*3.3. In Host-Pathogen Interaction*

HS chains provide the gateway for many microorganisms, ranging from normal microbiota to various pathogenic bacteria, viruses and parasites, by mediating adherence to the host cells. This is a crucial step for infection to occur and pathogens exploit the host HSPGs to accomplish it and invade host cells. The previously described structural diversity of the HSPGs offers multiple binding sites and the degree of variability within tissues results in the tissue-specific tropism of some infectious agents [5,51,68,69].

Among the pathogens that bind to host HS chains are parasites like *Plasmodium falciparum* [70]; bacteria, such as *Escherichia coli* [71], *Pseudomonas aeruginosa* [72], *Borrelia burgdorferi* [73] or *Mycobacterium tuberculosis* [74]; and many viruses, amongst which are found Human Papilloma virus, Herpes viruses and Human Immunodeficiency Virus-1 [75,76]. In addition, recently it was reported that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) entry in human cells is mediated through the binding to HS chains in a length and sequence-dependent manner [49,77–80]. The interference with the HS-mediated adhesion steps can represent an effective therapeutic approach for these pathogens and can be achieved by the competition with HS mimetics and other highly sulfated polysaccharides [81]. In addition, some pathogens can release GAGs from host cell surfaces and ECM, and use these solubilised GAGs to coat their surface, deceiving and eventually escaping immune detection [82].
