Why do some COVID-19 patients experience more severe symptoms than others? This question has puzzled the scientific community for five years, when the pandemic caused by the Sars-CoV-2 virus was declared by the World Health Organization (WHO). Although the answer has yet to be fully defined, research led by the Oswaldo Cruz Institute (IOC/Fiocruz) and published in the scientific journal BMC Infectious Diseases presents yet another element in solving the enigma, opening the door to the development of new therapies and strategies for predicting serious cases of the disease.
By analyzing blood samples from patients hospitalized with COVID-19, the study found a correlation between the severity of the disease and the dysregulation of the renin-angiotensin-aldosterone system (RAAS) — a set of proteins, enzymes, and other mechanisms that regulate blood pressure and the body’s inflammatory response. Among other data, the analyses identified reduced expression of proteins that act as receptors of the RAAS system in elderly patients and those with comorbidities, such as diabetes and hypertension, who developed more severe cases of COVID-19, with a higher mortality rate.
The study was conducted by researchers from the AIDS and Molecular Immunology Laboratory and the Graduate Program in Tropical Medicine at IOC, in partnership with the Evandro Chagas National Institute of Infectious Diseases (INI/Fiocruz). According to the authors, the results expand the evidence on the central role of RAAS receptors in the evolution of COVID-19.
"We already knew that a receptor of the RAAS system was directly involved in SARS-CoV-2 infection. A protein from this group, called ACE2, participates in the virus' entry mechanism into cells. The pathogen binds to this receptor so as to invade and infect the body," comments biomedical researcher Thais Fernandes, a master's graduate from the Graduate Program in Tropical Medicine at IOC.
To understand the influence of the coronavirus on the renin-angiotensin-aldosterone axis, the team decided to expand the analysis to all receptors within this group. "In addition to the ACE2 protein, we had the idea of investigating the behavior of other receptors in the system during infection. We observed that several of them — such as MAS1 and ACE — showed reduced expression in the most severe patients. This means that the infection compromises the body's essential regulatory mechanisms, such as inflammation and vascular function, which aggravates the symptoms, both in the acute phase and in the long term," she adds.
Another highlight of the article is the finding that the RAAS system remains deregulated over a long period of time, which may help explain the symptoms of the so-called 'long COVID'.
"We expected the RAAS system to be regulated after 300 days, in the second stage of the samples, but it wasn't. The data indicates a persistence of the virus in the body due to the prolonged deregulation of the system," says Dalziza Victalina de Almeida, researcher at IOC's AIDS and Molecular Immunology Laboratory, who supervised the research.
Fewer recipients and greater risk
The study analyzed blood samples from 88 people hospitalized at the Evandro Chagas National Institute of Infectious Diseases (INI/Fiocruz), both during the acute phase of COVID-19 and around 300 days after the onset of symptoms. For comparison purposes, samples of 20 healthy individuals were also included in the studies.
The results show that the coronavirus infection alone has the capacity to reduce the presence of receptors of the RAAS system, especially in the acute phase. Further, the disease tends to be even more severe in patients who already have naturally reduced rates of these molecules, such as the elderly or those with comorbidities — such as diabetes and high blood pressure.
In these groups, receptors such as ACE2 and MAS1, which help control inflammation and blood vessel health, are in much lower numbers than normal, both in the acute phase and months after infection. Significant changes in the expression of microRNAs (miRNAs) — small molecules that regulate gene expression — were also identified in patients with severe symptoms, which reinforces the impact of the infection on the body's regulatory mechanisms.
The discovery helps to answer why elderly individuals and those with comorbidities are at greater risk of developing more severe COVID-19 symptoms. Based on the findings, the researchers suggest that receptors such as ACE2 and MAS1 could be key actors in new therapeutic strategies against the disease.
"Creating specific therapies to regulate the expression of miRNAs, and therefore RAAS receptors, could bring new insight into the treatment of COVID-19. This would allow for creating more targeted medications and interventions with less impact on other bodily functions, which may already be weakened due to the disease," concludes Thais.