The «moonlighting protein» able to explain the T(h)1 immune lockdown in severe COVID-19()

COVID-19 is a major public health issue around the world and new data about its etiological agent, SARS-CoV-2, are urgently necessary, also translating the scientific knowledge acquired on its more similar predecessors, SARS-CoV-1 and MERS-CoV, the coronaviruses responsible for SARS and MERS, respectively. Like SARS-CoV-1, SARS-CoV-2 exploits the ACE2 receptors to enter the host cells; nevertheless, recent bioinformatics insights suggest a potential interaction of SARS-CoV-2 with the «moonlighting protein» CD26/DPP4, exactly how MERS-CoV works. CD26/DPP4 is overexpressed on T-helper type 1 (T(h)1) cells and its expression increases with aging, all factors which could well explain the T(h)1 immune lockdown, especially in the elderly, during fatal SARS-CoV-2 infections. Facing with this scenario, it is possible that T(h)1 and T-cytotoxic lymphocytes are the immune cells most affected by SARS-CoV-2, and that the immune system is forced to mount a T-helper type 2 (T(h)2) response, the only one still mountable, in the attempt to counteract the viral load. However, in this way, the symptomatic patient experiences all the negative effects of the T(h)2 response, which can seriously aggravate the clinical picture.