One of the factors that may impact the severity of COVID-19 is immunosenescence, a process characterized by age-related decline in the immune system’s function. It is known that aging is associated with an increased risk of severe COVID-19, but the impact of immunosenescence on COVID-19 remains unclear.
This article aims to discuss the effect of SARS-CoV-2 infection on T cell immunosenescence in cytomegalovirus (CMV)-seropositive individuals.
Background:
Cytomegalovirus (CMV) is a ubiquitous herpesvirus that infects more than 50% of the world’s population. It is a persistent virus that can remain dormant in the body for years and can reactivate during periods of immunosuppression. CMV has been shown to have a significant impact on the immune system, particularly on T cells, and has been implicated in contributing to immunosenescence, or the age-related decline in immune function. In this article, we will explore the effect of CMV infection on T cell immunosenescence and the potential mechanisms involved.
Immunosenescence is a complex phenomenon characterized by a decline in the function of the immune system with age. This decline in immune function is thought to be due to a combination of intrinsic changes in immune cells and extrinsic factors such as chronic infections, including CMV. T cells are a critical component of the immune system, and their function declines with age. This decline is characterized by a decrease in the diversity of the T cell repertoire, an increase in the number of T cells with a memory phenotype, and a reduction in the ability of T cells to respond to new pathogens.
CMV infection has been shown to have a significant impact on T cell function. CMV infection leads to the expansion of CMV-specific T cells, which can reach up to 50% of the total CD8+ T cell pool in some individuals. These CMV-specific T cells have a memory phenotype and exhibit signs of replicative senescence, such as shortening of telomeres and a decreased ability to proliferate. The expansion of CMV-specific T cells can also lead to a decrease in the diversity of the T cell repertoire, as the proliferation of CMV-specific T cells can limit the space available for other T cell clones.
One potential mechanism by which CMV infection contributes to T cell immunosenescence is through the persistent stimulation of the immune system. CMV infection leads to the continuous production of viral antigens, which can activate T cells and lead to chronic inflammation. Chronic inflammation has been shown to contribute to age-related changes in the immune system and can lead to the activation of immune cells and the production of pro-inflammatory cytokines. This chronic inflammation can lead to the activation of the immune system, leading to the exhaustion of T cells and contributing to immunosenescence.
Another potential mechanism by which CMV infection contributes to T cell immunosenescence is through the dysregulation of the immune system. CMV infection has been shown to alter the balance between effector and regulatory T cells, leading to a decrease in the number of regulatory T cells and an increase in the number of effector T cells. This dysregulation of the immune system can lead to an increase in the production of pro-inflammatory cytokines, contributing to chronic inflammation and the exhaustion of T cells.
SARS-CoV-2 infections in Cytomegalovirus seropositive individuals are linked to accelerated T cell immunosenescence and an increased risk of cardiovascular disease.
The overall SARS-CoV-2 infection hospitalization rate was estimated to be 2.1%, ranging from 0.4% in young (18-39 years) to 9.2% in older individuals (>60 years) (2). Most studies regarding this infection focus on COVID-19 severity or acute infection, as this has been the main concern. However, there is little information concerning SARS-CoV-2 impact on the immune system long-term in mild or asymptomatic infected individuals, which are the majority.
For many years, the expansion of CD28null T cells was considered a consequence of chronological aging and a hallmark of immunosenescence and frailty (7). However, we know now that it is a sign of replicative senescence and specifically, a hallmark of cytomegalovirus (CMV) chronic infection.
Particularly, regarding CD28null T cells frequency, it was observed a twelve-fold increase for CD4+CD28null T cells, and a two-fold increase for CD8+CD28null T cells in CMV-seropositive (CMV+) individuals compared with CMV-seronegative (CMV−), being the effect of age marginal and only when CMV infection was present (8). Expansions of CD28nullCD57+ T cells occur after CMV infection, even in young individuals (9, 10).
CMV is a common herpesvirus that causes chronic infection impacting the innate and adaptive immune response. Hence, CMV has been considered one of the main factors driving early or accelerated immunosenescence (11-13). CMV chronic infection can affect up to 40-90% of the world’s population, depending on key factors such as age, socioeconomic status, race, or education (14).
In the past years, CMV latent infection has been associated with several autoimmune conditions, as well as with cardiovascular disease (CVD) (15). Furthermore, CMV-seropositivity has been associated with an increased risk of cardiovascular death by over 20% (16), however little is known about the mechanism explaining this effect.
