Path to deadly sepsis varies by bacterial infection

October 10, 2018, Sanford Burnham Prebys Medical Discovery Institute
Credit: CC0 Public Domain

Sepsis remains a common and deadly condition that occurs when the body reacts to an infection in the bloodstream. Scientists know little about the early stages of the condition; however, physicians must act fast. Every hour that passes without one or more of the few treatments available increases the risk of death.

Now, researchers from Sanford Burnham Prebys Medical Discovery Institute (SBP) and UC Santa Barbara, in collaboration with scientists at UC San Diego, have discovered that host responses during progression can vary in important ways based on pathogen type. Understanding these responses may hold the key to developing more effective treatments. The study published today in Cell Host and Microbe.

Sepsis remains a major cause of human disability and death throughout the world. One-third of hospital deaths are due to sepsis, according to the Centers for Disease Control and Prevention (CDC), while on average, 25 percent of sepsis patients die. Often, sepsis survivors still battle serious conditions such as chronic pain, organ dysfunction or amputations.

Physicians currently diagnose sepsis based on a checklist of signs and symptoms. Pathogen identification occurs days later, if at all, following patient fluid cultures. Because of the need to act quickly, treatment for sepsis begins with broad-spectrum antibiotics and may proceed to anti-inflammatory drugs, and in some cases, vasopressors. No new, effective drugs that treat sepsis have been developed in decades.

"Sepsis is generally thought of as one singular disease, especially when viewing it clinically as it enters late stages. At this point, inflammation and coagulopathy have caused vascular and organ damage common to and septic shock," says Jamey Marth, Ph.D., senior author of the paper, professor at SBP's NCI-designated Cancer Center and professor and director of UC Santa Barbara's Center for Nanomedicine. "Our comparative approach to experimentally monitor the onset and progression of sepsis at the molecular level supports the view that there are different molecular pathways in the pathogenesis of sepsis depending on host responses to different microbes."

An improved sepsis model yields important findings

In contrast to other experimental models of sepsis, which release incompletely identified and quantified into the bloodstream, Marth and his team developed a more precise method that tracked pathogens over time. This method generated a reproducible protocol to follow sepsis onset and progression. The scientists then mapped host responses to five different human pathogens representing common strains and isolates from different patients.

In the study, the scientists found that in the onset and progression of sepsis caused by Salmonella or E. coli a protective mechanism normally present in the host was disrupted. These bacterial pathogens accelerated 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 activation of the host's own Toll-like receptor-4 (TLR-4), and both pathogens were thus able to activate inflammatory compounds and reduce the likelihood of host survival.

The scientists found that boosting the level of these protective anti-inflammatory enzymes 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 the Marth laboratory. "This study shows that the pathogen is interacting with the host to disable the protective role of AP activity by a previously unknown regulatory pathway. The findings demonstrate how both pathogen and host battle each other by altering the rate of protein aging and clearance—which itself is a newly discovered mechanism we recently reported that controls the half-lives and abundance of proteins in the blood."

In contrast, these host responses weren't seen in infections caused by other bacterial pathogens 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 responses to pathogens in sepsis, using state-of-the-art technical approaches, and hope to ultimately stratify the disease. 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," says Marth. "In the meantime, our findings indicate that AP augmentation could be a valuable first-line therapeutic defense against various Gram-negative infections, which have been escalating among cases of sepsis in the human population."

Explore further: Method identified to reduce risk of brain damage in leukemia survivors

More information: Cell Host and Microbe (2018). DOI: 10.1016/j.chom.2018.09.011 ,

Related Stories

Method identified to reduce risk of brain damage in leukemia survivors

September 25, 2018
Children with acute lymphoblastic leukemia (ALL) are at an extremely high risk of sepsis compared to the general population. In the first-published study of its kind, St. Jude Children's Research Hospital scientists have ...

Putting the brakes on sepsis

May 10, 2018
Sepsis—an extreme response to infection—can cause damage to multiple organ systems when it triggers an uncontrolled inflammatory response.

New method to increase survival in sepsis discovered

November 25, 2013
Sepsis, the body's response to severe infections, kills more people than breast cancer, prostate cancer and HIV/AIDS combined. On average, 30 percent of those diagnosed with sepsis die.

Gut microbes protect against sepsis—mouse study

February 22, 2018
Sepsis occurs when the body's response to the spread of bacteria or toxins to the bloodstream damages tissues and organs. The fight against sepsis could get a helping hand from a surprising source: gut bacteria. Researchers ...

New test to rapidly diagnose sepsis

May 17, 2017
Researchers have developed a test that can rapidly and reliably diagnose sepsis, a potentially life-threatening complication of bacterial infections.

'Bad' antibodies let blood infections rage

June 28, 2018
Certain antibodies in a patient's blood stream may enable life-threatening bacterial infections to spread instead of fighting them off, a University of Queensland study has found.

Recommended for you

Taking the virus out of a mosquito's bite

December 12, 2018
They approach with the telltale sign—a high-pitched whine. It's a warning that you are a mosquito's next meal. But that mosquito might carry a virus, and now the virus is in you. Now, with the help of state-of-the-art technology, ...

Study identifies a key cellular mechanism that triggers pneumonia in humans

December 11, 2018
The relationship between influenza and pneumonia has long been observed by health workers. Its genetic and cellular mechanisms have now been investigated in depth by scientists in a study involving volunteers and conducted ...

Human antibody discovery could save lives from fungal killer

December 11, 2018
A new way to diagnose, treat and protect against stealth fungal infections that claim more than 1.5 million lives per year worldwide has been moved a step closer, according to research published in Nature Communications.

Effect of oral alfacalcidol on clinical outcomes in patients without secondary hyperparathyroidism

December 11, 2018
Treatment with active vitamin D did not decrease cardiovascular events in kidney patients undergoing hemodialysis, according to a research group in Japan. They have reported their research results in the December 11 issue ...

Dialysis patients at risk of progressive brain injury

December 10, 2018
Kidney dialysis can cause short-term 'cerebral stunning' and may be associated with progressive brain injury in those who receive the treatment for many years. For many patients with kidney failure awaiting a kidney transplant ...

Silicosis is on the rise, but is there a therapeutic target?

December 6, 2018
Researchers from the CNRS, the University of Orléans, and the company Artimmune, in collaboration with Turkish clinicians from Atatürk University, have identified a key mechanism of lung inflammation induced by silica exposure, ...


Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.