According to a new study by scientists at the Gladstone Institutes and UC San Francisco (UCSF), people with Long COVID have dysfunctional immune cells that show signs of chronic inflammation and defective movement in organs, among other unusual activities.
The results of research were published in Nature Immunology.
Long Covid: here's what the new study revealed
The team analyzed immune cells and hundreds of different immune molecules in the blood of 43 people with and without long COVID. They looked specifically at the characteristics of each person's T cells, immune cells that help fight viral infections but can also trigger chronic inflammatory diseases.
Their findings, appearing in Nature Immunology, support the hypothesis that long COVID may involve low-level viral persistence. The study also reveals a discrepancy between the activity of T cells and other components of the immune system in people with long-term COVID-19.
“Our findings are an essential first step in understanding what is happening with T cells in long COVID,” says senior author Nadia Roan, Ph.D., a senior research scientist at Gladstone and a professor at UCSF. “This paves the way towards answering ongoing questions about different types of infection, the mechanisms that cause it, and how to treat and prevent it.”
Long COVID, also known in the medical community as “post-acute sequelae of COVID” or PASC, is broadly defined as symptoms that continue or emerge after an initial infection with the SARS-CoV-2 virus.
The trajectory can vary drastically from individual to individual; some have early COVID symptoms that never go away, some have symptoms that come and go, and others have new symptoms that appear weeks or months after the viral infection. Additionally, vaccination status and subsequent infections can impact a person's long-term COVID risk and disease progression.
“This is a very heterogeneous condition,” Roan says. “There is a diverse mix of long-lasting COVID cases, which makes it difficult to understand what is happening. That's why it was so important to eliminate some of this variability. We analyzed and compared a series of pristine samples uncomplicated by the effects of vaccination or re-infection, which can affect T cell and other immune responses.”
Roan's group collaborated with UCSF researchers, including infectious disease experts Michael Peluso, MD, and Timothy Henrich, MD, who are part of a multidisciplinary team running an observational study of COVID called LIINC, short for Long-term impact of infection with the new coronavirus.
The study follows a cohort of people who were infected once with long COVID and who were not vaccinated or reinfected during the following eight months. Those who had symptoms consistently throughout the entire study period were classified as having long-term COVID, while those who had no symptoms after the initial infection were classified as the control group.
To study participants' blood collected eight months after COVID infection, the team used six different technologies, including one they had previously deployed to deeply interrogate T cell function in the context of human immunodeficiency virus infection (HIV). The technique, called CyTOF, measures the levels of different molecules on the surface or inside of T cells.
While the overall number of T cells and the number of T cells that specifically react with the SARS-CoV-2 virus were similar between people with long COVID and those who recovered without persistent symptoms, the researchers identified several significant differences. Notably, a subset of T cells known as CD4 T cells, responsible for the overall coordination of immune responses, were in a more inflammatory state in people with long-term COVID.
“Not all people with long COVID had these pro-inflammatory cells, but we only saw them in the long COVID group,” says Kailin Yin, Ph.D., a postdoctoral fellow in Roan's lab and co-first author of the study . “It highlights the idea that there is no single uniform thing that characterizes all individuals with long-term COVID.”
In a different subset of T cells known as CD8 T cells, which normally kill cells infected by viruses or bacteria, researchers observed signs of exhaustion preferentially in people with long-term COVID. These signs, interestingly, were only observed in T cells that recognize the SARS-CoV-2 virus, not in the broader population of CD8 T cells.
“Such exhaustion is typically seen in chronic viral infections such as HIV and means that the T-cell branch of the immune system stops responding to a virus and no longer kills infected cells,” says Peluso, assistant professor in the Department of Medicine of UCSF and co. -first author. “This finding fits with some hypotheses that long COVID, or at least some cases of it, are caused by persistent infections by the SARS-CoV-2 virus.”
The team also discovered an unusually high number of “tissue-homing” T cells, that is, T cells that are prone to migrating to tissues throughout the body. This has been observed not only by CyTOF but also by two other technologies, including one that monitors individual cells for thousands of different proteins they are capable of producing.
