UND scientists try to turn down the heat

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News Article

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School of Medicine & Health Sciences


GRAND FORKS, N.D.—Infectious diseases pose a global public health threat, affecting the lives of millions of patients and exacting a heavy cost, with $120 billion in medical costs in the United States alone each year. Even typically nonlethal infections can be fatal if they gain a foothold in patients who suffer from many diseases such as cancer, heart failure, atherosclerosis, lung dysfunction, and trauma.

One of the defenses the human body employs to fight off infections is inflammation. However, severe infections and sepsis can co-opt the body's thermostat leading to runaway inflammation. Sepsis is a life-threatening medical condition that results from a systemic inflammatory response by the body to fend off a severe infection or to recover from a traumatic injury. In a way, the human body undergoes the equivalent of a friendly fire incident when it succumbs to sepsis.

In a last-ditch attempt to save the body, the patient's immune system reacts to the body's signal of impending peril with a defense that goes horribly wrong—it doesn't distinguish between molecular friend and foe. The onslaught of sepsis is frighteningly fast; it can progress from simple sepsis to severe sepsis to septic shock sometimes within hours. Sepsis affects a huge number of people each year and is fatal to about 40 percent of patients affected in ICUs. Controlling sepsis requires reducing the inflammation in afflicted organs.

A University of North Dakota research team, led by Associate Professor Min Wu, PhD, and Postdoctoral Fellow Xikun Zhou, PhD, in the Department of Basic Sciences at the School of Medicine and Health Sciences, reports they have discovered a new molecular fire extinguisher that can help to regulate inflammation during sepsis and other severe infections. Their research was recently published in >Nature Communications.

Wu and Zhou have determined that the regulator, a small snippet of the ribonucleic acid (RNA) molecule termed micro-RNA 302b, can cool down an overzealous inflammation process during infection. RNA plays a role in the expression of genes by transmitting genetic information from DNA to proteins produced by the cell. Proteins are essential to the growth and repair of the body's tissues. However, small-sized microRNAs do not directly transmit genetic signals but indirectly modify gene expression by binding to nucleic acids that they can almost perfectly bind.

Wu and Zhou have added micro-RNA 302b to the current very small pool of micro-RNAs that are known to regulate the immune system's inflammatory response, advancing the development of therapeutic models to better control infectious disease and modulate immune function.

"This study is a significant contribution to the emerging application of micro-RNAs to modulate cellular function by directly impacting gene expression," Wu said. "This approach holds great promise in therapy and diagnosis for many conditions such as cancer, fibrosis, trauma, and immune disorders."

Micro-RNA 302b directly targets a gene known as IRAK4. That gene is involved in activating the immune response through receptors that detect infection and tissue damage and signal the immune system to respond. Acting like a toll operator along the signaling pathway, micro-RNA 302b regulates the access and the effect the IRAK4 gene has in eliciting the immune system's inflammatory response.

Wu and his laboratory now plan to explore an emerging class of anti-inflammation therapeutic strategies, such as those based on small chemicals and recombinant proteins targeting IRAK and micro-RNA 302b.

"Although this study is based on infectious disease," said Malak Kotb, PhD, chair of the Department of Basic Sciences at UND, "it is broadly applicable to the inflammation that occurs in many other conditions such as psoriasis, inflammatory bowel disease, cardiovascular diseases, rheumatoid arthritis and sclerosis, which together torment and kill millions of people globally each year."

Funding for Wu and his team is provided by the National Institute of Allergy and Infectious Diseases at the National Institutes of Health.

The research paper titled "MicroRNA-302b augments host defense to bacteria by regulating inflammatory responses via feedback to TLR/IRAK4 circuits" is available online at http://www.nature.com/ncomms/2014/140410/ncomms4619/full/ncomms4619.html.