Fig. 1

The impact of age-related changes in the innate and adaptive immune system on COVID-19. The SARS-CoV-2 infects the cell by binding to the ACE2 receptor. After invasion, the virus can be detected by the cells of innate immunity (A, B), such as monocytes, macrophages, and DC. In young (A) it leads to an induction of a local inflammatory and robust interferon-I response, inhibiting the viral replication. Immune cells are recruited to the site of infection: NK cells kill infected cells, neutrophils clear the cell debris, and the functional APCs prime cells of the adaptive immunity (C). After activation, the CD4⁺ T cells release cytokines and activate B cells and plasma cells to produce the nAb. Cytotoxic CD8⁺ T cells can directly kill infected cells, preventing the viral spread. Neutrophils migrate to the sites of infection to clear the cell debris. The immune response of young individuals (A, C) efficiently resolves the infection and is capable of establishing an immune memory. The innate cells of elderly individuals (B) are functionally impaired and enable to induce robust antiviral type I IFN response for controlling virus replication. Inflammatory and SASP molecules attract further dysfunctional inflammatory neutrophils, monocytes, and inflammatory M1-macrophages to the sites of infection, establishing an inflammatory feedback loop and contributing to the so-called “cytokine storm”. These detrimental conditions inhibit effective T-cell priming and disturb efficient debris clearance. Aged cells of the adaptive immune system (D) also have multiple deficits, which prevent an effective antiviral immunity. Decreased T-cell numbers with reduced receptor repertoire, an accumulation of senescent T cells with impaired proliferative capacity, and elevated levels of inflammatory cytokines lead to the disturbed immune response to the SARS-CoV-2. Senescent B and T cells produce inflammatory cytokines, inhibiting the generation of mature B cells. Reduction in nAb and elevation of non-neutralizing antibodies and autoAb may augment the SARS-CoV-2 infection by ADE, leading to organ damage. Autoimmunity, SASP, and inflammaging promote a pro-thrombotic environment and contribute to the hyperinflammatory syndrome observed in severe COVID-19.

Abbreviations: DC: Dendritic cell; NK: natural killer cell; EC: endothelial cell; ACE2: angiotensin-converting enzyme 2; IFN: interferon; TLR: toll-like receptor; IL: interleukin; TCR: T-cell receptor; SASP: senescence-associated secretory phenotype; APC: antigen-presenting cell; TNF: tumor necrosis factor. SmCD8+: senescent memory CD8⁺ T cell; SmCD4⁺: senescent memory CD4⁺ T cell; SmBC: senescent memory B cell; ABC: age-associated B cells; ADE: antibody-dependent enhancement. Modified from [9].