The «moonlighting protein» able to explain the Th1 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 (Th1) cells and its expression increases with aging, all factors which could well explain the Th1 immune lockdown, especially in the elderly, during fatal SARS-CoV-2 infections. Facing with this scenario, it is possible that Th1 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 (Th2) 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 Th2 response, which can seriously aggravate the clinical picture.

Coronavirus disease 2019 (COVID-19) is a major public health issue around the world and new data about its etiological agent, the severe-acute-respiratory-syndrome-coronavirus-2 (SARS-CoV-2), are urgently necessary, also translating the scientific knowledge acquired on its more similar predecessors, the severe-acute-respiratory-syndrome-coronavirus-1 (SARS-CoV-1) and the Middle-East-respiratory-syndrome-related-coronavirus (MERS-CoV), the coronaviruses responsible for SARS and MERS, respectively. The discovery of MERS-CoV dates back to 2012, when it was initially identified in Saudi Arabia [1]. Also known as «camel flu», MERS is a potentially severe respiratory illness with a lethality rate of around 34% and today is still circulating among the population, in particular of the Arabian Peninsula, without a fully protective vaccine available [2]. Subsequent studies on MERS-CoV have highlighted that the virus enters the host cell through cluster of differentiation 26 (CD26), alias dipeptidyl peptidase-4 (DPP-4) receptor [3]. This «moonlighting protein»* is highly conserved across species, datum which explains the possible infection in camels and bats, and it is mainly expressed in the human bronchial epithelium and kidneys, as well as memory and naїve T lymphocytes [4]. In particular, it has been found overexpressed in T-helper type 1 (Th1) rather than T-helper type 2 (Th2) cells, and its expression in Th1 increases with aging [5], [6], [7]. As well known, naїve T-helper cells (Th0) can detect novel pathogens never encountered before, as is the current case of SARS-CoV-2. Depending on the infectious agent, Th0 then polarize the immune response into Th1, the default response in immunocompetent subjects to intracellular or phagocytosable pathogens (e.g. viruses, bacteria, protozoa, fungi) and mediated by macrophages and T-cytotoxic (Tc) cells, or into Th2, classically directed against extracellular non-phagocytosable pathogens (e.g. helminths), whose main effectors are eosinophils, basophils, mastocytes and B cells [8]. During our researches on COVID-19, for many clinic-laboratory aspects including lymphopenia quite similar to MERS, we have disclosed that the immune system mounts a Th2 response against SARS-CoV-2 in patients requiring intensive care, rather than a Th1 response, which would keep the infection under control by means of macrophages and Tc cells [9]. In addition, for the first time in worldwide literature, we have provide evidence that a life-threatening escalation from Th2 immune response to type 3 hypersensitivity (immune complex disease) in COVID-19 vasculitis takes place, and that the inflamed smooth muscle cells of blood vessels concur to the «cytokine storm» via interleukin-6 [10], [11]. In the last four months, two independent bioinformatics research groups have reported that the spike glycoprotein of SARS-CoV-2 not only binds the angiotensin converting enzyme 2 (ACE2) receptors [12], the same entry mechanism exploited by SARS-CoV-1, but potentially interacts also with CD26/DPP-4, a proposed pivotal event for hijacking and virulence, exactly how MERS-CoV works [13], [14]. Faced with this scenario, it is possible that Th1 and Tc lymphocytes are the immune cells most affected by the viral load, especially in the elderly, and that the immune system is forced to mount a Th2 response, the only one still mountable, in the attempt to counteract the pathogen by the action of Th2 effectors (Fig. 1 ). However, in this way, the symptomatic patient experiences all the negative effects of the Th2 response, which can seriously aggravate the clinical picture.

Fig. 1

During the ongoing SARS-CoV-2 outbreak in the Italian province of Modena, COVID-19 autopsies have been limited for biosafety reasons. However, three male patients, two Italian and one non-Italian, 67, 49 and 44 years old respectively, have been submitted to minimally invasive autopsies: in these cases, the white pulp of the spleen appears markedly reduced (A, hematoxylin and eosin, 4X objective), with CD8-positive Tc almost disappeared (B, clone SP57, 10X objective) and scanty CD4-positive Th still present (C, clone SP35, 10X objective), likely Th2 elements since surrounded by scattered CD138-positive plasma cells (D, clone B-A38, 10X objective) [immunohistochemistry chromogen: 3,3′-diaminobenzidine].

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Conflict of interest

No conflict of interest.