Age is a key risk factor associated with the severity of symptoms caused by SARS-CoV-2, and there is an urgent need to reduce COVID-19 morbidity and mortality in elderly individuals. We discuss evidence suggesting that trained immunity elicited by BCG vaccination may improve immune responses and can serve as a strategy to combat COVID-19 in this population.
COVID-19 is a disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The disease spreads very quickly and became a pandemic short after it emerged China in December 2019. Depending on the patients’ health conditions and age, COVID-19 clinical symptoms can range from an asymptomatic or mild disease to a very severe form. Pre-existing underlying health conditions such as diabetes, atherosclerosis, hypertension, cancer, immunocompromised states, chronic kidney disease, and overweight/obesity substantially increase COVID-19 mortality and morbidity. In addition, COVID-19 severity drastically increases with advancing age. In patients with severe disease, COVID-19 induces a complex dysregulation of both innate and adaptive immune responses, that sometimes result in a combination of inappropriate systemic inflammation (leading to pulmonary edema and respiratory insufficiency), as well as defects in specific components of the immune responses (e.g., interferon [IFN] pathway defects, lymphopenia), contributing to disease severity.1 Older people have a higher chance of developing a systemic inflammation when encountering COVID-19.4
Aging as a risk factor of COVID-19 progression
Aging is one of the main risk factors for increased susceptibility to many infectious diseases. Systematic analysis of more than 140 databases on 19 viral and 13 bacterial diseases demonstrated that severity increases with age and clinical symptoms markedly worsen in older ages. Although the COVID-19 pandemic affects people across all ages, children and young adults 10–19 years old show very mild or no symptoms. In contrast, the elderly are the most vulnerable group to the disease and are often hospitalized and require intensive care unit support. Subsequently, the mortality rate among this age group is significantly higher than among younger or middle-aged groups. Individuals under 20 years of age are almost half as susceptible to COVID-19 as those over 20. Clinical symptoms increased dramatically to 57%–82% in adults aged over 65–70 years.6Increased susceptibility to disease is a complex and multifactorial process. Physiologic alterations affect many organs such as the skin, epithelium, and mucosal tissue. In addition, poor disease outcome is closely associated with the immune system weakening during aging (Figure 1). Age-associated changes in both lymphocytes functions and proportions have been linked to chronic diseases. Lymphoid tissues deteriorate with rising age and fail to support lymphocyte hemostasis, which result in less T and B cells and finally less robust cellular and humoral immune responses. Evidence also shows that aging causes hematopoiesis shift from lymphoid toward myeloid progenitors. This may contribute to lower lymphoid cell numbers and a higher number of myeloid-derived cells such as monocytes/macrophages. With aging, the frequencies of naive CD4+ or CD8+ T cells decrease but the counts of memory CD4+ or CD8+ T cells increase or remain the same. Moreover, the normal function of T cell receptor (TCR) and cytokine production by T cells is also impaired.7 All changes in adaptive immunity parameters lead to a decline in their ability to build a proper immune response against new antigens, and thus poor response to infection or vaccination. This is referred to as immunosenescence (reduced proliferation) and exhaustion (reduced inflammatory mediators such as cytokine production). Exhausted T cells continuously produce small amounts of proinflammatory cytokines such as IFN-γ and tumor necrosis factor alpha (TNF-α) that induce low-grade inflammation in older people.
Figure 1COVID-19 alters innate and adaptive immune systems in the adult and the elderly
Age-related defects in the adaptive immune system against COVID-19
Recently, Moderbacher et al. showed that scarcity of all three arms of adaptive immunity, such as B cells (antibody-producing cells), CD4+T cells (helper T cells), and CD8+T cells (cytotoxic, or killer, T cells) play a crucial role in the severity of COVID-19 in the elderly. SARS-CoV-2-specific CD4+ and CD8+ T cell levels were significantly lower in acute COVID-19 samples in comparison to convalescent COVID-19 cases. The serological tests showed that many types of circulating antibodies against receptor-binding domain (RBD), Spike protein (S), and Nucleocapsid protein (N) as well as neutralizing antibodies against full-length SARS-Cov-2 S protein were pronounced in both acute and convalescent COVID-19. These neutralizing antibodies were associated with a protective response against COVID-19 and were tested as vaccine candidates in non-human primates.2 Conversely, strong SARS-CoV-2-specific CD4+ or CD8+ T cell responses were associated with protection against the disease and milder symptoms in the acute phase. With aging, frequencies of naive CD8+ and CD4+ T cells are dramatically reduced and their responses against diseases including COVID-19 are significantly altered.2 In order to mount a well-defined immune response against a pathogen, the immune system uses highly coordinated processes involving many cells and mediators. Moderbacher and her colleagues demonstrated that the alteration in coordination of the immune system in older people is a reason why they cannot compete with the novel coronavirus.2 Loss of the ability to coordinate CD4+ and CD8+ T cell responses, and lack of adequate coordination between the CD4+ T cell and antibody responses, lead to a severe form of COVID-19 in the elderly. Interestingly, there was a strong association between low frequencies of naive CD8+ and CD4+ T cells, severity of COVID-19, and age. On the other hand, acute cases that had high IFN-γ-producing CD8+ T cells exhibited mild symptoms.2 Intriguingly, pairwise analysis revealed a positive association between disease severity, antigen specific antibodies, and CD4+ and CD8+ T cells responses, but neutralizing antibodies alone were not a factor to reduce disease symptoms. This suggests that an efficient coordination between all three arms of the adaptive immunity is needed for protection against COVID-19, which is almost lacking in the elderly.2
