Sepsis is the leading cause of death of Brazil’s intensive care units (ICUs). Among patients progressing to the acute form of the disease, 40% die, and survivors often suffer from cardiovascular and neurological complications, as well as a significant decline in immunity that lasts for many years. after they were discharged from the hospital.
"Studies suggest that sepsis survivors face a seven times higher risk of developing a severe infection than individuals who have never had the disease. They are susceptible even to opportunistic pathogens that do not commonly cause disease in healthy people. We are beginning to understand why this happened. “
José Carlos Farias Alves Filho, Professor, University of São Paulo
Filho is the chief investigator for a study on the subject published in September 1st sa Immunity (LINK), a peer-reviewed medical journal issued by Cell Press.
Sepsis, also known as generalized infection or septicemia, is in fact a systemic inflammation that is often triggered by a localized infection out of control. The body’s immune response to the pathogen, which could be a bacterium, a fungus, or even a virus such as SARS-CoV-2, produces excessive amounts of inflammatory substances that damage the organism. More severe forms of sepsis can cause damage to vital organs, low blood pressure, and ultimately a form of severe circulatory failure known as septic shock.
To understand how this leads to immunosuppression, Alves Filho and his team conducted experiments on rats and immune cells isolated from the blood of septic patients. The investigation was conducted by Daniele Carvalho Bernardo Nascimento, along with a postdoctoral fellowship from the São Paulo Research Foundation – FAPESP. The researchers are affiliated with the Center for Research on Inflammatory Diseases, a Research, Innovation and Dissemination Center hosted by the Ribeirão Preto Medical School of the University of São Paulo (FMRP-USP).
“In other words, our findings showed that sepsis indicates 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, “Alves Filho said.” Increased levels 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 research has found that adenosine levels rise in the early stages of sepsis and it has an immunosuppressant effect. Adenosine binds to a receptor called A2aR on the surface of macrophages, which induces the production of interleukin-10 (IL-10), a molecule with anti-inflammatory action.
The novelty of this study is its demonstration that adenosine plays a major role in the development of post-sepsis immunosuppression and that a specific cell type is the source of additional adenosine found in the blood of septic animals. and people.
“All immune system cells express CD39 at different levels, but we found that a subclass of B lymphocytes called plasmablasts produces large amounts of this enzyme,” Alves Filho said. “We saw plasmablasts spread strongly after sepsis, and undergo metabolic reprogramming. They started to consume more glucose and therefore to produce more ATP. At the same time, they expressed a lot of enzyme[[[[CD39]responsible for hydrolyzing ATP and release of adenosine. It was as if soldiers could make their own ammunition. “
To induce severe sepsis in rats, the scientists used a model known as cecal ligation and puncture (CLP), which consists of a hole in the cecum (beginning of the large intestine) to allow the release of fecal material and bacteria into the peritoneal. cavity. The procedure mimics what happens in a patient with supurative appendicitis. Mice that survived sepsis were monitored for 90 days and found to be susceptible to opportunistic pathogens throughout the season. None of the animals were exposed to the bacteria Legionella pneumophila survived. Only 20% survived exposure to the fungus Aspergillus fumigatus.
To confirm the importance of adenosine in post-sepsis immunosuppression, they conducted experiments with drugs that inhibit CD39 or the A2A adenosine receptor. Survivors rise to 60% of those “treated” in this way before being exposed to opportunistic pathogens.
When the same experiment was performed on animals that were genetically modified to not express CD39 or A2aR, the survival rate was 70%.
Analysis of blood samples from septic patients admitted to general and designated hospitals by FMRP-USP (Hospital de Clínicas) that the worse their condition the higher the level of adenosine in their blood, and the higher the levels of plasmablasts expressing CD39.
Several other tests have been performed on rats to elucidate the step-by-step immunosuppression mechanism. In one experiment, healthy animals were given an infusion of plasmablasts isolated from septic animals, which were susceptible to opportunistic pathogens as a result.
A similar experiment was performed using human cells. Macrophages isolated from healthy subjects contained plasmablasts from septic patients and with opportunistic bacteria. Due to the action of adenosine, the defense cells are unable to kill the microorganism.
The mechanisms by which sepsis is caused by the proliferation of B lymphocytes that produce CD39 are still not understood. The researchers also plan to find out if the level of adenosine in the bloodstream of patients who survive severe sepsis will remain high in the long run, as they do in rats.
In a previous study, reported in an article published in Communications in Nature in 2017, a team led by Alves Filho showed that sepsis triggers the proliferation of another type of immunosuppressive cell known as regulating T cells or Tregs.
“We have already shown that sepsis triggers an increase in Tregs associated with IL-10 levels. In this study, we show that adenosine produced by plasmablasts is a mediator leading to IL-10 production. 10 of macrophages in septic survivors.So these two studies correlate: plasmablasts induce the production of IL-10 by macrophages, which may promote an increase in Tregs and make the patient more immunosuppressed, ”Nascimento said.
The identification of this novel mechanism should facilitate the search for interventions capable of combating immunosuppression. “We believe that if we succeed in curbing the growth of plasmablast, we can reduce immunosuppression and thus increase the life expectancy of sepsis survivors,” Nascimento said.
São Paulo Research Foundation
Birth, DC, et al. (2021) Sepsis expands a CD39+ plasmablast populations that promote immunosuppression through adenosine-mediated inhibition of macrophage antimicrobial activity. Immunity. doi.org/10.1016/j.immuni.2021.08.005.