Study Finds COVID-19 may Cause Severe Alterations in Immune System, Even in Mild Cases: Unesp Research

FAPESP/DICYT AGENCY – Preliminary data from a study carried out at the Paulista State University (Unesp), in Brazil, suggest that the infection caused by SARS-CoV-2 can cause severe alterations in the immune system even in young and healthy people with mild or moderate symptoms of COVID-19. In this work, Brazilian and Portuguese scientists analyzed defense cells from unvaccinated individuals between 30 and 180 days after infection.

“The immune cells of the patients infected with the virus were exhausted, something similar to what happens with the cells of people with obesity of grade II or III, with chronic diseases such as diabetes or the elderly. But it is something completely unexpected among young people with no health problems, ”he comments to Fabio Santos de Liraprofessor at the Unesp Faculty of Science and Technology (FCT-Unesp) at its campus in the town of Presidente Prudente.

These data, which were released at a conference organized by the International Society for Immunology and Exercise in the United States, are part of the FIT-COVID project, supported by the FAPESP. The objective of the group of scientists, which includes researchers from the state of São Paulo in Brazil and from the University of Coimbra (Portugal), is to investigate the effects of COVID-19 on the immune, vascular and autonomic nervous systems (an aspect of the central nervous system that controls breathing, blood circulation and other vital functions) of people under 40 years of age who presented mild and moderate symptoms of COVID-19. The proposal consists of monitoring the impact of the disease in volunteers for up to two years after infection.

“Our project aims to learn about the effects of COVID-19 on the young and healthy population, which was totally neglected at the beginning of the pandemic. Those people went to hospitals and were diagnosed, but because they had mild or moderate symptoms, no assistance was provided. Then they returned to their homes and carried out the isolation without any type of follow-up. But our studies are showing that even when these individuals became infected, they may have suffered strong damage in the systems analyzed”, affirms Santos de Lira.

The researcher explains that the main sign of the alterations observed in the immune system of these people was extreme fatigue. The group compared the immune system of 20 infected individuals with that of 20 uninfected individuals and observed a number of alterations in those who had COVID-19, including impaired lung function, a lower level of physical activity and – contrary to patients who had severe disease – a lower concentration of pro-inflammatory molecules known as cytokines, which are produced to signal the immune system to send more defense cells to the site of infection.

“It is a self-regulation of the immune system. Perhaps because of the low amount of cytokines, these people did not have the severe form of the disease. It was a mechanism that managed to counterbalance the effects of the virus. It happens that there was a decrease in interleukin-6 [un importante mediador de la respuesta inflamatoria conocida como tormenta de citoquinas]. Likewise, there was an increase in interleukin-10 and the soluble TNF-alpha receptor. [citoquinas antiinflamatorias]. And also an increase in prostaglandin, which is an inflammatory molecule, and an alteration in the lipid profile: it was recorded that these people exhibited an elevation in the fraction of triglycerides and more leptin [una hormona implicada en la regulación del apetito]”, Explain.

The extraction of the samples was carried out in May 2021, when that population had not yet been vaccinated. Apart from the data measured immediately after infection, the researchers took blood samples from these patients after they completed their vaccination schedules (when everyone had already been vaccinated) and will take them again one year after vaccination.

Exhaustion

The researcher explains that, because they are young and clinically healthy, it was expected that these people would exhibit small alterations in their immune system. “But what we saw when we analyzed the energy metabolism of immune cells is that it is completely altered. The virus manages to reprogram immune cells and bring them to a fully inflammatory status. Therefore, it is an extremely aggressive virus, even for young, healthy people who have proven to be without any clinical problem,” remarked Santos de Lira.

Another finding that materialized in this study was that of the partially protective role of physical activity against the detrimental effects of SARS-CoV-2 on the immune system. By analyzing defense cells, including monocytes and T cells, the researchers found that infected individuals had a reduced anti-inflammatory profile of regulatory T cells. Meanwhile, the level of PD1 proteins – whose function is to prevent T lymphocytes from attacking other cells in the body – was elevated in both CD4 and CD8 T lymphocytes.