Age-associated defects in the innate immune system
Innate immunity is the first line of defense that responds immediately upon encountering a threat. It also plays a crucial role in initiating an effective adaptive immunity. The innate immune system is affected by age to a lesser degree. Adaptive immune cells respond to inflammatory stimuli in an antigen-specific manner, whereas innate immune cells provide non-specific defense against invading agents. Neutrophils, monocytes, and natural killer (NK) numbers are preserved, but the number of dendritic cells (DCs) is reduced with increasing age. However, function of monocytes, NKs, and neutrophils such as chemotaxis and signal transduction are impaired in older individuals. Induction of adaptive immune responses require presentation of antigens to T cells by antigen-presenting cells (APCs) mainly DCs. Higher number of DCs not only enhances the innate immune response but also can mediate activation of adaptive immune response against pathogens. On the other hand, impaired DCs function causes delayed T cell responses and ultimately lower anti-viral responses.Age-associated decrease of Toll-like receptors (TLRs) such as TLR1, TLR3 expression could be another reason for weakening immune responses. Moreover, the expression of TLR7 in the lung is depleted with age, which may contribute to a poor immune response to COVID-19 in elderly patients. In addition, immune-response-related gene expression analysis revealed an age-related upregulation of innate immunity and downregulation of adaptive immunity, which was associated with viral replication and severity of COVID-19. Dysregulation of innate immune responses plays a central role in elevation of peripheral cytokines and chemokines levels such as interleukin-1 beta (IL-1β), IL-6, IL-8, and CXCL10 that are associated with immunopathogenesis and serious clinical signs in the late stages of severe SARS-CoV-2 infection.2 Elderly individuals might experience a sustained activation of innate immunity and increased circulating inflammatory mediators, which together with low level of cytokines that are constantly produced by T cells induce a chronic low-grade inflammation. It was noted that concentrations of inflammatory cytokines were increased with aging in the acute respiratory syndrome.4 Interestingly, Moderbacher et al. also showed that CXCL10, IL-8, and IL-6 production was increased in the acute phase of COVID-19 and positively associated with the severity of the disease. CXCL10 also showed a strong negative correlation to SARS-CoV-2-specific CD4+ and CD8+ T cells, suggesting that CXCL10 may serve as a surrogate marker in predicting poor CD4+ and CD8+ T cell response against COVID-19.2In elderly patients, failure to fight against SARS-CoV-2 infection is a complex process, and in addition to a less efficient immune system, several other factors can play a role:
- •Angiotensin-converting enzyme 2 (ACE2) is a highly specific receptor that facilitates SARS-CoV-2 entry into cells such as epithelial or alveolar cells. The expression of ACE2 in the lung, nasal epithelium, and other organs increases with age. Heightened receptor availability enhances the viral entry into the host cells and increases the number of infected cells. Therefore, the level of ACE2 expression can aggravate COVID-19 severity. Sajuthi et al. found that IL-4, IL-5, and IL-13 production significantly reduces ACE2, which correlated with a less severe COVID-19, whereas induction of type 1 IFN increases ACE2 expression.
- •Many elderly individuals suffer from underlying medical conditions and are therefore at a greater risk for a more severe disease progression.
- •Shifting lymphoid cell fractions to predominantly memory cells increases the chances that these cells may cross react with new antigens, which can induce an unwanted immune reaction and lead to a severe form of the disease.2
Trained immunity against COVID-19 in the elderly
In early life, children receive many vaccines against infectious diseases. Randomized trials have shown that vaccines such as the measles vaccine or Bacillus Calmette-Guérin (BCG) vaccine non-specifically reduced overall child mortality due to acute respiratory tract infections.1 Non-specific cross protection of vaccines against unrelated infectious diseases is mediated by epigenetic and metabolic changes in innate immune cells and is termed trained immunity or innate immune memory.1 Trained immunity can confer broader aspect of therapeutic strategies against infectious and non-infectious diseases such as atherosclerosis, the bladder cancer and destruction of cancer cells.1 Several investigations have reported a significant correlation between BCG vaccination and decreasing COVID-19 morbidity and mortality in countries where BCG vaccination is a part of the immunization program (reviewed by Sohrabi et al.1).
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