Innate Lymphoid Cells and Covid-19 Severity: Chicken or the Egg?

This is part of a series of stories about the protective role of innate lymphoid cells (ILCs) in the gut and other tissues, focusing on SARS-CoV-2 infection. Read part One part twopart threepart fourand part five

Recent discoveries point to the importance of innate lymphoid cells (ILCs) in protecting against diseases, including Covid-19. New research by Silverstein et al. suggests that lower blood ILC levels may help predict disease outcome. In particular, the decline in ILCs with age correlates strongly with an increased risk of severe Covid-19. They also show that the difference in concentrations of ILCs in the blood between men and women may contribute to the increased susceptibility of men to serious diseases.

Innate lymphoid cells and disease tolerance

Innate lymphoid cells are generally found in “barrier environments” – areas of our bodies that are constantly exposed to the outside world, such as our lungs and gastrointestinal tract – where they play an active role in regulating homeostasis. This includes responding to invasive and potentially harmful microorganisms.

When faced with an intrusive pathogen, our first priority is to contain it. This is where our immune system comes in, triggers inflammation and redirects immune cells to areas where they are needed most. Both the infectious pathogen and our inflammatory response can cause serious tissue damage. So a secondary priority of the immune system is to make sure that this damage is kept under control, known as ‘disease tolerance’. While disease tolerance mechanisms do not directly engage or eliminate the pathogen, they work to maintain the overall health of the host during infection, limiting disease severity.

In the case of SARS-CoV-2, the amount of virus circulating through a patient’s body, known as viral load, does not correlate neatly with the severity of Covid-19; some people, especially children, may have very high viral loads while remaining asymptomatic or only mildly symptomatic. This suggests that disease severity in Covid-19 is more directly determined by age-dependent disease tolerance mechanisms than by viral replication and viral loads.

Previous studies have shown that ILCs can contribute to disease tolerance, with one specific subset of the ILC family, group 2 innate lymphoid cells (ILC2s), having a particularly active hand. In response to tissue damage, ILC2s can produce a protein that amphiregulin (AREG). By binding to epidermal growth factor receptors (EGFR), amphiregulin helps to stimulate cell growth, cell survival and cell migration. In addition, ILC2-induced amphiregulin aids in the repair of damaged tissue while preserving the integrity of the epithelial lining in the lungs and gut.

But determining the extent to which ILC levels contribute to the severity of Covid-19 is trickier than it may seem at first. First, there are multiple factors that increase the risk of severe Covid-19. Two of the most common are age and gender: Men are more likely than women to get a serious disease, and the older you are, the greater the risk. Added to this is the fact that levels of lymphocytes — a class of white blood cells made up of T and B cells, as well as ILCs — are already reduced during SARS-CoV-2 infection, a phenomenon known as lymphopenia. Finally, lymphocyte levels also vary according to both age and sex, decreasing with age and lower in men right away.

The Challenge for Silverstein et al. was determining whether blood ILC levels had changed in Covid-19, independent of the above factors – age, sex and global lymphopenia. In addition, whether ILC levels correlated with Covid-19 severity.

To do this, the researchers compared blood samples from three groups: adults hospitalized for Covid-19, adults treated for Covid-19 who did not require hospitalization, and a control group of adults who were not infected with SARS. -CoV-2 .

The researchers first attempted to calculate a baseline for age- and gender-related lymphopenia, giving them a reference point to compare lymphopenia in Covid-19 patients. To do this, they collected measurements of peripheral blood mononuclear cells from 103 SARS-CoV-2 negative blood donors. Peripheral blood mononuclear cells are a large collection of immune cells, including lymphocytes, that circulate in the blood and act as the first line of defense in response to invading pathogens. The donors ranged from 2 to 79 years old, with an almost equal number of men and women.

Innate lymphoid cells decline drastically with age

Silverstein et al. focused on the lymphocyte measurements, focusing on the four major subsets: CD4+ T cells, CD4+ B cells, ILCs, and CD16+ natural killer (NK) cells. Although all subsets were affected by age, only ILCs consistently showed significant differences across all age groups. The median decrease for ILCs was 2-fold every 20 years, with a 7-fold absolute decrease from the youngest age group to the oldest. The age-dependent decline in ILCs was closely mirrored by the aggressive, age-dependent increase in Covid-19 mortality (Figure 1).

Men have fewer innate lymphoid cells than women

The team of researchers also found that ILC levels in men were naturally lower than in women (Figure 2). Again, this correlates with the fact that men are more likely to suffer from severe Covid-19 than their female counterparts. No other subset of lymphocytes, with the exception of CD4+ T cells, showed such a marked decrease based on sex.

The lower the ILC levels, the higher the risk of hospitalization

Next, the group of researchers wanted to confirm whether lymphocyte levels are actually lower in Covid-19 patients once the effects of age and gender are factored in. found that hospitalized Covid-19 patients showed a 1.33-fold reduction in total lymphocyte counts among PMBCs compared to their control group. This included 1.8-fold fewer ILCs and 2.3-fold fewer CD16 + NK cells compared to the control group (Figure 3). Such a significant decrease could not be seen in T and B cell levels. For the group of patients with less severe Covid-19, there was no decrease in ILCs and only a slight decrease in CD16+ NK cells.

Importantly, as the ILCs decreased, both the risk of hospitalization and the length of hospitalization increased significantly. Each 2-fold decrease in ILCs represented a 55% higher chance of hospitalization and an additional 9.4 days of hospitalization. None of the other lymphocyte subgroups affected the rate and duration of hospitalization in the same way. In addition, lower levels of ILCs in the blood were associated with an increase in common inflammatory markers.

While this study shows a clear correlation between ILCs and the severity of Covid-19, the authors admit that the direction of the causal arrows remains a bit unclear: which came first, the chicken or the egg? Do low blood ILC levels predispose us to severe Covid-19, or does severe Covid-19 cause our blood ILC levels to drop?

Silverstein et al. think low ILC levels are more likely to cause Covid-19 severity, not the other way around. First, unlike other lymphoid cells, ILCs decline exponentially with age. This decline is closely mirrored by an age-dependent, exponential increase in mortality from Covid-19. Second, men naturally have lower levels of ILCs in their blood, including those that produce amphiregulin, and they also have a higher risk of progressing to severe Covid-19. Finally, conditions that independently correlate with lower levels of ILCs in the blood, such as HIV-1 and obesity, increase the risk of being infected with and becoming seriously ill with SARS-CoV-2.

This work adds to the ever-growing list of studies that pinpoint innate lymphoid cells as an integral part of the innate immune response. Not only in challenging invading pathogens, but also in contributing to disease tolerance. Hopefully, these insights inspire others to pay more attention to ILCs, their multifaceted impact on SARS-CoV-2 infection, and more.

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