SARS-CoV-2 and immunity: modulation of TMPRSS2 expression by pro-inflammatory cytokines and impact of COVID-19 vaccination on systemic danger signals in SARS-CoV-2 infected patients

After the outburst of the COVID-19 pandemic, a global research effort has been made to unveil many aspects of COVID-19 pathogenesis, among which the outstanding role played by inflammatory cytokine milieu in the disease progression. At the time of our study indeed the molecular mechanisms orchestrating SARS-CoV-2 infection and disease pathogenesis were largely unknown. Yet, we investigated whether the host cytokine milieu could modulate SARS-CoV-2 receptors ACE2 and TMPRSS2 expression, hence influencing cell susceptibility to the virus infection. Also, we analyzed if this hyperinflammatory signature varies between vaccinated and non-vaccinated COVID-19 patients. Our results clearly indicated that the host inflammatory milieu, and in particular the pro-inflammatory cytokine IL1β, can favor SARS-CoV-2 infection by inducing TMPRSS2 overexpression. We shed light on the molecular mechanism behind this modulation, which may be therapeutically targeted. Moreover, in line with the net efficacy of COVID-19 vaccination in preventing a severe clinical manifestation of the disease, we revealed a significant reduction in the levels of IL1β and DAMPs molecules, as S100A8 and HMGB1, in vaccinated patients as compared to non-vaccinated ones.