“Interestingly, the level of physical activity of these patients partially protected against alterations in the immune system. The higher the level of physical activity, the greater the protection against disturbances in the [linfocitos T] CD8, but not CD4”, says the researcher. The researchers also analyzed muscle conditions by measuring hand pressure strength and performing tests such as sitting down and standing up, six-minute walks, and quadriceps strength.

“Among the muscle strength parameters, we only detected differences in the six-minute test. The COVID group covered a shorter distance than the control group. But when we analyzed the respiratory part – respiratory function, both absolute and relative, and the forced volume – everything appeared to deteriorate statistically in the infected group. All values ​​were lower. Therefore, this confirms that lung function was compromised in them and also exercise tolerance ”, he affirms.

The energy metabolism of the immune cells was also analyzed, which showed a predominance of glycolytic metabolism. [la generación de energía mediante la rotura de la glucosa] in the body’s energy production. “The predominance of glycolytic metabolism means that there is a proinflammatory character. Therefore, the cells are exhausted, as they are producing many resting cytokines and, when stimulated, they do not respond. This whole picture shows a huge deficiency in the immune system, ”he says.

Alterations in the nervous system

Apart from monitoring the immune system of young individuals who had COVID-19 before being vaccinated, FIT-COVID is analyzing the damage caused to the autonomic nervous system, which works involuntarily to make heartbeats, for example. The data shows that five months after being cured of the disease, the damage to the autonomic nervous system was diluted and it returned to normal. The results of this arm of the research were disclosed in two scientific articles published in the journal Environmental Research and Public Health in February 2022 and in January of this year (read more at: agencia.fapesp.br/38157/).

It should be remembered that the autonomic nervous system is divided into two parts: the sympathetic system and the parasympathetic system. The sympathetic system is responsible for changes in the body in alert situations, preparing it to face or flee in the presence of threats. Therefore, it requires more energy expenditure. This aspect is responsible for raising heart rate and blood pressure, releasing adrenaline, contracting and relaxing muscles, dilating the bronchi, dilating the pupils and increasing perspiration. Meanwhile, the parasympathetic nervous system normalizes the functioning of the internal organs after the alert situation. In this part of the study, analysis of heart rate up to 180 days after people became infected showed increased sympathetic activity during rest.

“It is expected that at rest the parasympathetic activity appears higher than the sympathetic, since the sympathetic nervous system is related to physical activity. If a person suddenly needs to run for some reason, the sympathetic nervous system controls the body’s responses to that stress, such as increased heart rate. Therefore, especially in young and healthy adults, what would be expected would be parasympathetic activity at rest greater than sympathetic activity,” he explains. Ana Paula Coelho Figueira Freireprofessor at the Universidade do Oeste Paulista (Unoeste) and first author of the articles.

Coelho Freire points out that the imbalance in the autonomic nervous system detected in young and healthy people who were infected with SARS-CoV-2 may be related to higher inflammatory levels. “Some factors that may be associated with this imbalance in the autonomic nervous system, and its recovery five months later shows control of the inflammatory storm over time. It is the immune system recovering and lowering the inflammatory levels, which can impact the autonomic nervous system, that is, the resolution of inflammation itself over time”, says Coelho Freire.

“Heart rate variability demonstrated that the higher indices of the sympathetic system may be related to eventual cardiovascular comorbidity and even sudden death,” he says.

Coelho Freire emphasizes that, even with the recovery of the autonomic nervous system after five months, this finding provides a greater perspective for researchers and health professionals who aim to understand the course of the disease. “Even young adult individuals are not exempt from exhibiting compromises caused by COVID-19. Even with the autonomic nervous system restored in a time window of five months, it is relevant to deepen the understanding of the action of the disease, especially among this young population”, affirms the researcher.

Apart from monitoring these patients two years after being infected, FIT-COVID has a second phase of studies that aims to analyze the immune cells of Olympic athletes who were not infected with SARS-CoV-2 before being vaccinated. “Our goal is to isolate the immune cells of these Olympic athletes – who are known to be highly efficient – ​​and to observe in the laboratory how they react to the blood serum of these young and healthy people. We want to know if these cells manage to mitigate the pro-inflammatory effects of the serum of infected individuals before the vaccine and after the vaccine”, affirms Santos de Lira.