Sepsis, also known as widespread infection or septicemia, is a systemic inflammation caused by a localized infection that becomes uncontrollable.
The body’s immune response to the pathogen, which can be a bacteria, fungus, or even a virus like SARS-CoV-2, generates excessive levels of inflammatory molecules that harm the organism.
Severe sepsis can result in organ damage, low blood pressure, and, eventually, a type of abrupt circulatory failure called septic shock.
“Studies suggest survivors of sepsis face a sevenfold higher risk of developing severe infections than individuals who have never had the disease. They’re susceptible even to opportunistic pathogens that don’t usually cause disease in healthy people. We’re starting to understand why this happens,” said José Carlos Farias Alves Filho, Professor, University of São Paulo.
Professor Filho and his team used mice and immune cells taken from the blood of septic patients to study how this leads to immunosuppression. Daniele Carvalho Bernardo Nascimento carried out the research with the support of a postdoctoral fellowship from the So Paulo Research Foundation – FAPESP.
“Simply put, our findings show that sepsis induces the proliferation of a subpopulation of B lymphocytes that express large amounts of CD39, an enzyme that breaks down ATP [adenosine triphosphate, the main source of energy for cellular processes] to release adenosine into the bloodstream,” said the professor.
“The increased level of adenosine in the blood reduces the activity of macrophages, the defense cells that phagocytize bacteria, fungi and other potential threats to the organism.”
Previous studies had found that adenosine levels rise during the early stages of sepsis and that this has an immunosuppressive effect. Adenosine binds to the A2aR receptor on the surface of macrophages, causing the release of interleukin-10 (IL-10), an anti-inflammatory protein.
The study’s originality is that it shows that adenosine plays a major role in the establishment of post-sepsis immunosuppression and that one specific type of cell is the source of the extra adenosine seen in the blood of septic animals and people.
“All immune system cells express CD39 at varying levels, but we found that a subclass of B lymphocytes called plasmablasts produce large amounts of this enzyme,” Alves Filho added. “We saw plasmablasts proliferating strongly after sepsis, and undergoing metabolic reprogramming. They began to consume more glucose and hence to produce more ATP. At the same time, they expressed large amounts of the enzyme [CD39] responsible for hydrolyzing ATP and releasing adenosine. It’s as if soldiers could produce their own ammunition.”
To develop severe sepsis in mice, the researchers utilized a technique known as cecal ligation and puncture (CLP), which involves perforating the cecum (the beginning of the large intestine) to allow faecal debris and bacteria to enter the peritoneal cavity. The method mimics what happens in a suppurative appendicitis patient. Mice who survived sepsis were observed for 90 days and found to be extremely vulnerable to opportunistic infections throughout. The bacterium Legionella pneumophila killed all of the animals that were exposed to it. Only 20% of those exposed to the fungus Aspergillus fumigatus survived.
Adenosine is important for people who have had surgery to stop their bodies from fighting off infections afterwards. To prove this, they tried to block CD39 or the A2A adenosine receptor with drugs. The survival rate increased to 60% of those “treated” in this manner prior to exposure to opportunistic infections.
When the same experiment was conducted on mice that had been genetically engineered to not express CD39 or A2aR, the survival rate was 70%.
Blood samples from septic patients admitted to FMRP-general USP’s and teaching hospital (Hospital de Clnicas) revealed that the higher the quantity of adenosine in their blood, the higher the level of CD39-expressing plasmablasts.
Several further tests in mice were carried out in order to piece together the immunosuppressive process. In one test, healthy animals were given an infusion of plasmablasts obtained from septic animals, making them vulnerable to opportunistic infections.
Human cells were also used in a similar technique. Macrophages from healthy people were mixed with plasmablasts from septic patients and an opportunistic bacterium. Defense cells were unable to eliminate the bacteria due to the activity of adenosine.
The processes by which sepsis drives B cells that generate CD39 to proliferate are currently unknown. The researchers also intend to investigate if adenosine levels in the circulation of humans who survive severe sepsis remain elevated for an extended period of time, as they do in mice.
In a previous study, published in Nature Communications in 2017, the group led by Alves Filho demonstrated that sepsis stimulates the proliferation of another type of immunosuppressive cell known as regulatory T cells, or Tregs.
“We had already demonstrated that sepsis triggers an increase in Tregs that correlates with levels of IL-10. In this study, we show that the adenosine produced by plasmablasts is a mediator that leads to IL-10 production by macrophages in septic survivors. So these two studies connect: plasmablasts induce production of IL-10 by macrophages, which in turn can promote an increase in Tregs and make the patient even more immunosuppressed,” Nascimento added.
The discovery of this unique pathway should aid in the hunt for immunosuppressive-fighting therapies.
“We believe that if we succeed in inhibiting plasmablast growth, we can reduce immunosuppression and thereby increase the life expectancy of sepsis survivors,” Nascimento said.
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