Implications of Glycosaminoglycans on Viral Zoonotic Diseases

Abstract

Zoonotic diseases are infectious diseases that pass from animals to humans. These include diseases caused by viruses, bacteria, fungi, and parasites and can be transmitted through close contact or through an intermediate insect vector. Many of the world’s most problematic zoonotic diseases are viral diseases originating from animal spillovers. The Spanish influenza pandemic, Ebola outbreaks in Africa, and the current SARS-CoV-2 pandemic are thought to have started with humans interacting closely with infected animals. As the human population grows and encroaches on more and more natural habitats, these incidents will only increase in frequency. Because of this trend, new treatments and prevention strategies are being explored. Glycosaminoglycans (GAGs) are complex linear polysaccharides that are ubiquitously present on the surfaces of most human and animal cells. In many infectious diseases, the interactions between GAGs and zoonotic pathogens correspond to the first contact that results in the infection of host cells. In recent years, researchers have made progress in understanding the extraordinary roles of GAGs in the pathogenesis of zoonotic diseases, suggesting potential therapeutic avenues for using GAGs in the treatment of these diseases. This review examines the role of GAGs in the progression, prevention, and treatment of different zoonotic diseases caused by viruses.

The diverse role of heparan sulfate and other GAGs in SARS-CoV-2 infections and therapeutics

“…This is proposed to rely on GAG-binding to the HS receptors of viruses, inducing steric hindrance and hereby inhibition of infection ( Cagno et al, 2019 ). Prominent examples are herpes simplex virus, dengue virus, human immunodeficiency virus, yellow fever virus, zika virus and many more ( Bauer et al, 2021 ; Cagno et al, 2019 ; Kamhi et al, 2013 ). The mechanism of inhibition of SARS-CoV-2 infection appears to rely on three different binding positions of GAGs on the S-protein ( Paiardi et al, 2022 ): (1) The binding of GAGs to the S-protein can induce a direct competition of attachment to the HSPGs by binding to a GAG-binding site ( Fig.…”

“…SARS-CoV-2 is closely related to the two major coronaviruses that previously caused epidemic outbreaks, i.e., Middle East Respiratory Syndrome (MERS) and SARS-CoV-1 ( Chen, Boon, Wang, Chan, & Chan, 2021 ), however, neither resulted in a pandemic. Coronaviruses are referred to as zoonotic viruses, which are often transmitted by so called spill-over events, when humans and animals are in close contact ( Bauer, Zhang, & Linhardt, 2021 ; Zhong et al, 2003 ). The outcome of a spill-over event is determined by a successful zoonotic infection process.…”

“…Thus, analogous receptors between the species are a prerequisite. One commonly known receptor is heparan sulfate (HS), which is used by many viral agents for binding, e.g., hepatitis virus, human immunodeficiency viruses (HIV), influenza virus, herpes virus ( Bauer et al, 2021 ; Cagno, Tseligka, Jones, & Tapparel, 2019 ; Kamhi, Joo, Dordick, & Linhardt, 2013 ). HS co-receptor-binding has also been reported for different coronaviruses ( Cagno et al, 2019 ; Haan et al, 2005 ; Lang et al, 2011 ; Madu et al, 2007 ; Milewska et al, 2014 ; Vicenzi et al, 2004 ), including SARS-CoV-2 ( Clausen et al, 2020 ).…”

“…Mutations in the HSPGs are associated with many diseases and can impact susceptibility to infectious diseases ( Sarrazin et al, 2011 ). Moreover, the cell specific GAG pattern is known to be a portal of binding and entry for many pathogens like viruses ( Bauer et al, 2021 ; Kamhi et al, 2013 ; Kim, Li, & Linhardt, 2017 ; Kovensky et al, 2017 ). The negative charge of the HSPGs interacts with basic residues of viral surface glycoproteins or capsid proteins.…”

“…The negative charge of the HSPGs interacts with basic residues of viral surface glycoproteins or capsid proteins. Several viral pathogens use these receptors to facilitate entry ( Bauer et al, 2021 ; Cagno et al, 2019 ). The presence of HSPGs on most human cells could abet a broad cell tropism of HS-receptor-binding viruses.…”