The lungs of a recently deceased severe case of covid-19 they closely resemble a Roman colosseum right after a bloody combat. To realize this detail, which contains a possible therapeutic route against the coronavirus, the immunologist Ignacio Melero had to immerse himself on a microbiological scale in the samples taken from the first 12 autopsies obtained at the University of Navarra Clinic.
Autopsies were a thorny business in the early stages of the pandemic. On the one hand, there was its intrinsic value in understanding the processes that were happening inside the bodies that the virus led to death; on the other, all the legal complications derived from the consent of the relatives and the inherent risk of performing autopsies, which led the Spanish Society of Pathological Anatomy to advise against them until the safety of forensic pathologists could be guaranteed.
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With the de-escalation, they began to take place and thus, Melero and all the other detectives of that micrometric world were able to observe on the battlefield an unusual number of traps or nets, similar to the reciarians that the gladiators threw on their victims. These networks – in fact they are known as NET, network in English and an acronym for Neutrophil Extracellular Traps– are those used by leukocytes, a type of white blood cell, to deal with bacteria that threaten the body.
“It’s a very curious mechanism,” says Melero. “Neutrophils, when they are close to bacteria, are capable of dying by extruding the DNA from their nucleus as if it were a network, which traps the bacteria and does not let them move.” Upon exiting the interior of the white blood cell, the nets become coated with sticky plasma, which is also very toxic to pathogens. “We have found that the lung of the patient with severe covid has a huge amount of these ‘nets’, which are especially common, for example, in pus: pus is a collection of networks “. But not only for them, but also for tissues, where they are very intertwined. So, when the globules start unfortunately to remove networks of this type on the lungs of a seriously ill person with covid-19, that toxicity ends up affecting them.
But why does the organism do this to itself? Based on this evidence, Melero and his team began to investigate how exactly SARS-CoV-2 does it to provoke this fatal outcome. Recently, they have obtained a grant from the BBVA Foundation to continue with this line of research and try to turn it into new weapons for clinically cope with illness caused by the virus.
The first clue that the microscope offered of those organs obtained ‘postmortem’ was a exacerbated presence of macrophages. These are another type of defense, key to the body due to its ability to engulf pathogens. Somehow, there was a connection between their busy presence and the frenzy of neutrophils spewing out toxic webs of DNA.
“This inflammatory reaction is known to be behind the death of many patients by what we call adult respiratory distress (SARS) and this is precipitated by many types of diseases, such as bacterial sepsis or acute pancreatitis or the one in a fire and inhales toxic fumes, “explains Melero.
What is the relationship between both events? Is this misunderstanding between two of our types of defenses what causes the aggravation of patients who end up in the ICU?
Advanced microscopy put an even bigger magnifying glass on those macrophages to find out what kinds of messages they send to neutrophils. “What we are beginning to have is a very accurate picture of the mechanisms that cause tissue destruction and perpetuate and increase this inflammatory reaction“Says the immunologist.” Another thing we know is that some of the cytokines released by macrophages are among the best inducers of ‘nets’ in other cells. “
They are mechanisms that even these researchers do not fully understand, but that it is probably precipitating the virus itself.
Although these types of studies are classified as basic science, they end up having immediate applications. For example, a similar one at the University of Oxford ended up crystallizing in the use of corticosteroids such as dexamethasone in patients with severe covid-19.
Although these types of studies are classified as basic science, they end up having immediate applications
“We are focusing a lot on a cytokine called interleukin–8“explains Melero. Fortunately, scientists have developed (for other purposes) drugs capable of blocking this type of activation. But autopsies have revealed something else.” Since we have the preliminary data on netosis, there is an enzyme called PAD4 which is absolutely necessary for this release of the ‘nets’ to occur, which in principle occurs to defend ourselves against bacteria and fungi “.
Again, there are already PAD4 inhibitors that have been developed for other diseases and in which pharmaceutical companies like GSK or Bristol-Myers Squibb already work. The strategy, as you will see, is to short-circuit the signals that SARS-CoV-2 sends our immune police to provoke an exaggerated response, which ends up killing us.
The answers would never have been revealed to us were it not for the generosity of the patients who agreed to donate organ samples from their loved ones to science, something Melero insists on underlining. “They are very precise samples of tissue that have not been obtaining for different very complicated logistical reasons“, he admits,” but they are proving very valuable in trying to identify the weak points of the pathogens of this viral infection, and once discovered, identify which ones are actionable or interventible and try to direct therapeutic tools on them “.