Popularization of research advances on COVID-19

Website developed by 100pour100 MEDECINE

An “activation loop”: the modelling of inflammatory progression

Patients infected with SARS-CoV-2 may develop severe pneumonia, requiring respiratory support. Even though this condition affects only a minority of infected patients, it is the principal cause of death. Different clinical observations suggest that the inflammatory reaction caused by infection of the alveolar cells by SARS-CoV-2 may be different to that caused by other infectious agents.

Researchers in the medical faculty at Feinberg, USA, studied the inflammatory reaction linked to the appearance of pneumonia. They carried out 88 bronchoalveolar lavages of patients having had respiratory problems following SARS-CoV-2 infection and compared the results with 211 lavages carried out before and during the pandemic on patients having symptoms of pneumonia linked to other pathogens. They completed the study by comparing 42 lavages of intubated patients without pneumonia.

Analysis of these lavages showed that patients with pneumonia linked to SARS-CoV-2 had an increase in white blood cells, most notably in T CD4+, CD8+ lymphocytes as well as in monocytes in the alveoli.

Due to the ability of dendritic cells (specific monocytic cells) to interact with their micro-environment, the genes of these cells were analysed. In patients with SARS-CoV-2, there was a tendency towards an increase in the level of expression of genes involved in the reaction to interferon, a cytokine that plays a part in increasing inflammation. An increase in the level of expression of CCL7, CCL8 and CCL13 chemokines, involved in the recruitment of other immune cells to the site of infection, was also observed. This is known as chemotaxis.

By analysing lavages carried out 48 hours before intubation or at least 48 hours after intubation, COVID-19 patients were shown to have persistence of T-cells, key players in the defence against the virus. By examining the clinical data of patients in remission infected with SARS-CoV-2, it was also possible to show that after intubation there is a progressive decrease in interferon-dependent responses and viral gene expression. These results suggest therefore that once patients recover, adaptive immune responses decrease, returning to normal levels.

A more detailed study of each cell present in the bronchoalveolar lavages of 12 patients (10 COVID-19 patients with pneumonia, one patient with bacterial pneumonia and one control patient without pneumonia) in the 48 hours following their intubation showed overexpression of interferons produced by the T lymphocytes in COVID-19 patients. But more significantly an overexpression of the CCL2 chemokine within the macrophages present in the alveolar tissue was observed. These macrophages provide general lung monitoring. By a system of phagocytosis, they are capable of eliminating dead cells or pathogens by absorbing them. They can also liberate chemokines to be able to recruit other immune cells. Researchers were able to show that certain infected macrophages, those belonging to the TRAM2 sub-population, overexpress genes coding for chemokines and cytokines important in the T-lymphocytic response. However, non-infected TRAM1-type macrophages secrete normal levels of these same molecules.

This study provides a new hypothesis for the pathophysiology of slow-progression COVID-19 pneumonia:

  • The virus seems to infect the organism and initially replicate within nasopharynx epithelial cells, which express higher levels of the ACE2 receptor compared to lower respiratory epithelial cells.
  • By different mechanical movements, certain viruses may reach the pulmonary alveoli
  • The virus is thought to infect epithelial cells as well as macrophages (by absorption of epithelial cells that are themselves infected) present within tissues. Once they are infected, the macrophages will overexpress certain genes in order to facilitate inflammation and the migration of T lymphocytes towards the infection site.
  • Within the infected alveoli, the T-cells will then activate and produce IFNg, which in turn will activate the macrophages infected with SARS-CoV-2, giving them their TRAM2 phenotype, thus creating an activation loop.

This is what can be represented schematically as follows:

error: Content is protected !!