanism breaks, Indiana University scientists find

July 28, 2016

INDIANAPOLIS - When the body encounters an infection, a molecular signaling system ramps up the body's infection-fighting system to produce more white blood cells to attack invading bacteria. Now researchers have discovered that when facing a massive bacterial infection resulting in sepsis, that same signaling system malfunctions, damaging the body's ability to fight the invaders.

In addition to suppressing the mature blood cells battling against the infection, malfunctioning of this signaling system results in permanent damage to the body's blood producing cells - called hematopoietic stem cells - that are located in the bone marrow. The research, by scientists at the Indiana University School of Medicine, was published recently in the journal Stem Cell Reports. http://www.cell.com/stem-cell-reports/fulltext/S2213-6711(16)30057-1

Sepsis is a life-threatening response by the body's inflammatory system that can result from severe bacterial infections. It is a growing problem: The number of hospitalizations for sepsis more than doubled from 2000 to 2008, reaching more than 1.1 million, according to the Centers for Disease Control and Prevention. Patients with severe sepsis or septic shock have a mortality (death) rate of about 40%-60%, with the elderly having the highest death rates. Newborns and pediatric patients with sepsis have about a 9%-36% mortality rate.

"Our goal is to find out what causes this bone marrow failure during serious infections, and find ways to prevent it," said Nadia Carlesso, M.D., Ph.D., professor of pediatrics and of medical and molecular genetics at the IU School of Medicine.

Most research has focused on understanding and managing the late consequences of sepsis while little is known about the changes occurring in the bone marrow at early stages of the response to bacterial infection, when the opportunity for effective treatment might still be available. Dr. Carlesso's group has pioneered the study of bone marrow responses during acute infection. Using laboratory models of severe sepsis her group has discovered that the blood-producing stem cells fail to continuously generate mature neutrophils, which are the most critical bacteria-fighting cells.

"In this research we determined that in cases of severe infection and sepsis, a key mechanism in the body's response to infection is broken. These findings point to potential new targets for protecting the immune system during major infections," Dr. Carlesso said.

The IU researchers focused on a set of proteins called toll-like receptors, which function as sentinels on the surfaces of cells. When the receptors detect the presence of invading bacteria, they send signals to the body's immune response system. The IU researchers looked at toll receptor 4 (TLR4), which activates two signaling pathways that stimulate the production of more neutrophils during common infections, but suppress it during severe infections.

In a laboratory model of sepsis using mice, the researchers found that two abnormal effects activated by toll receptor 4 during severe infection -- the suppression of neutrophil production and the damage to the bone marrow's blood-producing stem cells -- are mediated by two different molecules downstream of TLR4.

"This study is a good start, as provides a more precise map to follow, but more research is needed to better understand this process and develop better, and much needed, therapeutic strategies for sepsis," said Dr. Carlesso.
-end-
The research was supported by grants from the National Institutes of Health (R01 HL068256-05, R01 DK097837-09 and R01 HL124159-01, the MPN Research Foundation, Ralph W. and Grace M. Showalter Research Trust Fund, the American Heart Association and the National Institute of Diabetes and Digestive and Kidney Diseases Center of Excellence in Molecular Hematology.

In addition to Dr. Carlesso, investigators contributing to this research were Huajia Zhang, Sonia Rodriguez, Lin Wang, Soujuan Wang, Henrique Serezani, Reuben Kapur and Angelo A. Cardoso.

Drs. Carlesso and Kapur are members of the Herman B Wells Center for Pediatric Research. Drs. Carlesso, Cardoso, Kapur and Serezani are members of the Indiana University Melvin and Bren Simon Cancer Center.

Indiana University

Related Bone Marrow Articles:

3D atlas of the bone marrow -- in single cell resolution
Stem cells located in the bone marrow generate and control the production of blood and immune cells.
Dangerous bone marrow, organ transplant complication explained
Scientists have discovered the molecular mechanism behind how the common cytomegalovirus can wreak havoc on bone marrow and organ transplant patients, according to a paper published in the journal Cell & Host Microbe.
Viagra shows promise for use in bone marrow transplants
Researchers at UC Santa Cruz have demonstrated a new, rapid method to obtain donor stem cells for bone marrow transplants using a combination of Viagra and a second drug called Plerixafor.
Bone marrow may be the missing piece of the fertility puzzle
A woman's bone marrow may determine her ability to start and sustain a pregnancy, report Yale researchers in PLOS Biology.
Cells that make bone marrow also travel to the womb to help pregnancy
Bone marrow-derived cells play a role in changes to the mouse uterus before and during pregnancy, enabling implantation of the embryo and reducing pregnancy loss, according to research published Sept.
Uncovering secrets of bone marrow cells and how they differentiate
Researchers mapped distinct bone marrow niche populations and their differentiation paths for the bone marrow factory that starts from mesenchymal stromal cells and ends with three types of cells -- fat cells, bone-making cells and cartilage-making cells.
Zebrafish help researchers explore alternatives to bone marrow donation
UC San Diego researchers discover new role for epidermal growth factor receptor in blood stem cell development, a crucial key to being able to generate them in the laboratory, and circumvent the need for bone marrow donation.
New material will allow abandoning bone marrow transplantation
Scientists from the National University of Science and Technology 'MISIS' developed nanomaterial, which will be able to restore the internal structure of bones damaged due to osteoporosis and osteomyelitis.
Blood diseases cured with bone marrow transplant
Doubling the low amount of total body radiation delivered to patients undergoing bone marrow transplants with donor cells that are only 'half-matched' increased the rate of engraftment from only about 50 percent to nearly 100 percent, according to a new study by Johns Hopkins researchers.
Vitamin D and immune cells stimulate bone marrow disease
The bone marrow disease myelofibrosis is stimulated by excessive signaling from vitamin D and immune cells known as macrophages, reveals a Japanese research team.
More Bone Marrow News and Bone Marrow Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.