Microbial adherence to and invasion through proteoglycans

Abstract

Although many microorganisms bind to cell surface heparan sulfate (Tables 3 and 4), questions about the nature of these interactions remain unanswered. Are specific oligosaccharide sequences required for binding? Do microbes bind to subsets of proteoglycans that differ in protein or glycosaminoglycan composition (64)? Does binding to the core protein as well as to the carbohydrate chains occur (44)? What is the amino acid sequence in the carbohydrate binding domains of adhesins? What is the role of heparin- binding proteins on host cells? Recent studies suggest that some proteoglycans reside in focal adhesions (112), where they participate in cell attachment to substrata and intracellular signaling (59). Thus, future studies should focus on whether microbial binding to proteoglycans also results in a signal transduction event that subsequently triggers processes helpful to the microbe (e.g., invasion). Although the in vitro evidence for heparan sulfate-microbial cell interactions is compelling, the role of heparan sulfate in microbial pathogenesis is not well established. Examination of virulent and nonvirulent isolates may reveal a correlation with heparan sulfate-dependent adherence and expression of heparin-binding proteins on the microbial cell surface. Another approach suggested by in vitro studies is to administer fragments of heparin or heparan sulfate to infected animals and subsequently determine microbial distribution, tissue colonization, and host survival. Tile ability of exogenous heparin and related polysaccharides to inhibit vital replication suggests that this approach might lead to polysaccharide-based antiviral pharmaceutical agents (23, 58, 87, 88). Another approach worth consideration is to inhibit the production of proteoglycans metabolically by using β-D-xylosides (29). Cultured cells take up β-D-xylosides rapidly and use them as primers for the assembly of single glycosaminoglycan chains, which are then secreted (37). Priming also diverts the synthesis of the chains from endogenous proteoglycans, resulting in the expression of underglycosylated proteins on the cell surface. Recent studies show that β-D-xylosides when injected into animals prime glycosaminoglycan chains and that the compounds are apparently well tolerated (9, 10). The secreted glycosaminoglycan chains may block microbial attachment by competition, and the reduction in cell surface receptors should reduce the number of binding sites on the host cells. Thus, β-D-xylosides may be a double-edged sword to fend off infection.