Glycosaminoglycans and infection

Abstract

Glycosaminoglycans (GAGs) are complex linear polysaccharides expressed in intracellular compartments, at the cell surface, and in the extracellular environment where they interact with various molecules to regulate many cellular processes implicated in health and disease. Subversion of GAGs is a pathogenic strategy shared by a wide variety of microbial pathogens, including viruses, bacteria, parasites, and fungi. Pathogens use GAGs at virtually every major portals of entry to promote their attachment and invasion of host cells, movement from one cell to another, and to protect themselves from immune attack. Pathogens co-opt fundamental activities of GAGs to accomplish these tasks. This ingenious strategy to subvert essential activities of GAGs likely prevented host organisms from deleting or inactivating these mechanisms during their evolution. The goal of this review is to provide a mechanistic overview of our current understanding of how microbes subvert GAGs at major steps of pathogenesis, using select GAG-pathogen interactions as representative examples.

Figure 1

Pathogens that subvert GAGs at major portals of entry. A partial list of pathogens that subvert GAGs at the respiratory tract, gastrointestinal tract, urogenital tract, skin, and ocular surface, and those that are blood- or Vector-borne and co-opt GAGs for their infection are shown.

Figure 2

Mechanisms of GAG subversion. Select examples of several major mechanisms of GAG subversion are shown. A) Direct receptor: N. gonorrhoeae binds to the HS moiety of HSPGs (syndecan-1 and -4) and activates an intracellular signaling pathway via the cytoplasmic domain of the core protein that leads to gonococcal internalization. B) Co-receptor: binding of coronavirus to cell surface HS increases the local virus density, enabling coronavirus to interact with its entry receptor ACE2. Without HS, coronavirus does not interact efficiently with ACE2. C) Complex formation: cell surface HS forms a multimeric complex with C. trachomatis and growth factors (GFs), and the complex gets shed by MMPs and signals via GF receptors (GFR), leading to bacterial internalization and GF overexpression. D) Shedding: S. aureus α-toxin induces HSPG (syndecan-1) shedding and HS chains of HSPG ectodomains bind to and inhibit cationic antimicrobial peptides secreted by neutrophils, promoting S. aureus survival.