Immune Recognition of Fungal Polysaccharides

Abstract

The incidence of fungal infections has dramatically increased in recent years, in large part due to increased use of immunosuppressive medications, as well as aggressive medical and surgical interventions that compromise natural skin and mucosal barriers. There are relatively few currently licensed antifungal drugs, and rising resistance to these agents has led to interest in the development of novel preventative and therapeutic strategies targeting these devastating infections. One approach to combat fungal infections is to augment the host immune response towards these organisms. The polysaccharide-rich cell wall is the initial point of contact between fungi and the host immune system, and therefore, represents an important target for immunotherapeutic approaches. This review highlights the advances made in our understanding of the mechanisms by which the immune system recognizes and interacts with exopolysaccharides produced by four of the most common fungal pathogens: Aspergillus fumigatus, Candida albicans, Cryptococcus neoformans, and Histoplasma capsulatum. Work to date suggests that inner cell wall polysaccharides that play an important structural role are the most conserved across diverse members of the fungal kingdom, and elicit the strongest innate immune responses. The immune system senses these carbohydrates through receptors, such as lectins and complement proteins. In contrast, a greater diversity of polysaccharides is found within the outer cell walls of pathogenic fungi. These glycans play an important role in immune evasion, and can even induce anti-inflammatory host responses. Further study of the complex interactions between the host immune system and the fungal polysaccharides will be necessary to develop more effective therapeutic strategies, as well as to explore the use of immunosuppressive polysaccharides as therapeutic agents to modulate inflammation.

Difficult but Not Impossible: in Search of an Anti-Candida Vaccine

“…Peripheral blood mononuclear cells (PBMCs) are responsible for the underlying mechanism for producing higher levels of proinflammatory cytokines due to the deletion of the α1,6mannosyltransferase. Blocking of cell surface receptors, such as TLR4 and β-glucans, has been shown to decrease its virulence [31].…”

The complement system in Aspergillus fumigatus infections and its crosstalk with pentraxins

“…Despite of this shielding effect, dormant conidia are phagocytosed and killed, which highlights the crucial role of soluble PRMs, including the complement system, in the early immune response to this opportunistic pathogen [23]. Furthermore, as conidia swell and germinate, the rodlet and melanin layers are shed, and the polysaccharidic PAMPs not only become exposed but also change in structure and composition, a process that continuously redefines the host-pathogen interface throughout the fungus' life cycle [20]. We, therefore, examine the dynamics of complement activation as this mold transits from dormant conidia to adult hyphae ( Fig.…”

“…These can penetrate into the lung alveoli and initiate a germination program, first evolving into swollen conidia (~6 lm across), then generating germlings and filamentous hyphae (mycelium), which eventually form conidiophores that, in turn, make and disseminate new conidia [3]. The fungal cell wall undergoes dramatic modifications, as conidia turn into hyphae, with shedding of the outer layers (that mostly comprise RodA and DHN melanin) and exposure of the inner polysaccharides (i.e., the PAMPs aand b-glucans, chitin, GM, and GAG) [20]. As a reflection of the changing pathogen surface, activation of the complement system proceeds in a stage-dependent fashion, with varying involvements of the three pathways (LP, CP, and AP) [23].…”

“…Recognition of the fungal particles is also mediated by soluble pattern recognition molecules (PRMs), including components of the complement system, collectins, and pentraxins [20]. Despite the impressive structural diversity across these humoral PRMs, their general mode of action resembles that of antibodies ('ante-antibodies'), inasmuch as they have opsonic activity and facilitate recognition of pathogens (including A. fumigatus) by phagocytes, either directly or via complement-dependent pathways [21].…”

Glucuronoxylomannan in theCryptococcusspecies capsule as a target for CAR+T-cell therapy

“…Fungal cell wall glycans and exopolysaccharides are the first point of physical contact in fungal-host interactions, and these polysaccharides are common to multiple fungi [21]. Pattern recognition receptors present on innate immune cells recognize these glycans and eliminate fungal spores, germinating hyphae, and yeast.…”