Immunopathology of galectin-3: an increasingly promising target in COVID-19

Abstract

The pandemic brought on by the outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) has become a global health crisis, with over 22 million confirmed cases and 777,000 fatalities due to coronavirus disease 2019 (COVID-19) reported worldwide. The major cause of fatality in infected patients, now referred to as the "Cytokine Storm Syndrome" (CSS), is a direct result of aberrant immune activation following SARS-CoV2 infection and results in excess release of inflammatory cytokines, such as interleukin (IL)-1, tumor necrosis factor α (TNF-α), and IL-6, by macrophages, monocytes, and dendritic cells. Single cell analysis has also shown significantly elevated levels of galectin 3 (Gal-3) in macrophages, monocytes, and dendritic cells in patients with severe COVID-19 as compared to mild disease. Inhibition of Gal-3 reduces the release of IL-1, IL-6, and TNF-α from macrophages in vitro, and as such may hold promise in reducing the incidence of CSS. In addition, Gal-3 inhibition shows promise in reducing transforming growth factor ß (TGF-ß) mediated pulmonary fibrosis, likely to be a major consequence in survivors of severe COVID-19. Finally, a key domain in the spike protein of SARS-CoV2 has been shown to bind N-acetylneuraminic acid (Neu5Ac), a process that may be essential to cell entry by the virus. This Neu5Ac-binding domain shares striking morphological, sequence, and functional similarities with human Gal-3. Here we provide an updated review of the literature linking Gal-3 to COVID-19 pathogenesis. Dually targeting galectins and the Neu5Ac-binding domain of SARS-CoV2 shows tentative promise in several stages of the disease: preventing viral entry, modulating the host immune response, and reducing the post-infectious incidence of pulmonary fibrosis.

Keywords: COVID-19; cytokines; ARDS; fibrosis; galectin; galectin-3; sialic acid.

Figure 1.. A dual attachment model for SARS-CoV2.

Evidence has shown that a pocket in the NTD of SARS-CoV2 is capable of binding N-acetylneuraminic acid (Neu5Ac). This strongly supports a dual attachment model for SARS-CoV2, where NTD-Neu5Ac interactions facilitate initial host cell recognition by the virus and stabilize its entry via ACE2 receptors.

Figure 2.. Gal-3 may amplify the cytokine storm syndrome associated with severe COVID-19.

During severe SARS-CoV2 infection, increased plasma concentrations of Gal-3 are observed in circulating macrophages, monocytes, and dendritic cells. When secreted, Gal-3 can then agonize TLR4 receptors on their surfaces and induce the release of inflammatory cytokines such as IL-1, IL-6, and TNF-α. This process also results in the secretion of further Gal-3, resulting in a positive feedback loop that may contribute to the development of CSS.

Figure 3.. Gal-3 contributes to a pro-fibrotic microenvironment in COVID-19.

During SARS-CoV2 infection, transcriptional upregulation of VEGF, TGF-ß, and fibronectin (FN) is seen in the pulmonary epithelium, creating a pro-fibrotic microenvironment. Secretion of Gal-3 by macrophages contributes to fibrosis by increasing the expression of TGF-ß receptors on the surface of fibroblasts. The fibroblasts and myofibroblasts are then activated by TGF-ß mediated signaling, stimulating the deposition of extracellular matrix and collagen that leads to fibrotic damage. Cytokines induced by Gal-3 expression such as IL-1, IL-6, and TNF-α further accelerate this process.