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Environmental Factor, June 2012

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Researchers pinpoint key protein that protects against septic shock

By Cindy Loose

Perry Blackshear, M.D., D.Phil.

This study is the latest of more than 235 peer-reviewed papers Blackshear has published in leading biomedical journals. (Photo courtesy of Steve McCaw)

Lian-Qun Qiu, Ph.D.

Qiu was first author on the study. (Photo courtesy of Steve McCaw)

Deborah Stumpo, Ph.D.

Stumpo has co-authored more than 50 papers since 1981, 45 of them with Blackshear. (Photo courtesy of Steve McCaw)

Patients with simple urinary tract infections may be protected from more severe infections and even death by just one microscopic protein in one specific class of white blood cells.

That startling insight, which also may apply to other types of bacterial infections, is one of a number of findings from a recent study by three NIEHS scientists. Various types of bacterial infections, including  those caused by Gram-negative bacteria, have become increasingly menacing as more and more of them become resistant to existing antibiotics.

Led by NIEHS lead researcher Perry Blackshear, M.D., D.Phil., the team showed that life-threatening septic shock was abnormally likely when low doses of a Gram-negative bacterial toxin were injected into mice that were genetically engineered to lack the protein tristetraprolin (TTP) in myeloid cells, a major class of white blood cells. This was true even though only myeloid cells were altered to lack TTP. 

Exploring differences in host susceptibility

The study is part of a larger, decades-long project that is exploring the differences in susceptibility to infection among individuals, particularly how that susceptibility is related to a deficiency in TTP production. The project is also aimed at identifying small molecules that could be used in developing drugs to increase TTP amounts or actions.

“The body has a very complicated way of dealing with the primary response to infection,” said Blackshear. “In some cases, when a simple infection occurs, the body responds in overwhelming ways that can be fatal.”

TTP, a focus of the NIEHS team studying differential susceptibility to infection in individuals, is both an anti-inflammatory protein and an anti-Tumor Necrosis Factor (TNF) protein. An excess of TNF has been implicated in a number of chronic diseases, including autoimmune diseases such as rheumatoid arthritis and Crohn’s disease, as well as in the more acute septic shock syndrome caused by infections.

Genetically engineered mouse lacks TTP

Previous studies have shown that mice genetically engineered to lack TTP develop early-onset, severe inflammatory indications, including extreme drops in weight, arthritis, inflammation of the left heart valves, myeloid hyperplasia, and autoimmunity.

Blackshear, in collaboration with two members of the Polypeptide Hormone Action Group, research fellow Lian-Qun Qiu, Ph.D., and staff scientist Deborah Stumpo, Ph.D., advanced the work at NIEHS by genetically engineering a mouse in which TTP was knocked out only in myeloid cells. The mice exhibited only minimal signs, characterized by a slight slowing of weight gain, compared to the severe physical signs seen in mice in which TTP was knocked out in all cell types.

However, the mice with only myeloid-specific TTP deficiency were highly and abnormally susceptible to a low-dose injection of lipopolysaccharide, or LPS, a major component of the cell wall of Gram-negative bacteria. The low LPS dose given produced no signs in normal mice. However, the mice with TTP deficiency in their myeloid cells rapidly developed signs of severe infection, extensive organ damage, and TNF levels 110 times greater than in the control group.

The scientists concluded that while myeloid cells aren’t the only ones in which TTP plays an important role in fighting infection, the TTP in myeloid cells specifically is critical for fighting off septic shock caused by Gram-negative bacteria such as E. coli.

The study appeared in the May issue of the Journal of Immunology.

Citation: Qiu LQ, Stumpo DJ, Blackshear PJ. 2012. Myeloid-specific tristetraprolin deficiency in mice results in extreme lipopolysaccharide sensitivity in an otherwise minimal phenotype. J Immunol 188(10):5150-5159.

(Cindy Loose is a contract writer with the NIEHS office in Bethesda, Md.)

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