The bullwhip effect, T-cell telomeres, and SARS-CoV-2

Abstract

Both myeloid cells, which contribute to innate immunity, and lymphoid cells, which dominate adaptive immunity, partake in defending against SARS-CoV-2. In response to the virus, the otherwise slow haematopoietic production supply chain quickly unleashes its preconfigured myeloid element, which largely resists a bullwhip-like effect. By contrast, the lymphoid element risks a bullwhip-like effect when it produces T cells and B cells that are specifically designed to clear the virus. As T-cell production is telomere-length dependent and telomeres shorten with age, older adults are at higher risk of a T-cell shortfall when contracting SARS-CoV-2 than are younger adults. A poorly calibrated adaptive immune response, stemming from a bullwhip-like effect, compounded by a T-cell deficit, might thus contribute to the propensity of people with inherently short T-cell telomeres to develop severe COVID-19. The immune systems of these individuals might also generate an inadequate T-cell response to anti-SARS-CoV-2 vaccination.

Figure 1

Haematopoiesis HSCs are at the top of the hierarchy and UPCs are at the bottom of the hierarchy. The figure shows only eight of the more than 30 strata of cell replication. Telomeres are depicted as red caps on the chromosomal ends. HSCs=haematopoietic stem cells. UPCs=unipotent cells.

Figure 2

Smoothing a bullwhip-like effect in haematopoiesis by slowing the production of blood cells (A) Bullwhip effect in commerce. (B) Bullwhip-like effect in a setting of fast production–supply (hare) of blood cells. (C) Preferred system of slow production–supply (tortoise) that reduces the effect.

Figure 3

The effect of age-dependent shortening of telomeres in white blood cells on T-cell clonal expansion in two adults Person 1 has longer telomeres than person 2. Person 1 reaches age of onset at an older age than person 2. Both people start with maximal T-cell clone size.

Figure 4

Telomere length in white blood cells across the adult population and the risk of severe COVID-19 because of short telomeres Colour intensity indicates risk of severe disease. White blood cell telomere length data are from Steenstrup and colleagues. Risk of telomere-length-dependent severe disease is based on a model by Anderson and colleagues.