The coronavirus disease 2019 (COVID-19) pandemic has shown a disproportionate tendency to cause severe or critical disease and death in men, and in older adults, in the first wave at least. But why does its causative virus – the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) – show this predisposition?
A new study, released as a preprint on the bioRxiv* server, shows that the immunological features of severe COVID-19 are already present in healthy older adults and in men, before they are infected, indicating a possible explanation for this differential susceptibility towards the virus.
Need for the study
People over 70 years of age, and those with other chronic health conditions, have suffered the most from COVID-19. However, the 50-year mark indicates the point at which COVID-19 mortality angles upward steeply in men rather than in women across all populations.
An earlier study showed that men with COVID-19 had increased levels of interleukins IL-8 and IL-18, and of non-classical monocytes, while women with the infection had a higher frequency of T cell activation.
The researchers behind the current paper showed changes in various cytokines and chemokines, growth factors and mediators of inflammation at different stages of COVID-19. Thus, patients who required intensive care unit (ICU) admission had a different profile compared to those with severe COVID-19.
The current study aimed to examine “whether such differences are induced by the disease severity itself, or the potential to respond differently was already present in the healthy steady-state condition.” Since such immunological differences may have been affected by the season, they looked into this aspect as well.
The researchers analyzed some immune cell and circulating proteins in relation to COVID-19 severity in two groups of healthy individuals, in the Netherlands, both over 50 years of age. They also examined the differences in immunological responses to the virus at various time points, using information available in one of the groups.
They used samples of peripheral blood, separating the immune cells. These were then exposed to inactivated SARS-CoV-2. The peripheral blood mononuclear cells (PBMCs) were from both men and women, both old and young, and collected at different times of the year.
What were the results?
The study shows that the total T cell count falls with age, the resulting lymphopenia predisposing the elderly to severe COVID-19. Multiple subsets of T cells, which have been reported to be lower in frequency in patients with severe COVID-19, were also found to be inherently lower in men and in older people.
The greatest effect was seen with naïve CD8+ and other T cells in the elderly of both sexes. Naïve T regulatory cells (Tregs) are also lower in the elderly in males, but memory Tregs are higher. Total B cell counts also drop with increasing age, and in females, plasmablasts as well.
Thus, the reduced frequencies of naïve CD4+, CD8+, Treg, and B cells, along with CD56bright NK cells, seen in severe COVID-19, are already present in people over the age of 50 years.
When compared to males, females showed significantly higher numbers of all cell types, including neutrophils and all the cells mentioned above. This indicates that in males, as in the elderly, these cell types are depleted.
Immune protein markers such as hepatocyte growth factor (HGF), interleukin-8 (IL-8), and monocyte chemoattractant protein-1 (MCP-1), which are higher with severe COVID-19, are already higher in healthy older people. While HGF is higher in men, it increases in women with age.
Plasma levels of markers such as IL-8, IL-18, MCP-1, MCP-2, and CCL3 were all higher in males. Increased levels of the first two are linked to poor immunological response and an adverse outcome. The others are key inflammatory mediators.
Anti-inflammatory proteins IL-10 and PD-L1 are also higher in healthy males and in severe COVID-19, perhaps because of immune exhaustion. IL-6 and OPG are severity markers that are sex-independent.
Aging was also associated with lower TNF-related activation-induced cytokine (TRANCE) levels, especially in men. This could perhaps be because it is released by T cells, which are low in elderly subjects and in severe COVID-19.
Finally, the concentration of IL-1RA is higher in elderly people, and they also had an aberrant IFN-γ response in the summer, relative to younger people.
When exposed to SARS-CoV-2 in vitro, the PBMC responses in those who had higher levels of MCP-1 and IL-8 at baseline were characterized by IL-1RA increases. With higher MCP-1 levels, gamma-interferon (IFN-γ) production dropped following viral exposure.
Thus, the higher MCP-2, IL-8, and MCP-1 levels at baseline show the failure to mount an optimal immune response.
Seasonal variations in cytokine production in response to SARS-CoV-2 were found, with higher IL-1 pathway mediators in the elderly such as IL-1β and IL-1RA. However, IFN-γ production was higher in the young, after stimulation, in fall and summer, but not in the elderly, in whom the effect of the change in season failed to manifest.
What are the implications?
The immune characteristics of severe COVID-19, described by a differential abundance of immune cells and circulating inflammatory proteins, are intrinsically present in healthy men and the elderly.”
The study thus shows that the increased vulnerability of males and elderly people to SARS-CoV-2 is probably partly due to the pre-existing decline in total and differential T and B cell counts, which are reflected in severe COVID-19. This is probably because they cannot eliminate the virus efficiently under such conditions.
One of the biggest differences in immune cell types between males and females was the SARS-CoV-2-specific CD4+ cell types. Their presence in higher numbers is linked to mild COVID-19, related to the speedy induction of these cells.
Defects in triggering these cells in specific immunity when challenged by the virus were associated with severe COVID-19 and higher mortality.
Low interferon responses indicate an impaired antiviral T and NK cell response to the viral infection leading to severe COVID-19. The loss of NK and T cells may underlie the underproduction of IFN-γ.
One important point is that these defects are present in the whole population, not at the individual level: while the elderly as a group have lower immune responses, there are certainly aged individuals who have effective immune reaction.”
Nonetheless, these findings help explain why these groups are at increased risk of severe COVID-19. Further research should probe the importance of these mediators in the antiviral response, helping to shape preventive and therapeutic measures.
bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.