Alpha-1-antitrypsin antagonizes COVID-19: a review of the epidemiology, molecular mechanisms, and clinical evidence

Abstract

Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution. We next underscored that measures to prevent severe COVID-19 currently exists but teeters on a balance and that current treatment for severe COVID-19 remains grossly suboptimal. We then reviewed the epidemiologic and clinical evidence that AAT deficiency increases risk of COVID-19 infection and of more severe disease, and the experimental evidence that AAT inhibits cell surface transmembrane protease 2 (TMPRSS2) - a host serine protease required for SARS-CoV-2 entry into cells - and that this inhibition may be augmented by heparin. We also elaborated on the panoply of other activities of AAT (and heparin) that could mitigate severity of COVID-19. Finally, we evaluated the available clinical evidence for AAT treatment of COVID-19.

Keywords: COVID-19; SARS-CoV-2; alpha-1-antitrypsin; heparin; serine protease; serpin.

Figure 1.

In silico modeling demonstrating the interaction between TMPRSS2 and AAT and how heparin stabilizes the TMPRSS2–AAT complex. (A) Heparin molecules (colored stick figures) stabilize TMPRSS2–AAT association by acting as electrostatic bridges. Electrostatic potential surfaces of the TMPRSS2–AAT complex (blue = positive, red = negative) showing docked heparin 4mers binding to repelling electropositive patches at the molecular interface of TMPRSS2 and AAT. (B) Molecular surface of TMPRSS2 (cyan) showing bound reactive center loop (RCL) of AAT (magenta cartoon). Catalytic residues are labeled. P1 sidechain of AAT occupies the S1 site of TMPRSS2, superimposed on the TMPRSS2 inhibitor nafamostat (wheat). (C) Location of electropositive Lys/Arg residues (TMPRSS2 = cyan; AAT = magenta) in the vicinity of electronegative heparin (gray sticks) binding sites at the TMPRSS2(cyan)–AAT(magenta) interface. Semi-transparent molecular surface is shown, and Lys/Arg residues that contribute to unfavorable electrostatics at the interface are shown and labeled (sidechain nitrogen atoms colored blue). AAT = alpha-1-antitrypsin; TMPRSS2 = Transmembrane Protease, Serine 2. Reproduced with permission from Springer Nature (Bai et al. [87]).

Figure 2.. Mechanisms by which AAT may help antagonize SARS-CoV-2 and ameliorate the pathogenic mechanisms of COVID-19.

AAT has: (i) anti-viral infection effects by inhibiting TMPRSS2 and possibly through induction of autophagy, (ii) anti-inflammatory effects, and (iii) anti-apoptotic and anti-elastase functions, protecting infected cells from injury and death. An increase in protease (neutrophil elastase, MMP-2, MMP-12) to anti-protease ratio may not only deplete AAT but elastase and MMP-12 are known to cleave AAT at a site other than the reactive center loop of AAT (denoted by inhibitory red ‘arrows’). AAT = alpha-1-antitrypsin; ACE2 = angiotensin converting enzyme 2; MMP-2 = matrix metalloproteinase-2; MMP-12 = matrix metalloproteinase-12; NETs = neutrophil extracellular traps; TMPRSS2 = Transmembrane Protease, Serine 2.

Figure 3.. Mechanisms by which ADAM17 may contribute to the hyperinflammatory pathogenesis of COVID-19.

(A) ADAM17, also known as TNF converting enzyme, is able to cleave membrane-bound TNF (mTNF) to soluble TNF (sTNF), enhancing the inflammatory and injurious response such as acute lung injury and edema. In addition, the inflammatory response induces MMP-2 in neutrophils, causing further injury to the lung extracellular matrix. Activated ADAM17 is also cleaves mACE2 to soluble ACE2 (sACE2). This process may enhance inflammation by preventing mACE2 from catalyzing pro-inflammatory angiotensin to the less inflammatory metabolites (angiotensin–(1–7) and angiotensin–(1–9)). While soluble ACE2 is able to bind free virus, reduction in mACE2 increases both inflammation and egress of newly synthesized viral particles to infect other cells. (B) During the basal state, IL-6 signals by first binding to membrane-bound IL-6R (on macrophages), followed by engagement of the IL-6-IL-6R complex with gp130, which contains an intracellular signaling moiety that IL-6R lacks. The classical type of IL-6 signaling is known as cis-IL-6 signaling. (C) During an inflammatory state (insult), the cell surface protein ADAM17 is activated and cleaves membrane-bound IL-6R (mIL-6R) from the cell surface. The soluble IL-6R (sIL-6R) binds to IL-6 and the complex can directly bind to gp130 on all cell types to provide another mode of signaling that is more widespread and known as trans-IL-6 signaling. ACE2 = angiotensin converting enzyme 2; ADAM17 = a disintegrin and metalloprotease 17; IL-6 = interleukin-6; IL-6R = IL-6 receptor; MMP2 = matrix metalloproteinase-2; TNF = tumor necrosis factor.