Nav: Home

A mechanism that makes infants more likely than adults to die from sepsis is discovered

July 03, 2019

An immune mechanism that makes babies more likely than adults to die from sepsis has been identified by scientists affiliated with the Center for Research on Inflammatory Diseases (CRID in Ribeirão Preto, São Paulo State (Brazil). The study is published) in Critical Care.

The scientists are planning to test new therapeutic approaches based on the discovery. "We're designing a clinical trial with drugs that have been approved for human use and are known to induce this immune mechanism.The goal is to improve the survival rate for infants with sepsis," said Fernando de Queiroz Cunha, CRID's principal investigator. CRID is one of the Research, Innovation and Dissemination Centers (RIDCs funded by São Paulo Research Foundation - FAPESP.

Sepsis (sometimes referred to as blood poisoning) is systemic inflammation usually triggered by a localized bacterial infection that spins out of control. The body's immune response to combat the pathogen ends up damaging multiple organs and tissues.

Symptoms include fever or low temperature, difficulty breathing, low blood pressure, a fast heart rate, and an abnormally high or low white blood cell count. The condition may remain active even after the initial threat has been eliminated. Its most severe form can lead to lesions that impair the function of vital organs, septic shock and death.

"In any experimental animal model of sepsis, all the parameters used to measure the severity of the condition are higher in infants. There's more systemic inflammatory response, more organ impairment, and higher mortality," said Cunha, who is a Full Professor in the Department of Pharmacology at the University of São Paulo's Ribeirão Preto Medical School (FMRP-USP).

In humans, it is more difficult to compare infant and adult mortality rates, he explained, because, before contracting sepsis, the adult patient may have been weakened by diseases such as diabetes, cancer, heart failure or hypertension (high blood pressure). "Most adults who die as a result of septic shock already had serious health problems," Cunha told.

Given their knowledge that organ injury is more severe in young individuals, both human and murine, the group decided to determine exactly what substances are produced by the immune system during sepsis. Their hypothesis was that defense cells in infants must produce more oxidizing substances, such as oxygen and nitrogen free radicals. What they found, however, was the opposite.

"We took a long time to understand why infants have more tissue injury if they produce smaller amounts of free radicals. Finally, we decided to investigate NETs [neutrophil extracellular traps]," Cunha said.

Neutrophils are white blood cells that form the front line of the immune system, phagocytosing (killing) bacteria, fungi and viruses. NETs are structures composed of DNA and granular proteins that rapidly trap and kill pathogens.

"This immune mechanism was first described about ten years ago. In some situations, for poorly understood reasons, the immune system activates an enzyme called PAD-4, which increases the permeability of the neutrophil nucleus. When this happens, the genetic material in the nucleus decondenses and forms networks, which are released by the cell into the extracellular medium to trap and kill bacteria," Cunha said.

NETs are typically activated by bacterial infections, he added, as well as some viruses, including chikungunya, the arbovirus that causes the most tissue injury. The mechanism also occurs in some autoimmune disorders. "The main problem is that NETs aren't just toxic for pathogens: they also damage human cells. In fact, they do more damage than oxygen and nitrogen free radicals."

Tests involving pediatric patients were conducted in collaboration with a research group led by Professor Ana Paula Carlotti, attached to the ICU at FMRP-USP's teaching and general hospital (Hospital das Clínicas). Laboratory analysis showed that neutrophils from infants produced 40% more NETs than those taken from adults, in the case of humans. The difference was 60% in mice. The group then set out to use experimental models to understand how this immune mechanism works in sepsis.

Traps deactivated

The experiments with mice involved a group of two-week-old infants and a group of healthy young adults. Both received an intraperitoneal injection of intestinal bacteria and developed sepsis.

"A dose of bacteria sufficient to kill 100% of infants killed only 50% of the adults. That's a significant difference. Moreover, in the days following the injection, the infant mice displayed higher levels of bacteremia [bacteria in the bloodstream] and of biochemical markers indicating organ injury," Cunha said.

When NETs were broken down with recombinant human DNase (a drug used to treat cystic fibrosis), the survival rate jumped from 0 to 50% in the infant group. In the adult group, the proportion of mice that survived sepsis rose from 50% to 60%.

