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New hope for sepsis treatment
SAN DIEGO—Generally when the body is faced with an infection, the immune system steps up to eradicate it, sending immune cells to destroy the invading bacteria. In the case of sepsis, however, the immune system floods the body with too severe of a response, leading to widespread inflammation—which can then progress to septic shock and death.
At present, the standard of care consists of antibiotic regimens, but as antibiotic-resistant bacteria become more prevalent, treatment becomes more difficult. But a new target might be available: PHLPP1. When researchers from the University of California (UC) San Diego School of Medicine removed the enzyme in a mouse model of sepsis, they found that the mice experienced better outcomes. Their results appeared in eLife in a paper titled “PHLPP1 counter-regulates STAT1-mediated inflammatory signaling.”
“Severe sepsis strikes more than a million Americans every year, and 15 to 30 percent of those people die. The number of sepsis cases per year is increasing the U.S., because the average age of the population is on the rise and people with chronic diseases are living longer,” says Dr. Victor Nizet, an expert on bacterial infections and one of the UC San Diego School of Medicine researchers involved with this work. “Sepsis is more common and more dangerous in the elderly and in those with chronic diseases. Sepsis accounts for approximately for $25 billion in healthcare expenditures annually. There is currently no drug approved for sepsis beyond antibiotics and supportive care in the ICU. Antibiotic-resistant infections can lead to sepsis, and the ever-expanding antibiotic resistance crisis is worsening the situation. Identifying specific sepsis treatment or prevention strategies is therefore a critical public health priority.”
“Discoveries like ours of fundamental signaling pathways that control immune cell behavior during sepsis offer clues for controlling the dangerous inflammation of sepsis while preserving the critical bacterial killing properties of white blood cells,” he added.
PHLPP1 (PH domain Leucine-rich repeat Protein Phosphatase 1) controls certain cell behaviors by removing small chemical tags known as phosphates from other proteins. The enzyme plays a role in several biological processes, such as immune response and tumor suppression, and the authors note that “PHLPP1 inhibition could be a strategy to promote cartilage regeneration and repair” as well.
One specific way in which PHLPP1 impacts inflammation is by removing phosphates from the STAT1 transcription factor, which controls inflammatory genes.
“Most research on inflammation has typically focused on kinases, enzymes that add phosphate tags to other proteins,” said Dr. Alexandra Newton, a professor in the Department of Pharmacology at the UC San Diego School of Medicine and senior author of the eLife paper. “It’s exciting to have a completely new target for sepsis—the enzymes that remove them.”
This is hardly the first time Newton’s team has worked with PHLPP1, as they were the ones to discover it a few years ago. So far, their work with the enzyme has focused on its role in tumor suppression. For this work in inflammation, they worked together with Dr. Chris Glass and his team, also of UC San Diego School of Medicine, as well as Nizet.
Newton’s team provided Nizet with genetically modified mice that lacked the PHLPP1 gene, to which Nizet and his team introduced live E. coli bacteria and lipopolysaccharide (LPS), a component of the bacterium’s cell wall that triggers the immune system. What they found was that compared to normal mice, those lacking PHLPP1 saw much better survival outcomes—all normal mice died of infection-induced sepsis after five days, but at that point half of the PHLPP1-deficient mice were still alive.
“This is the first evidence that we have that PHLPP1 is associated with sepsis. We originally discovered PHLPP1 when looking for a phosphatase to dephosphorylate and inactivate the proto oncogene, Akt. So for the first few years after its discovery, we focused on its role in terminating the signaling by Akt, and its role as a tumor suppressor,” Newton tells DDNews.
“But then we asked the question: what else does PHLPP1 do? For this, we looked at all the genes turned up or down when PHLPP1 is absent, and found that many of these were involved in inflammation,” she continues. “We took two approaches: a biochemical one, which revealed that PHLPP1 acts as the brakes to suppress inflammatory responses in macrophages, and then we looked at the physiology and asked, what happens if you challenge mice with E. coli infection? That’s when we saw the dramatic protection from sepsis-induced death in mice lacking PHLPP1, indicating PHLPP1 may be a potential therapeutic target for sepsis. We still do not know the mechanism behind this, as the biochemistry dealt with one very specific cell type, macrophages, and in the mouse, every type of cell was missing PHLPP1, so many mechanisms could be at play.”
Moving forward, Newton says there is plenty of other work to be done to further explore their findings. She explains that they want to make tissue-specific knock-out models of PHLPP1—ones in which the enzyme is only deleted in macrophages—so that they can “understand the primary mechanism driving its role sepsis, thus bringing us closer to targeting it therapeutically.” They also want to determine how a lack of PHLPP1 offers protection against sepsis.
“We would want to specifically target that cell type/mechanism and not interfere with other functions, such as its role as a tumor suppressor,” she notes. “This is possible, but only once we understand the biology at the molecular level. For example, the role of PHLPP1 in suppressing inflammation in macrophages depends on its ability to get into the nucleus, so this ability could be crippled with no effect on its tumor suppressive function of Akt, which depends on other properties of PHLPP1.”
Along with other collaborators, Newton and her team have screened thousands of compounds to identify ones capable of inhibiting PHLPP1, which they plan to test in lab and animal models of sepsis.