The Functions of SARS-CoV-2 Receptors in Diabetes-Related Severe COVID-19

Abstract

Angiotensin-converting enzyme 2 (ACE2) is considered a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) receptor of high importance, but due to its non-ubiquitous expression, studies of other proteins that may participate in virus internalisation have been undertaken. To date, many alternative receptors have been discovered. Their functioning may provide an explanation for some of the events observed in severe COVID-19 that cannot be directly explained by the model in which ACE2 constitutes the central point of infection. Diabetes mellitus type 2 (T2D) can induce severe COVID-19 development. Although many mechanisms associated with ACE2 can lead to increased SARS-CoV-2 virulence in diabetes, proteins such as basigin (CD147), glucose-regulated protein 78 kDa (GRP78), cluster of differentiation 4 (CD4), transferrin receptor (TfR), integrins α₅β₁/α_vβ₃, or ACE2 co-receptors neuropilin 2 (NRP2), vimentin, and even syalilated gangliosides may also be responsible for worsening the COVID-19 course. On the other hand, some others may play protective roles. Understanding how diabetes-associated mechanisms can induce severe COVID-19 via modification of virus receptor functioning needs further extensive studies.

Keywords: ACE2; CD147; CD4; GRP78; NRP2; SARS-CoV-2; TfR; diabetes mellitus type 2; integrins; sialic acid; vimentin.

Figure 1

Basic characteristics of selected SARS-CoV-2 receptors. (A) Relative affinity of wild-type SARS-CoV-2 spike protein binding (1/K_D): K_D values: ACE2—30 nM [5], CD4—27 nM [56], TfR—2.95 nM [23], CD147—185 nM [36], ASGR1—124.6 nM [61], AXL—882 nM [64], NRP1—166.2 nM [98], GRP78—55.2 nM [40]; in comparison: TMEM106B—20 μM [71]. (B) Tissue-specific expression of selected genes encoding SARS-CoV-2 receptors. Expression data available from: Human Protein Atlas [92], v23.0.proteinatlas.org.

Figure 2

Probable ACE2-dependent mechanism of SARS-CoV-2 infection in tissues with low ACE2 expression. ACE2—angiotensin-converting enzyme 2, TLR4/7/8—toll-like receptors 4/7/8, IFN-γ—interferon gamma.

Figure 3

Regulation of membrane translocation of transferrin receptor (TfR) in adipocytes. IR—insulin receptor; IRS1—substrate of insulin receptor 1; GLUT4—glucose transporter 4; ADAM—a disintegrin and metalloproteinase domain-containing protein; Ang II—angiotensin II; arrows correspond to changes of synthesis/secretion rates of specified proteins or changes of pH; yellow dots: insulin molecules; orange dots: glucose molecules; blue dots: ionised iron.

Figure 4

Hypoxia-mediated acidification of the extracellular space enhancing SARS-CoV-2 cell entry. ROS—reactive oxygen species; CKC—citric acid cycle; ERK1/2—extracellular signal-regulated kinases 1 and 2, associated with cell senescence; AGEs—advanced glycation end products. The arrow corresponds to the change in pH in the extracellular space.