Coronavirus Receptors as Immune Modulators

Abstract

The Coronaviridae family includes the seven known human coronaviruses (CoV) that cause mild to moderate respiratory infections (HCoV-229E, HCoV-NL63, HCoV-OC43, HCoV-HKU1) as well as severe illness and death (MERS-CoV, SARS-CoV, SARS-CoV-2). Severe infections induce hyperinflammatory responses that are often intensified by host adaptive immune pathways to profoundly advance disease severity. Proinflammatory responses are triggered by CoV entry mediated by host cell surface receptors. Interestingly, five of the seven strains use three cell surface metallopeptidases (CD13, CD26, and ACE2) as receptors, whereas the others employ O-acetylated-sialic acid (a key feature of metallopeptidases) for entry. Why CoV evolved to use peptidases as their receptors is unknown, but the peptidase activities of the receptors are dispensable, suggesting the virus uses/benefits from other functions of these molecules. Indeed, these receptors participate in the immune modulatory pathways that contribute to the pathological hyperinflammatory response. This review will focus on the role of CoV receptors in modulating immune responses.

Figure 1:. Common characteristic immunological features of coronavirus infections.

Induction of immune response begins with the binding and internalization of coronaviruses leading to elevated levels of proinflammatory chemokines and cytokines, specifically IFN-γ, IL-6, IL-8, IP-10, TNF-α, MCP-1, IL-1β and IL-17 among others. Increased chemokine and cytokine release causes neutrophil and macrophage accumulation as well as lymphopenia (CD4⁺ T cells, CD8⁺ T cells and B cells).

Figure 2:. Role of coronavirus receptors in modulating IL-6 levels.

Evidence for the role of coronavirus receptors in modulating IL-6 levels is strong and is observed in various normal and disease models. A) IL-6 production is enhanced by crosslinking CD13, while CD13 blocking antibodies inhibit IL-6 production. Also, IL-6 and soluble IL-6R induce CD13 expression and activity suggesting a possible positive feedback loop between CD13 and IL-6 expression. B) Both the membrane bound and soluble CD26 induce IL-6 expression that can be inhibited using CD26 inhibitors such as anagliptin and alogliptin. C) Ang II, the substrate for ACE2 triggers the production of IL-6, while the product of ACE2 enzymatic activity, Ang-(1–7) opposes Ang II signaling and inhibits IL-6 production. Consequently, loss of ACE2 or treatment with an ACE2 inhibitor (MLN-4760) induces IL-6 production and alternatively, activation of endogenous ACE2 with XNT–(1-[(2-dimethylamino) ethylamino]-4-(hydroxymethyl)-7-[(4-methylphenyl) sulfonyl oxy]-9H-xanthene-9-one} reduces IL-6 production.