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.

RETRACTED ARTICLE: Mesenchymal stem cells ameliorate renal fibrosis by galectin-3/Akt/GSK3β/Snail signaling pathway in adenine-induced nephropathy rat

“…Galectin-3 can regulate numerous biological processes, such as pre-mRNA splicing, cell growth, apoptosis, differentiation, transformation, angiogenesis, inflammation, fibrosis, and host defense [12]. Galectin-3 also plays a vital role as a diagnostic, and prognostic biomarker, or a therapeutic target for cardiovascular diseases, chronic kidney diseases, autoimmune and nonautoimmune nephropathies, fatty liver, viral infection, autoimmune diseases, neurodegenerative disorders, and tumor formation [21,[27][28][29][30][31]. Galectin-3 can be secreted extracellularly but also can shuttle into the nucleus.…”

Plasma Markers of Disrupted Gut Permeability in Severe COVID-19 Patients

“…96,97 Therefore, galectins represent potential therapeutic targets to reduce cytokine storm during COVID-19. 98,99 Second, galactosylated glycans on circulating antibodies link Dectin-1 on phagocytes to FcγRIIB on myeloid cells to prevent the inflammation mediated by complement activation. 31 Loss of galactose, as observed during COVID-19, decreases the opportunity to activate this important anti-complement activation checkpoint, thereby promoting inflammation.…”

Covid‐19 and oral diseases: Crosstalk, synergy or association?

“…Higher plasma levels of galectins (including Gal‐1, Gal‐3 and Gal‐9) are reported in Covid‐19 subjects 82 . In addition, macrophages, monocytes and dendritic cells in patients with severe symptoms compared with mild symptoms suggests their pathological role in the disease severity 83,84 . Inhibition of Gal‐3, a proinflammatory galectin, suppresses cytokine secretion in macrophages indicating its therapeutic potential as a target for Covid‐19 treatment 85 .…”