Cryptococcus and Phagocytes: Complex Interactions that Influence Disease Outcome

Abstract

Cryptococcus neoformans and C. gattii are fungal pathogens that cause life-threatening disease. These fungi commonly enter their host via inhalation into the lungs where they encounter resident phagocytes, including macrophages and dendritic cells, whose response has a pronounced impact on the outcome of disease. Cryptococcus has complex interactions with the resident and infiltrating innate immune cells that, ideally, result in destruction of the yeast. These phagocytic cells have pattern recognition receptors that allow recognition of specific cryptococcal cell wall and capsule components. However, Cryptococcus possesses several virulence factors including a polysaccharide capsule, melanin production and secretion of various enzymes that aid in evasion of the immune system or enhance its ability to thrive within the phagocyte. This review focuses on the intricate interactions between the cryptococci and innate phagocytic cells including discussion of manipulation and evasion strategies used by Cryptococcus, anti-cryptococcal responses by the phagocytes and approaches for targeting phagocytes for the development of novel immunotherapeutics.

Keywords: Cryptococcus; Cryptococcus gattii; Cryptococcus neoformans; cryptococcosis; fungal immunity; innate immune response; medical mycology.

FIGURE 1

Macrophage activation: protection against Cryptococcus is associated with M1 or classically activated macrophages. M1 macrophages are induced by exposure to the Th1 cytokine IFN-γ. M1 macrophages are efficient killers as they have increased nitric oxide (NO) and ROS production. M2 or alternatively activated macrophages are associated non-protective immune responses to Cryptococcus. M2 macrophages are not efficient killers and allow Cryptococcus to grow and proliferate within the macrophage and may lead to dissemination. In addition, macrophage phenotype is plastic, allowing for macrophages to switch between M1 and M2 phenotypes based on cytokines present in their environment.

FIGURE 2

Dendritic cell cryptococcal killing and antigen presentation. Immature dendritic cells efficiently phagocytose and kill opsonized Cryptococcus neoformans cells, leading to DC maturation, shown by upregulation of costimulatory molecules (MHC II, CD80, CD86) and antigen presentation to CD4⁺ T cells. In contrast, C. gattii can also be phagocytosed and killed by DCs, but leads to a downregulation of DC maturation and expression of costimulatory molecules MHC II, CD80, CD86 and reduces antigen presentation to T cells.

FIGURE 3

Cryptococcal Pattern Recognition Receptors. Cryptococcus has multiple pathogen associated molecular patterns (PAMPs) that are recognized by many types of pattern recognition receptors (PRRs). GXM is recognized by TLR2 and TLR4. Cryptococcal mannan can be recognized by the C-type lectin receptors Dectin-2, DC-SIGN, and CD206 or mannose receptor. B-glucans found in the cryptococcal cell wall can be recognized by Dectin-1, and cryptococcal DNA can be recognized by the endosomal receptor TLR9.