8
stimuli28 and with human ontogeny29. Monocytes, likewise other immune cells, are important
during the natural history of COVID-19, either orchestrating the immune response or
succumbing due to pyroptosis and cytokine storm4,6.
We next examined a possible correlation between HERV-K in the TA with immune-
modulation and/or coagulopathy. For this purpose, Spearman correlation analysis for levels
of cytokines, coagulation factors and immune cell counts were scored in deceased and
discharged patients (Extended Figure 3). Tobe conservative when assumingstatistical
significance, we additionally performed regression analysis, for those markers that passed
Spearman correlation, evaluating differences in angular and/or linear coefficients (Figure
3). As a general tendency for the endogenous mediators, HERV-K reduced their levels in
the TA (Extended Figure 3A)and favored inflammation in the peripheral plasma
(Extended Figure 3B). HERV-K negatively associates with two survival/growth factors for
immune cells in the blood, granulocyte colony-stimulating factor (G-CSF)30 and nerve
growth factor (NGF)31(Figure 3A). Consistently, surviving patients presented higher NGF
levels than those who died (Figure 3A). Surprisingly, HERK-K and other HERVs had been
reported as inducers of both G-CSF32 (in immune cells) and NGF33(in neurons), however,
HERV activation in CNS is associated mainly with the onset and progression of
neurological diseases34, and the induction of G-CSF was evaluated only with a domain of
the HERV-K TM protein32. As a function of HERV-K levels, other regulatory/anti-
inflammatory signals were also decreased in the plasma of deceased, such as IL-1Ra and
IL-13 (Figure 3A), which respectively antagonizes IL-1-dependent stimulus and favors an
allergenic-like/TH2 response35,36. Interesting, the reduction of IL-13production is reported
also by a HERV-H-LTR-derived protein, together with the inhibition of CD4 and CD8 T cell
responses37. Deceased patients respond to higher HERV-K levels increasing IL-17 (Figure
3A), a further pro-inflammatory mediator that may upregulate IL-6, CRP and airway
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