Masquerading microbial pathogens: capsular polysaccharides mimic host-tissue molecules

REVIEW ARTICLE Masquerading microbial pathogens: capsular polysaccharides mimic host-tissue molecules Brady F. Cress1, Jacob A. Englaender2, Wenqin He1, Dennis Kasper3, Robert J. Linhardt1,2,4 & Mattheos A.G. Koffas1,2 1 Department of Chemical and Biological Engineering, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA; 2Department of Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA; 3 Department of Microbiology and Immunobiology, Harvard Medical School, Boston, MA, USA; and 4Department of Chemistry, Chemical Biology, Center for Biotechnology and Interdisciplinary Studies, Rensselaer Polytechnic Institute, Troy, NY, USA Received 25 June 2013; revised 16 October 2013; accepted 19 December 2013. Final version published online 27 January 2014. DOI: 10.1111/1574-6976.12056 MICROBIOLOGY REVIEWS Editor: Miguel Camara Keywords capsular polysaccharides; glycosaminoglycans; polysialic acid; bacterial pathogens; immune system evasion; combating antibiotic resistance. Abstract The increasing prevalence of antibiotic-resistant bacteria portends an impending postantibiotic age, characterized by diminishing efficacy of common antibiotics and routine application of multifaceted, complementary therapeutic approaches to treat bacterial infections, particularly multidrug-resistant organisms. The first line of defense for most bacterial pathogens consists of a physical and immunologic barrier known as the capsule, commonly composed of a viscous layer of carbohydrates that are covalently bound to the cell wall in Gram-positive bacteria or often to lipids of the outer membrane in many Gram-negative bacteria. Bacterial capsular polysaccharides are a diverse class of high molecular weight polysaccharides contributing to virulence of many human pathogens in the gut, respiratory tree, urinary tract, and other host tissues, by hiding cell surface components that might otherwise elicit host immune response. This review highlights capsular polysaccharides that are structurally identical or similar to polysaccharides found in mammalian tissues, including polysialic acid and glycosaminoglycan capsules hyaluronan, heparosan, and chondroitin. Such nonimmunogenic coatings render pathogens insensitive to certain immune responses, effectively increasing residence time in host tissues and enabling pathologically relevant population densities to be reached. Biosynthetic pathways and capsular involvement in immune system evasion are described, providing a basis for potential therapies aimed at supplementing or replacing antibiotic treatment. Introduction Bacterial capsular polysaccharides (CPSs) are major virulence factors that confer protective effects to their bearers against a wide range of environmental pressures, most notably against the immune system during infection of their animal hosts. Although capsules are often associated with descriptions of pathogenic bacteria due to the large proportion of encapsulated invasive pathogens, nonpathogenic and commensal bacteria also benefit from the ability to envelope themselves with a capsule (Hafez et al., 2009; Dasgupta & Kasper, 2010). In Gramnegative bacteria, capsular polysaccharides are often attached to the outer membrane at their reducing end ª 2013 Federation of European Microbiological Societies. Published by John Wiley & Sons Ltd. All rights reserved through covalently linked lipids that are inserted into the lipid bilayer of the membrane. This provides a surface layer of water-saturated, high molecular weight polysaccharides that limit desiccation in the face of harsh environmental conditions, block infection by most bacteriophages, and thwart phagocytosis and other host immune responses by physically restricting access to cell surface antigens. These polysaccharide cloaks are likely rational targets for wide-spectrum therapeutic compounds aimed at replacing or supplementing antibiotic treatment of microbial infections, as removal of the capsule exposes bacteria to routine immune clearance pathways mediated frequently by activation of the complement system. FEMS Microbiol Rev 38 (2014) 660–697 Correspondence: Mattheos Koffas and Robert Linhardt, Rensselaer Polytechnic Institute, Troy, NY, USA. e-mail: and Masquerading microbial pathogens Historical perspective FEMS Microbiol Rev 38 (2014) 660–697 1999). Serotyping systems for other species were developed in a similar manner, but the relative ease of Gram-negative CPS structural characterization and the genetic tractability of E. coli enabled more rapid development of the E. coli antigen classification scheme. Owing to their antigenicity in mammals, most CPS structures elicit T lymphocyte-independent immune responses that induce IgM antibody production but fail to stimulate T-cell-dependent IgM-IgG switching, an important attribute to ensure long-lasting immunity (Weintraub, 2003; Avci & Kasper, 2010). However, purified CPSs from some of the most commonly isolated strains were determined to be nonimmunogenic due to structural identity with human glycans (Edwards et al., 1982; Johnson, 1991; H
erias et al., 1997). Capsule-deficient mutants of these strains generally exhibit decreased virulence, persistence, and serum sensitivity (Pluschke et al., 1983; H
erias et al., 1997). As discussed in greater detail later, antibody generation proved difficult against purified mammal-like bacterial CPSs composed of hyaluronan (HA), heparosan, or certain congeners of unsulfated chondroitin or polysialic acid (PSA). It should be noted here that there are reports of antibodies generated against these CPSs under unique circumstances (Frosch et al., 1985; Jennings et al., 1985; Kabat et al., 1986; Kr€ oncke et al., 1990; Finke et al., 1991; Troy, 1992; Born et al., 1996). However, careful consideration should be given to possible antigenic determinants for antibodies generated in such experiments and whether access to the epitopes would result in protective responses in vivo. If serum-accessible portions of these CPSs are identical to mammalian glycans, it seems unlikely that antibodies could be elicited against these ‘self’ epitopes. In some cases, antibodies were raised in autoimmune animal hosts, where self-protection capacity was diminished due to immune dysregulation (Bitter-Suermann et al., 1986). Immune response by healthy animal hosts requires other possible explanations to clarify this paradox: 1 The CPS possesses an exposed antigenic determinant not found in the corresponding mammalian glycan, such as a deacetylated amino sugar or terminal unsaturated bond generated by a lyase (a class of enzymes acting to cleave acidic polysaccharides through an eliminase mechanism, in contrast to hydrolyzing glycosidases, Linhardt et al., 1986) or some other nonself-chemical decoration. 2 CPS purification exposes a nonmammalian antigenic determinant, like an anchoring moiety composed o (...truncated)