UCSB Biologists Trace Molecular Pathways of Sepsis

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UCSB Biologists Trace Molecular Pathways of Sepsis
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Source: University of California, Santa Barbara

A major cause of human disability and death throughout the world, sepsis is a condition that begins with an infection, progresses rapidly and can set off a chain of effects that result in multiple organ failure and irreparable damage to the body. Because of the condition’s rapid onset, physicians must respond immediately to the symptoms with broad-spectrum antibiotics for infection, drugs to combat inflammation and, in the more critical cases, vasopressors to manage shock.

Because sepsis is so difficult to detect in its early stages, however, little has been known about how it develops. This may explain why no new effective drugs to treat sepsis have been developed in decades, while it remains one of the leading causes of hospital deaths. Sepsis also can result in serious disabilities for those who survive.

Now, researchers at UC Santa Barbara, Sanford Prebys Medical Discovery Institute (SBP) in La Jolla, California, and UC San Diego have developed a method for tracking, on a molecular level, the development of sepsis. Their resulting discoveries could, in turn, lead to more advanced therapies for sepsis that reduce its mortality, minimize the lifelong 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 paper, “Accelerated Aging and Clearance of Host Anti-inflammatory Enzymes by Discrete Pathogens Fuels Sepsis” is published in the journal Cell Host & Microbe.

“Sepsis is generally thought of as one singular disease, especially as it enters late stages,” said UC Santa Barbara biology professor Jamey Marth, who is 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.”

An improved sepsis model yields important findings 
In contrast to previous experimental models of sepsis, which typically release multiple and incompletely identified pathogens into the bloodstream, 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, 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,” said Won Ho Yang, Ph.D., lead author and a senior scientist in the Marth 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,” said Marth, who is the Carbon Professor of Biochemistry and Molecular Biology at UC Santa Barbara, as well as the Mellichamp Chair of Systems Biology. “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.” 

Research on this project was also conducted by Douglas M. Heithoff, Peter V. Aziz, Benjamin Haslund-Gourley and Michael J. Mahan, SBP and UC Santa Barbara; Julia S. Westman, Sonoko Narisawa, Anthony B. Pinkerton and José Luis Millán, SBP; and Victor Nizet, M.D., UC San Diego. 

Research reported in this press release was supported by National Institutes of Health (NIH) Heart, Lung, and Blood Institute (HLBI) grants HL125352 and HL131474. Additional support was provided by the Swedish Research Council 2017-00192 and the Wille Family Foundation.

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a-1542363339 Oct 15, 2018 04:57 PM
UCSB Biologists Trace Molecular Pathways of Sepsis

So scary. I hear about sepsis and MRSA more and more lately. I had a cyst removed, it was seriously infected and they did actually test for staph and MRSA. I don't remember them doing that before, so I'm not sure if that is always standard or if they test now out of precaution. Very scary.

Bndtech Oct 16, 2018 06:24 AM
UCSB Biologists Trace Molecular Pathways of Sepsis

Your part is being very observant when you are in a care facility; the biggest problem is training to those new to health care. I have been to many different facilities even Dental are not immune. My observations were always the same, the persons caring for you do not know when to change their gloves after handling medical equipment, bandages and you; then, turn and handle computers, lighting equipment, tables etc. without changing the gloves. You have to ask, did you change your gloves after handling the computer? As for prior to going to the hospital, you just have to be careful and wash your hands or use the most common prevention everywhere you go - clear antiseptic lotion. That's what I do now, I have that stuff everywhere I go. Other than that, I am sorry to say, you just can not prevent getting Sepsis, MRSA, Staph infections because it is EVERYWHERE! You just need to keep your Immune System healthy. God Bless hope this helps.

a-1542363339 Oct 15, 2018 09:16 AM
UCSB Biologists Trace Molecular Pathways of Sepsis

Sepsis being the outcome is horrific. Even in this study, it appears they're trying to unfold all the levels and specifics, so we can better see that this is not one disease, but instead a cascading event of situations not yet understood. Sepsis as an outcome is locked away in hospitals across the country. Death in this category is nothing more than a lump sum negative that's kept private and not tracked on a shared on a national scale. Unfortunately, it'd not be accurate to assume that death with sepsis is always death by sepsis. I think on the majority, most people are actually suffering from and thus dying from other runaway diseases. But it cannot be ignored that there is a large portion of people who are not dying from their disease, but instead, end up getting sepsis and then die from sepsis. And thus we know, hospitals know, that better practices and procedures can be employed. We can work to better understand underlying precursors and how they set the stage. We can ask that healthcare be much more transparent. We can stop using death by sepsis as a catch-all category that collects as some type of "other" event. The stories written here about those that have survived are miraculous. These are the percentage of few who lived through it. Sadly, a huge majority do not.

a-1542363339 Oct 15, 2018 07:18 AM
UCSB Biologists Trace Molecular Pathways of Sepsis

Holy cow. I'm scared. How many people have died from sepsis complications at Cottage in S.B & Goleta in the last 5 years? Anyone know? How many infections? Is it worse here than other hospitals?

