Chapter 4 The Capsule of the Fungal Pathogen Cryptococcus neoformans

Abstract

The capsule of the fungal pathogen Cryptococcus neoformans has been studied extensively in recent decades and a large body of information is now available to the scientific community. Well‐known aspects of the capsule include its structure, antigenic properties and its function as a virulence factor. The capsule is composed primarily of two polysaccharides, glucuronoxylomannan (GXM) and galactoxylomannan (GalXM), in addition to a smaller proportion of mannoproteins (MPs). Most of the studies on the composition of the capsule have focused on GXM, which comprises more than 90% of the capsule's polysaccharide mass. It is GalXM, however, that is of particular scientific interest because of its immunological properties. The molecular structure of these polysaccharides is very complex and has not yet been fully elucidated. Both GXM and GalXM are high molecular mass polymers with the mass of GXM equaling roughly 10 times that of GalXM. Recent findings suggest, however, that the actual molecular weight might be different to what it has traditionally been thought to be. In addition to their structural roles in the polysaccharide capsule, these molecules have been associated with many deleterious effects on the immune response. Capsular components are therefore considered key virulence determinants in C. neoformans, which has motivated their use in vaccines and made them targets for monoclonal antibody treatments. In this review, we will provide an update on the current knowledge of the C. neoformans capsule, covering aspects related to its structure, synthesis and particularly, its role as a virulence factor.

Introduction

The adaptation of microorganisms to their environment is often associated with the acquisition of certain attributes that help improve survival in specific ecological niches. Such adaptations include signal transduction pathways that optimize metabolism to respond to the nutritional environment, stress conditions and interaction with other biological systems, such as other microbes, environmental predators and symbiotic hosts. In addition, it is common to find morphological changes and the development of specialized structures that provide the microbe with survival benefits during its life cycle. Among these structures, many microbes possess capsules surrounding their cell body. Microbial capsules are usually composed of polysaccharides although some organisms, like Bacillus anthracis, have capsules composed of polymerized d‐glutamic acids. Microbial capsules play important roles in the lives of these microorganisms, providing resistance to stressful conditions (such as dehydration) and playing a key role in the interaction with the environment.

Although capsules are commonly found among bacteria, there are a few encapsulated fungal species. The best characterized fungal capsule belongs to Cryptococcus neoformans. The capsule of this microorganism has been extensively studied because it is the main virulence factor of this pathogenic organism (McClelland et al., 2006). In the environment, the capsule plays a role in the protection of the organism against some stress conditions, such as dehydration (Aksenov et al., 1973). The C. neoformans capsule has some functional similarities to those of encapsulated bacteria such as, Streptococcus pneumoniae and Haemophilus influenzae (De Jesus et al., 2008, Kang et al., 2004). In fact, the cryptococcal polysaccharide is known to share some antigenic determinants with certain pneumococcal polysaccharides (Maitta et al., 2004b, Pirofski and Casadevall, 1996). The capsule is important for virulence, since acapsular mutants do not produce disease in murine models (Fromtling et al., 1982). The definitive experiment establishing the capsule as a virulence factor was accomplished when acapsular mutants were created and shown to be significantly less virulent than wild‐type or capsule‐reconstituted strains (Chang and Kwon‐Chung, 1994). These mutants can survive and replicate in normal laboratory conditions but exhibit a markedly reduced virulence during infection in murine models. Interestingly, acapsular strains can be pathogenic for severely immunocompromised hosts implying a residual pathogenic potential for nonencapsulated yeast cells (Salkowski and Balish, 1991). These studies established that the capsule plays a predominant role in the interaction with the host. Consequently, this structure has been the main focus of attention in many experimental studies. Furthermore, studies have also shown that the capsular polysaccharide has strong immunomodulatory properties and promotes immune evasion and survival within the host (Monari et al., 2006a, Vecchiarelli, 2000). Besides mammalian hosts, studies focused on the capsule have also been extended to include environmental predators such as amoebae, since C. neoformans is both a pathogen and an environmental yeast and therefore interacts with multiple types of hosts.

A vast amount of knowledge has been accumulated on the biology, structure and role of the capsule during infection. The purpose of this review is to give an overview on the main aspects of the capsule, including its structure, synthesis and in particular, its role as a virulence factor.