Scientists at the University of California Santa Barbara (UCSB), Sanford Prebys Medical Discovery Institute (SBP), and UC San Diego say they have developed a method for tracking the development of sepsis on a molecular basis. They believe their discoveries could, in turn, lead to more advanced therapies for sepsis that reduce its mortality, minimize the life-long effects for survivors or even prevent the cascade of life-threatening effects before it begins, while reducing the billions of dollars spent every year to treat the condition.
Their study (“Accelerated Aging and Clearance of Host Anti-inflammatory by Discrete Pathogens Fuels Sepsis”) is published in Cell Host & Microbe.
“Sepsis is a life-threatening inflammatory syndrome accompanying a bloodstream infection. Frequently secondary to pathogenic bacterial infections, sepsis remains difficult to treat as a singular disease mechanism. We compared the pathogenesis of murine sepsis experimentally elicited by five bacterial pathogens and report similarities among host responses to Gram-negative Salmonella and E. coli. We observed that a host protective mechanism involving detoxification of lipopolysaccharide by circulating alkaline phosphatase (AP) isozymes was incapacitated during sepsis caused by Salmonella or E. coli through activation of host Toll-like receptor 4, which triggered Neu1 and Neu3 neuraminidase induction,” write the investigators.
“Elevated neuraminidase activity accelerated the molecular aging and clearance of AP isozymes, thereby intensifying disease. Mice deficient in the sialyltransferase ST3Gal6 displayed increased disease severity, while deficiency of the endocytic lectin hepatic Ashwell-Morell receptor was protective. AP augmentation or neuraminidase inhibition diminished inflammation and promoted host survival. This study illuminates distinct routes of sepsis pathogenesis, which may inform therapeutic development.”
“Sepsis is generally thought of as one singular disease, especially as it enters late stages,” says Jamey Marth, Ph.D., the Carbon Professor of biochemistry and molecular biology at UCSB, as well as the Mellichamp Chair of systems biology and the director of the campus's Center for Nanomedicine, in addition to being a professor at SBP. “At this point, inflammation and coagulopathy have caused the vascular and organ damage common to severe sepsis and septic shock. Our comparative approach to monitor the onset and progression of sepsis at the molecular level supports the view that there are different molecular pathways in sepsis depending on host responses to different pathogens.”
In contrast to previous experimental models of sepsis, which typically release multiple and incompletely identified pathogens into the bloodstream, Dr. Marth and his team developed a more quantitative method that tracked the pathogen and host over time, beginning with infection. This method generated a reproducible protocol that allowed the scientists to map host responses, in this case to five different human pathogens representing common strains and isolates from different patients.
In the study, Dr. Marth's team found that in the onset and progression of sepsis caused by Salmonella or E. coli, a protective mechanism normally present in the host was disabled. The mechanism that the bacteria used included a means to accelerate the molecular aging and clearance of two anti-inflammatory alkaline phosphatase (AP) enzymes, called TNAP and IAP, which are normally present in the host bloodstream. This was achieved through pathogen activation of the host's own Toll-like receptor-4 (TLR-4), and both pathogens were thus able to induce inflammatory compounds and reduce the likelihood of host survival.
The scientists found that boosting the level of protective anti-inflammatory AP activity or using neuraminidase inhibitors to block the downstream effect of TLR-4 activation on NEU1 and NEU3 induction were both highly therapeutic approaches as inflammatory markers were reduced and host survival increased, indicating a potential direction for drug development.
“It has been known that AP isozymes can reduce inflammation in the context of some diseases and pathogens. Indeed, AP is currently in clinical trials focused on inflammatory diseases, including colitis and sepsis,” says Won Ho Yang, Ph.D., lead author and a senior scientist in Dr. Marth's laboratory at both UCSB and SBP. “This study shows that the pathogen is interacting with the host to disable a protective response. The findings also demonstrate how both pathogen and host battle each other by altering the rates of protein aging and clearance, which itself is a newly discovered regulatory mechanism we recently reported that controls the half-lives of proteins in the blood.”
In contrast, these responses weren't seen in infections caused by other bacteria tested, including methicillin-resistant Staphylococcus aureus (MRSA) and Streptococcus pneumoniae. The different host responses, in this case, appeared divided between Gram-positive and Gram-negative bacteria, which describes the existence or absence of an inflammatory compound found on Gram-negative strains.
“We are continuing to map and compare host responses to different pathogens in sepsis, using state-of-the-art technical approaches, and hope to ultimately stratify the disease,” says Dr. Marth. “It's possible that sepsis is similar to cancer, in that we now know that cancer is a not a single disease but represents hundreds of diseases at the molecular level.”