"The difference between the groups when treated with DNase was small, clearly showing that greater infant susceptibility is associated with higher levels of NETs," Cunha said.

In another experiment, the group replaced DNase with a compound designed to inhibit PAD-4, the enzyme that triggers the activation of NETs. In this case, the survival rate for the infant group was 40%.

"It was somewhat less effective than DNase because it's not actually a specific PAD-4 inhibitor. One of our goals for future research is the development of a specific drug to inhibit PAD-4," Cunha said.

The group analyzed the expression of the PAD-4 gene, which encodes the PAD-4 enzyme, in neutrophils from patients and from mice. In both cases, PAD-4 expression was higher in infants with sepsis than in adults with the same condition. The reasons are unknown and are currently being sought by David Fernando Colón Morelo, the first author of the article. Cunha is Morelo's PhD supervisor.

Morelo has a doctoral scholarship from FAPESP and is now doing a research internship at Bonn University in Germany.

"We're also studying the role of NETs in other diseases involving organ injury, such as rheumatoid arthritis and lupus," Cunha said.
-end-
About São Paulo Research Foundation (FAPESP)

The São Paulo Research Foundation (FAPESP) is a public institution with the mission of supporting scientific research in all fields of knowledge by awarding scholarships, fellowships and grants to investigators linked with higher education and research institutions in the State of São Paulo, Brazil. FAPESP is aware that the very best research can only be done by working with the best researchers internationally. Therefore, it has established partnerships with funding agencies, higher education, private companies, and research organizations in other countries known for the quality of their research and has been encouraging scientists funded by its grants to further develop their international collaboration. You can learn more about FAPESP at http://www.fapesp.br/en and visit FAPESP news agency at http://www.agencia.fapesp.br/en to keep updated with the latest scientific breakthroughs FAPESP helps achieve through its many programs, awards and research centers. You may also subscribe to FAPESP news agency at http://agencia.fapesp.br/subscribe.

Fundação de Amparo à Pesquisa do Estado de São Paulo

Related Immune System Articles:

The immune system may explain skepticism towards immigrants
There is a strong correlation between our fear of infection and our skepticism towards immigrants.
New insights on how pathogens escape the immune system
The bacterium Salmonella enterica causes gastroenteritis in humans and is one of the leading causes of food-borne infectious diseases.
Understanding how HIV evades the immune system
Monash University (Australia) and Cardiff University (UK) researchers have come a step further in understanding how the human immunodeficiency virus (HIV) evades the immune system.
Carbs during workouts help immune system recovery
Eating carbohydrates during intense exercise helps to minimise exercise-induced immune disturbances and can aid the body's recovery, QUT research has found.
A new model for activation of the immune system
By studying a large protein (the C1 protein) with X-rays and electron microscopy, researchers from Aarhus University in Denmark have established a new model for how an important part of the innate immune system is activated.
More Immune System News and Immune System Current Events

Best Science Podcasts 2019

We have hand picked the best science podcasts for 2019. Sit back and enjoy new science podcasts updated daily from your favorite science news services and scientists.
Now Playing: TED Radio Hour

Anthropomorphic
Do animals grieve? Do they have language or consciousness? For a long time, scientists resisted the urge to look for human qualities in animals. This hour, TED speakers explore how that is changing. Guests include biological anthropologist Barbara King, dolphin researcher Denise Herzing, primatologist Frans de Waal, and ecologist Carl Safina.
Now Playing: Science for the People

#534 Bacteria are Coming for Your OJ
What makes breakfast, breakfast? Well, according to every movie and TV show we've ever seen, a big glass of orange juice is basically required. But our morning grapefruit might be in danger. Why? Citrus greening, a bacteria carried by a bug, has infected 90% of the citrus groves in Florida. It's coming for your OJ. We'll talk with University of Maryland plant virologist Anne Simon about ways to stop the citrus killer, and with science writer and journalist Maryn McKenna about why throwing antibiotics at the problem is probably not the solution. Related links: A Review of the Citrus Greening...