Scientists have developed a new way to track, on the molecular level, how deadly sepsis develops. They’re hopeful the finding could save lives and reduce suffering.
Sepsis is one of the leading causes of hospital deaths—and can result in serious disabilities for those who survive. It begins with an infection but can rapidly result in organ failure and septic shock.
To treat sepsis, physicians need to respond quickly with antibiotics and other medications to fight inflammation and manage shock.
It’s very difficult to detect in its early stages, and until now little has been known about how it develops. That may explain why it’s been decades since researchers have developed a new effective drug to treat the condition.
Similar to cancer?
“Sepsis is generally thought of as one singular disease, especially as it enters late stages,” says Jamey Marth, professor of biochemistry and molecular biology at the University of California, Santa Barbara.
“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, the more quantitative method tracks the pathogen and host over time, beginning with infection, which generates a reproducible protocol allowing scientists to map host responses—in this case to five different human pathogens representing common strains and isolates from different patients.
“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.”
In the current study, researchers 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.
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, a senior scientist in the Marth laboratory at UCSB and Sanford Prebys Medical Discovery Institute, and lead author of the paper, which appears in Cell Host & Microbe.
“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,” Marth says. “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.”
The National Institutes of Health, the Heart, Lung, and Blood Institute, the Swedish Research Council, and the Wille Family Foundation funded the work.
Source: UC Santa Barbara