“This was really interesting because in other studies we are doing in mice, we also see high levels of tissue receptors associated with behavioral changes after recovery from SARS-CoV-2 infection,” says Roan. “In this current study, we don't look at specific tissues, but our findings indirectly suggest that in the long run of COVID, something is happening within the tissues, recruiting T cells to migrate there.”
Finally, researchers have shown that in people with long-term COVID-19, levels of antibodies against SARS-CoV-2 are unusually high and do not synchronize as they usually do with levels of T cells that fight the virus.
This finding highlights the idea that during a long period of COVID, there is a breakdown in coordination between different arms of the immune system,” says Henrich, a professor in the UCSF Department of Medicine.
It is important to note that the new study was not designed to test any potential treatments for long COVID or to evaluate the feasibility of using T cell markers as a diagnostic tool. But, says Roan,
this points to new avenues to investigate in this regard. His team is already planning future experiments on T cells found within specific tissues of people with long-term COVID and will examine how antiviral and anti-inflammatory drugs might change the characteristics of T cells associated with the disease.
“In the long term, testing interventions will be critical,” says Roan. “With a lot of these associations related to long COVID, we don't know which is the chicken and which is the egg until we test the treatments.”
Long COVID, which affects almost two million people in the UK, is not caused by an inflammatory immune reaction to COVID-19, according to research led by the University of Bristol. Emerging data shows that immune activation can persist for months after COVID-19.
In a further study, the researchers wanted to find out whether persistent immune activation and ongoing inflammatory response could be the underlying cause of long COVID.
To investigate this, the Bristol team collected and analyzed immune responses in blood samples from 63 patients hospitalized with mild, moderate or severe COVID-19 early in the pandemic and before vaccines were available.
The team then tested the patients' immune responses at three months and again at eight and 12 months after hospital admission. Of these patients, 79% (82%, 75%, and 86% of mild, moderate, and severe patients, respectively) reported at least one ongoing symptom, with dyspnea and excessive fatigue being the most common.
Dr Laura Rivino, a lecturer at Bristol's School of Cellular and Molecular Medicine and lead author of the study, explained: “Long COVID occurs in one in 10 cases of COVID-19, but we still don't understand what causes it.
Several proposed theories include whether it could be triggered by an inflammatory immune response to the virus that still persists in our body, sending our immune system into overdrive, or by the reactivation of latent viruses such as human cytomegalovirus (CMV) and Epstein Barr virus (EBV). ). ”
The team found that patients' immune responses at three months with severe symptoms showed significant dysfunction in T cell profiles, indicating that inflammation may persist for months even after they have recovered from the virus.
Reassuringly, the results showed that even in the most severe cases the inflammation in these patients resolved on time. At 12 months, both the immune profiles and inflammatory levels of patients with severe disease were similar to those of mild and moderate patients.
Patients with severe COVID-19 were found to exhibit a greater number of long COVID symptoms than mild and moderate patients. However, further analysis by the team revealed no direct association between prolonged COVID symptoms and immune inflammatory responses, for the markers measured, in any of the patients after adjusting for age, sex and disease severity.
Importantly, there was not a rapid increase in immune cells targeting SARS-CoV-2 at three months, but in T cells targeting persistent, dormant cytomegalovirus (CMV), a common virus that It is usually harmless but can remain in the body for life once. infected with it – showed an increase to low levels.
This indicates that the sustained T cell activation observed at three months in severe patients may not be driven by SARS-CoV-2 but may instead be “bystander-driven”, i.e. driven by cytokines.
Dr Rivino added: “Our findings suggest that prolonged immune activation and long COVID may independently correlate with severe COVID-19. Larger studies should be conducted examining larger numbers of patients, including vaccinated and unvaccinated COVID-19 patients if possible.” patients and measuring a broader range of markers and cytokines.
“Understanding whether inflammation and immune activation are associated with long COVID would allow us to understand whether targeting these factors may be a useful therapy for this debilitating condition.”
#Long #Covid #immune #cells #dysfunctional
