Researchers from the UCR School of Medicine have discovered a new human protein, resistin, that could aid in the treatment of sepsis and published the details in a research paper titled “Human resistin protects against endotoxic shock by blocking LPS-TLR4 interaction.” Sepsis is a complication that can occur when a person is affected by a pathogenic infection and chemicals are released into the bloodstream to fight the infection. These chemicals cause an inflammatory response in the body that can lead to multiple organ failure, septic shock, a dramatic drop in blood pressure and sometimes death.
An easy way to understand sepsis is trying to imagine “burglars coming into the house, who are shooting randomly and destroying the house,” said Meera Nair, assistant professor of Biomedical Sciences and the lead author of the research paper. “You can eliminate the burglars by calling the police, but there will still be damage to the house.”
In an interview with the Highlander, Nair explained exactly how they were able to obtain the data to prove resistin’s viability as a form of treatment for sepsis.
Nair was able to identify resistin by examining preclinical mouse models that showed that “worm infection can improve the prospects of sepsis.” This form of treatment is called helminth therapy, which utilizes parasitic helminths, or worms, to treat autoimmune and other inflammatory disorders in humans. These worms have been found in the digestive system of humans from the age of Neanderthals, so they have evolved together with the mammalian immune system over many thousands of years. Their ability to alter and suppress immune responses could be beneficial to people with autoimmune and inflammatory diseases by helping control excessive inflammatory responses.
Nair, after exploring such mouse models, found that these worms turn on the protein resistin in mice because she was “always interested in this family of proteins, called the resistin-like proteins, and I identified the mouse protein back when I was doing my Ph.D.”
She further explained that the human resistin protein’s main function is to protect the body, specifically to decrease an exacerbated inflammatory response. Nair was able to test and show that worm infection caused human resistin to be turned on by verifying resistin’s function in humans by utilizing transgenic mouse models.
Nair also said that she “supplemented this work by going into the field and getting blood samples from children with worms. The children that were infected with worms had more resistin, but the resistin protein was actually bad for the children because it meant a lowered immune response to a foreign body.” She correlated this finding to sepsis by asking whether we could take advantage of the fact that resistin was downregulating immune responses to cure inflammatory diseases.
Nair also investigated whether resistin was responsible for other chemical immune reactions in the body. She was able to find that resistin actually decreased the number pro-inflammatory cytokines, which normally cause fever, inflammation and tissue destruction, by binding to toll-like receptor 4 (TLR4), which identifies foreign bodies in the human system.
One such foreign body that TLR4 identifies is “Lipopolysaccharide (LPS), which is on the surface of gram-negative bacteria. It is the major danger signal in cases of bacterial infections that lead to sepsis, because when bacteria die they release LPS which tells our immune to go into overdrive. Therefore, pathogenesis of LPS is dependant on LPS, thus LPS is a major causative agent of pushing this inflammation into overdrive,” said Nair.
Nair proved this hypothesis by modeling how resistin could fit into the pocket of TLR4 and provided experimental evidence that this modeling worked.
Nair’s hopes to further these findings in the future by testing resistin with human blood samples from septic patients and has already made such plans with the Riverside University Health System Medical Center.