Bndtech Oct 15, 2018 07:08 AM
UCSB Biologists Trace Molecular Pathways of Sepsis

I never expected to get Sepsis, but it happened to me after a simple Outpatient Back Operation Jan 2015, 5 days later, I would suffer a major Bilateral Pulmonary Embolism (massive clots in both lungs). I went to Cottage with all the heart attack symptoms so they put me in the Catheter room to install a Catheter in my Right Femoral Artery. Well, somehow a Technician dysected and shredded my Artery with the Catheter; this was unfortunate for me and after 24 hours of ICU/Surgery/Recovery, I was sent to a Nursing Care Center in Goleta so my surgery points to repair the Artery was cared for. 8 days of wound care at the Nursing Care, then 5 days home care with Visiting Nurses, I one Nurse said my leg was hot and I should go back to Cottage. GREAT! Back in Cottage still Jan 2015; at first they thought I had a DVT in my right leg, opened it up and it was 300cc of Sepsis with further tests of MRSA. I was shutting down internally and eventually ended up on Life Support. I don't remember much other than what my Girlfriend, Diane told me; she said that at the end, 2 Clergy walked into the room with the Doctors saying that there was nothing more they could do while she held my hand, she said let him fight because she knew me. I had remembered a strange feeling of peace while laying on a gurney covered in a white sheet up to my head, I remember that I was pointed to a window of light and it appeared that I was floating out that window. I had no pain and was very good with my life and felt I could let go, but, then I awoke and I spent the rest of Feb 2015 in Cottage, 10 surgeries and pain you could never imagine, nearly losing my Right Leg / lots of Vinco cocktails via picc line. I am alive thanks to Dr Lee, Dr Belkin, Dr Suger, all the ICU Staff and all the ER Surgeons that kept me alive. I am most grateful of my Girlfriend who stood by my side everyday and even worked from my room. BUT, Sepsis was NOT done with me yet, Jan 2018; exactly 3 years from the last incident; I was exercising in the pool, got out, showered and went home. I then broke out into a chill down to the bone; my respiration increased to 120 and my BP was over 140. Confused and in bed with my clothes on and 3 blankets shivering I called Diane and said I needed to get to Cottage. Dr Sugar was back, along with Dr Lee and Dr Belkin; Dr Sugar found that I was Strep/Sepsis in the right leg again. But, I had no reasons, no cuts, nothing except maybe a dermatitis infection; 7 days of antibiotics via picc line in the hospital, 7 days at home antibiotics via picc line. I recovered, thanks to the quick response from Cottage Staff, because they knew my history. So yes, once you get Sepsis, your susceptible to get it again; this is why I am exercising 5x a week to stay healthy, eating healthy to and keeping mentally fit. MW

BullseyeB Oct 14, 2018 02:50 PM
UCSB Biologists Trace Molecular Pathways of Sepsis

LarryQ and BeBe, I am so glad that you were both able to recover from your experiences. I have also had sepsis in 2012, 2015 and in 2016. My bout with it in 2015 was very scary. I spent three months at Cottage Hospital that time. My systems were shutting down, had to have breathing treatments, Picc line and several rounds of antibiotics before finding the right coctail of med's that worked. The thing that I never knew until last year was that once you have had sepsis, you apparently are more susceptible to getting it again. This shocked me. Not to mention all the lovely side effects from such aggressive antibiotic therapy such as c-diff! That was NOT a lovely situation! Now I have to be careful about that too! I too am grateful the doctors stayed on top of it and treated it aggressively in spite of the side effects. I am glad to hear of this study and the progress they are making in figuring out how to combat this serious condition.

larryq Oct 14, 2018 12:58 PM
UCSB Biologists Trace Molecular Pathways of Sepsis

I had it in Dec. age 57. When I checked into cottage I was dx'ed as death pending . They notified my family they have made me comfortable ( paralyzed with Fentanyl ) and I had maybe a couple hours. My family came (I was knocked out cold ) and after they left I was wheeled to the hall out side the morgue where I became fully conscious and confused. I could hear voices and some said is he ready yet and some guy flashed a pen light in my eyes and replied not yet. Now it all came back I tried to say something nothing came out tried to spit at them , scream, blink my eye lids, sit up . Nothing . Not knowing at the time paralytic drugs had been used I settled into the idea that I Was already deceased and still totally conscious , real mind trip. Back upstairs upon final review an astute Radiologist found the cause of the Sepsis. It was a small perforation on the posterior (back side ) of my Duodenum . I don't remember when but I was plucked out certain death and my family says they called for surgical consent and only gave me a 2% chance of survival. The fact I survived is very unusual . They made me a case study of my recovery for the journals .. At the time I thought they were conducting medical experiments and trying to kill me. Fun delusions... sorry for your brother.

a-1542363339 Oct 14, 2018 10:59 AM
UCSB Biologists Trace Molecular Pathways of Sepsis

My brother died of sepsis at age 59. Granted, he had some other health issues and had an untended infection when he went to the hospital. I had never heard of sepsis. Since his death, I see sepsis over and over again as a cause of death. Hope they make some headway understanding how this condition can ravage one's body so quickly.

therealbebe Oct 14, 2018 11:30 AM
UCSB Biologists Trace Molecular Pathways of Sepsis

I'm sorry for your loss. My grandmother and a close friend both died of sepsis as well. It moves quickly. I was "borderline" septic from pneumonia a few years back, and they spent several hours trying to stabilize my blood pressure and fever in the ER. Very scary. I genuinely thought that my then-toddler would be growing up without a mom. Grateful the doctors stayed on top of it and treated it aggressively. It was close.

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