Paradoxical roles of alveolar macrophages in the host response to Cryptococcus neoformans

Abstract

Cryptococcus neoformans (Cn) is a fungal pathogen that is a serious health threat to immunocompromised individuals. Upon environmental exposure, infectious fungal propagules are inhaled into the host's lungs. The anticryptococcal actions of alveolar macrophages (AM), the predominant host phagocyte of the innate immune system in the lungs, are fundamental in determining whether containment and clearance of the pathogen occurs by the development of an adapted immune response or whether infection is established and progresses to disease. However, the fungus is also capable of surviving the antimicrobial actions of AM and exploits these host phagocytes to establish infection and exacerbate disease. In addition, there is evidence suggesting that cryptococcosis may occur following reactivation of latent cryptococcal infection. Currently, the role of AM and the fungal factors contributing to latent cryptococcosis are unknown. This review examines the AM-Cn interaction and how it affects the development of pulmonary disease with a focus on host and pathogen factors enabling latency to occur.

Figure 1

Strategies for Cryptococcus neoformans survival in host alveolar macrophages. Following inhalation, infectious Cryptococcus neoformans (Cn) propagules enter the alveolar spaces of the lungs and are confronted by resident alveolar macrophages (AM). Upon phagocytosis, the nascent phagosome surrounds the internalized cryptococcal cell. Phagosome maturation proceeds with the fission and fusion of vesicles including endosomes (E) and then lysosomes (L), which ultimately result in formation of the phagolysosome. Antimicrobial molecules, acidic pH, and low level of nutrients all normally contribute to the killing of internalized pathogens. In addition to its polysaccharide capsule, laccase activity/melanin production, and ability to grow at 37°C, Cn has several other mechanisms enabling it to survive in the phagolysosome. Cn expresses superoxide dismutases 1 (SOD1) and −2 (SOD2) that catalyze the dismutation of antimicrobial superoxide (O₂⁻) to produce hydrogen peroxide (H₂0₂) and molecular oxygen (O₂). Inositol phosphosphingolipid-phospholipase C1 (Isc1) metabolizes fungal inositol sphingolipids into phytoceramide and is essential for intracellular survival by imparting defense from acidic, oxidative, and nitrosative stresses. Phospholipase B1 (Plb1) is associated with the cell membrane but can also be cleaved from its glycosylphosphatidylinositol anchor and secreted. Plb1 can act as a PLB, a lysopholipase (LPL), and a lysophospholipase transacylase (LPTA) to cleave host lipids. Plb1 contributes to the production of fungal eicosanoids, which are capable of scavenging macrophage-derived arachidonic acid. Ferro-O₂-oxidoreductase Fet3 and the iron permease Ftr1, molecular components involved in iron transportation across the plasma membrane, and the Cuf1-dependent copper transporter, Ctr4, are highly expressed during intracellular residency in order to sequester the metal molecules indispensible for survival. Cn autophagy genes ATG3 and ATG9 are stress-induced, resulting in the formation of autophagic vesicles (AV) possessing Atg8. There are three possible outcomes of the AM-Cn interaction: 1) the cryptococcal cells are contained and cleared in a concerted effort of the innate and adaptive immune responses; 2) Cn enter a latency stage, allowing for possible reactivation and subsequent symptomatic disease at a later time; or 3) Cn survive and the infection progresses to establish pulmonary cryptococcosis, which can disseminate to cause systematic disease including life-threatening meningoencephalitis. Which of these outcomes occurs is dependent on the balance between Cn fitness and AM anticryptococcal activity.