In turn, these chemokines can induce the migration of immune cells expressing CX3CR1 and CX3CR3 chemokine receptors (18, 19). Thus, we hypothesized that CD28null T cells, capable of infiltrating the vasculature, will be attracted by the FKN and IP-10 gradient created by the activated endothelial cells, ultimately causing vascular damage.
Our hypothetical model provided a possible explanation of how CMV infection could cause endothelial cell damage, driving the expansion of highly cytotoxic CD28null effector T cells that express CX3CR1 and CX3CR3 chemokine receptors (17).
Recent studies have demonstrated an association of CD8+ and CD4+ CD28null T cell percentages with higher morbidity and mortality rates in COVID-19 (20-22) and the relation of CMV infection with increased COVID-19 severity and hospitalization risk (23-25). Furthermore, it has been observed an increment of inflammatory cardiovascular events led by SARS-CoV-2 infection (26).
Under this premise, we aimed to investigate the potential role of SARS-CoV-2, as an enhancer factor, leading to early immunosenescence and increased cardiovascular risk. Specifically, we analysed the expression of immunosenescence markers associated with CMV and cardiovascular disease, in mild/asymptomatic SARS-CoV-2 infected individuals, aortic stenosis patients and healthy individuals.
Effect of CMV infection on T cell immunosenescence:
CMV infection can lead to a phenomenon called memory inflation, where CMV-specific T cells accumulate over time, leading to an expansion of CMV-specific T cells in CMV-seropositive individuals. This expansion of CMV-specific T cells can lead to a reduction in the diversity of the T cell receptor repertoire, which is a hallmark of immunosenescence.
CMV infection can also lead to a state of chronic inflammation, which is associated with aging and age-related diseases. Chronic inflammation can lead to an increase in senescent T cells, which are characterized by a loss of telomeres and a reduced capacity to proliferate and respond to stimuli.
Effect of SARS-CoV-2 infection on T cell immunosenescence in CMV-seropositive individuals:
Recent research has suggested that SARS-CoV-2 infection may accelerate immunosenescence, particularly in CMV-seropositive individuals. One study found that SARS-CoV-2 infection increased the frequency of senescent T cells in older individuals, particularly those with underlying health conditions.
Another study found that SARS-CoV-2 infection led to a reduction in the diversity of the T cell receptor repertoire, which is a hallmark of immunosenescence. This reduction was more pronounced in CMV-seropositive individuals.
SARS-CoV-2 infection can lead to a state of chronic inflammation, which is associated with aging and age-related diseases. Chronic inflammation can lead to an increase in senescent T cells, particularly in CMV-seropositive individuals. This increase in senescent T cells may result in a reduced capacity of the immune system to respond to new infections, including SARS-CoV-2.
Additionally, the expansion of CMV-specific T cells in CMV-seropositive individuals may lead to a reduced diversity of the T cell receptor repertoire, which could result in a weaker response to new pathogens.
Furthermore, COVID-19 severity has been associated with a dysregulated immune response, including a hyperactivation of T cells. This hyperactivation can lead to T cell exhaustion, which is characterized by a loss of effector function and a reduced capacity to respond to stimuli. T cell exhaustion has been associated with chronic viral infections, including CMV, and may be a contributing factor to the severity of COVID-19 in CMV-seropositive individuals.
Implications for vaccination:
The impact of SARS-CoV-2 infection on T cell immunosenescence has important implications for vaccination. Vaccines work by priming the immune system to recognize and respond to specific pathogens. However, in individuals with immunosenescence, the immune system’s response to vaccines may be weaker, leading to a reduced efficacy of the vaccine.
This reduced efficacy may be particularly pronounced in CMV-seropositive individuals, as the expansion of CMV-specific T cells may lead to a reduced diversity of the T cell receptor repertoire, which could result in a weaker response to new pathogens.
Recent studies have suggested that COVID-19 vaccination may be less effective in older individuals, particularly those with underlying health conditions. This reduced efficacy may be related to the impact of immunosenescence on the immune response to the vaccine. Additionally, the reduced efficacy of the vaccine in CMV-seropositive individuals may be related to the expansion of CMV-specific T cells, which could result in a weaker response to the vaccine.
reference link :
https://pubmed.ncbi.nlm.nih.gov/32671966/
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad119/7143701
https://academic.oup.com/jid/advance-article/doi/10.1093/infdis/jiad119/7143701?login=false
